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	CBD Offers New Hope for Seizure Relief

Cannabidiol (CBD), a cannabinoid produced by the cannabis plant, is receiving growing attention because it has potential medical benefits for a wide array of conditions, including epilepsy. Epidiolex is the first prescription CBD made available. It was approved by the United States Food and Drug Administration (FDA) on June 2018. Epidiolex was approved for treating seizures in two forms of epilepsy that are especially difficult to treat. These are Dravet syndrome and Lennox-Gastaut syndrome (LGS). Both adults and children over two years old who suffer from one of these rare forms of epilepsy can be prescribed Epidiolex.

LGS and Dravet syndrome are two of the most severe forms of epilepsy. They are treatment-resistant which means that most common epilepsy medications do not work for these conditions. CBD is being studied for effectiveness with other kinds of epilepsy, and the introduction of Epidiolex to the market has created much buzz around CBD for seizures.

In this article, we will go over some of the basics about CBD and seizures. If you have any questions about CBD for epilepsy, talk to your doctor. Never make any medical changes without consulting your physician.
What Are CBD and Medical Marijuana?

Medical marijuana (or medical cannabis) is cannabis grown for medical or therapeutic purposes. Cannabis produces an abundance of compounds known as cannabinoids. Research shows that the cannabinoids produced by marijuana plants have potential essential health benefits. Cannabinoids can be used for medical purposes because they act on the body’s cells (including the brain). Cannabinoids do this through interaction with the body’s endocannabinoid system. The most commonly known and cultivated cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). The latter is known for producing a “high” experience that CBD does not cause.

Medical marijuana is specifically bred for certain cannabinoids, so strains can be bred to have extremely low THC content. This brings many of the benefits of cannabinoids to the body without THC’s “high” effects. The distinction between high and low THC strains is often termed marijuana and hemp. However, they are simply varieties of the same cannabis species.

Epidiolex is a CBD-based seizure medication for patients two years or older who have Lennox-Gastaut or Dravet syndrome. The FDA recently approved this medication. It is the first medical marijuana product to be approved by the FDA and the first drug for the treatment of seizures from Dravet syndrome. Research into the potential uses of CBD and other cannabinoids for people suffering from seizures is ongoing. Medical cannabis has been hotly debated, especially politically, in recent years. Many legal difficulties made the use of medical marijuana difficult or even impossible to study until very recently. However, research on medical cannabis oil with neurological conditions, including epilepsy, has been conducted longer.

Lab studies, patient testimonies, and small clinical studies in recent years show CBD may reduce seizures. While the evidence is still growing, it currently indicates many positive potential qualities. New studies continue to show evidence that CBD can help patients with epilepsy. Dr. Orrin Devinsky is a professor of neurosurgery, psychiatry, and neurology at NYU School of Medicine. He found that cannabidiol significantly reduced seizures for patients with severe epilepsy. LGS could potentially be effectively treated using CBD. LGS is a treatment-resistant type of epilepsy, so this gives hope to many patients.
What Causes Seizures, and How Can CBD Help?

Seizures are caused by erratic electrical brain activity that spreads. They can cause altered states of consciousness and uncontrollable movements. Most antiepileptic drugs slow down the electrical brain activity to prevent seizures. Dravet syndrome and LGS are often treated using medications that are less commonly prescribed for other epilepsies. Both Dravet syndrome and LGS often need additional antiseizure medications to keep seizures under control.

However, both Dravet syndrome and LGS can be specifically treated using CBD. While it is not yet clear how the process works, CBD can reduce certain kinds of seizures. CBD works through the endocannabinoid system located throughout the body. This lets CBD have widespread effects on nerve cells in the brain that could be having impacts on seizures. In order to pinpoint the process further, researchers are currently studying CBD in more depth.

As a developmental disorder, LGS starts during early childhood. LGS causes multiple kinds of seizures, along with physical and cognitive development problems. LGS causes seizures that are more difficult to manage than other types. LGS seizures require different medication regimens than most epilepsy patients use.

Dravet syndrome, like LGS, is a developmental disorder that starts during early childhood. Dravet syndrome causes many seizure types, including seizures triggered by high body temperatures. People suffering from Dravet syndrome commonly have learning difficulties and behavioral difficulties.

Unfortunately, people with Dravet syndrome or LGS can still have regular seizures even while being treated. One of the most important potential uses of CBD is its potential to reduce the severity and seizure frequency for these patients. Studies are still being conducted on CBD’s effectiveness. Research already suggests that CBD could reduce symptoms if used with other anti-seizure medications.

In 2019, a review of studies done on Epidiolex indicated that the frequency of sustained seizures was reduced anywhere from 30 to 63 percent. The review also showed that patients treated with Epidiolex had seizures that were around half as severe as before. Seizures were accompanied by a less severe postictal state (post-seizure period).

Other studies that use CBD for controlling seizures focus on refractory seizures. Refractory seizures are not as easy to control with typical antiseizure medications. It is not yet known whether CBD will benefit these types of seizures or if people with different seizure types will respond well to it. Until benefits for other seizure types are established, CBD will not be approved as a treatment option for them by the FDA.

Currently, CBD as a treatment of epilepsy is still controversial since it is derived from medical marijuana. Cannabis has been known primarily as a recreational drug. This cultural stigma has slowed clinical research over previous decades. Thankfully, this is changing as cultural attitudes toward cannabis become more favorable. The American legal system continues to evolve on cannabis. Currently, CBD is only clinically established to be effective for a select number of medical conditions. Nevertheless, emerging evidence shows hopeful signs for CBD’s wide applicability in medicine. Research shows a potential quality-of-life improvement for people with many different conditions.
What Is the Legal Status of Medical Marijuana Products Like CBD?

The 2018 Farm Bill exempted hemp and hemp-derived products (like CBD) from the Controlled Substances Act. Before this, hemp products were classified as Schedule I cannabis. That meant they had no recognized medical use and a high potential for abuse. Both characteristics have been shown to be false. Pressure has grown from patients, doctors, and patient advocates on the federal government to legalize hemp. There are now no federal restrictions on CBD. Hemp can be legally cultivated, products can be legally manufactured, and both can be bought and sold throughout the United States. This does not mean that CBD is appropriate for everyone. Still, CBD has finally been recognized as having important medicinal value for many patients.

More than half of the states have laws that allow cannabis to be recommended to patients for specified medical conditions. These patients are then able to enter medical dispensaries to buy cannabis products. State medical cannabis programs are unaffected by the Farm Bill. Regulations involving medical cards, registrations, renewals, and recommendations from physicians are still required.

The FDA approved Epidiolex in June 2018. Medical providers can now prescribe Epidiolex for patients suffering from Dravet syndrome or LGS. This places Epidiolex among the numerous approved prescription seizure medications available. The DEA rescheduled Epidiolex to Schedule V in late September. The federal government then made provisions so Epidiolex can be brought to market. Unlike many state programs, health care providers need no special licenses to prescribe Epidiolex. So far, the FDA has approved no other medical formulations of cannabis for seizures or any other conditions.
Before Taking CBD for the First Time

Remember that less is often more with CBD, according to clinical trials. This is especially true when trying to treat epilepsy with cannabis products, like CBD or other cannabinoids. In one recent study on Epidiolex, patients actually seemed to perform better with 10 milligrams of the medication than with 20 milligrams. They also experienced fewer adverse events. Epidiolex is 99 percent pure CBD. Some doctors believe CBD is better with side effects compared to other available seizure medications. This may be especially true of seizures that are especially difficult to control, such as those with Dravet syndrome and LGS.

Epidiolex is made from a highly refined, pharmaceutical-grade CBD. This distinguishes it from the CBD in states with legal medical marijuana programs or even simply CBD products on store shelves. It is not known how well these products could aid people with epilepsy since the FDA does not regulate them. It is also unclear if CBD helps people who have more common forms of epilepsy. Caution is advised for anyone attempting to treat their epilepsy with CBD. Patients should consult their doctors before making any dietary, supplemental, or medicinal changes.
How to Take CBD for Seizures

Before using CBD or any cannabis product, consumers should consult with their physicians. This helps doctors alert patients to any potential side effects as well as monitor their symptoms more effectively. Obviously, to use Epidiolex, patients would need a prescription from their doctors. However, many CBD products exist as over-the-counter supplements, meaning anyone can consume them so long as it is legal in their state.

Epidiolex is offered to patients in liquid form as an oral solution. The recommended dose of the medication is based on patient weight. Ten milligrams for every kilogram each day is the most effective dose and is commonly split into two daily doses. Patients begin by taking a smaller dose of 2.5 milligrams per kilogram. After the first week, patients increase their dosage to the target amount. In more extreme cases, Epidiolex can be increased up to 20 milligrams per kilogram daily, but this comes with increased risks of adverse events. Like other anti-seizure medications, Epidiolex should be taken at the same scheduled time. Patients should never skip or combine doses.

Patients with Dravet syndrome or LGS can sometimes have difficulty ingesting oral medications. This is because of difficulty swallowing, cognitive issues, or behavioral challenges. It can often be difficult to get children to take medications. This leads many parents and doctors to develop personalized strategies to ease the process.
What Are the Side Effects of CBD?

When smoked, cannabis potentially has some of the same risks to lungs and heart health as other types of smoking. Although cannabis is a plant, it is broken down by the body’s liver like many other medications. Medication interactions can occur even with medications made from plants or plant oil. Certain side effects may be due to the form of CBD taken since oils could potentially cause an upset stomach or diarrhea. This is suggested by the fact that even placebo participants often reported these symptoms.

Certain medication interactions can occur that people with epilepsy should be aware of before using CBD. Patients with increased liver enzymes three times the normal rate or more were also taking VPA (valproic acid). VPA is a commonly prescribed seizure treatment. VPA levels were not raised when taken with CBD. It is believed that a byproduct or component of VPA may interact with CBD as it breaks down, putting some patients at increased risk of liver problems. Patients using Onfi (clobazam) experienced tiredness when using CBD, which may be caused by the drug interacting with CBD.

Most people do not seem to have any serious side effects from CBD or other cannabinoids. However, as with any medicine, supplement, or even dietary change, side effects are possible. Thankfully, in the minority of cases where they do occur, the side effects of CBD are generally mild and short-lasting. The potential side effects of prescription Epidiolex include:

    Fatigue
    Drowsiness
    Sleeping Problems
    Fever
    Decreased Appetite
    Diarrhea
    Rashes
    Vomiting
    Rhinitis/Upper Respiratory Tract Infection
    Lethargy
    Weakness
    Status Epilepticus (a long-lasting seizure that needs emergency medical attention)

Studies showed that these side effects were most common in the first two weeks of using Epidiolex. Generally, side effects lessened after this initial period. Many studies on Epidiolex involved other antiseizure drugs. Side effects could be from other medications or a mixture of those medications with Epidiolex.

Severe side effects that need immediate attention include jaundice, abdominal pain, and vomiting. Dark-colored urine could be a potential symptom of liver injury. Others are intense mood changes, such as depression, anxiety, or suicidal thoughts and feelings.

By itself, CBD shows no evidence of potential for abuse. CBD also does not produce the psychoactive “high” typically associated with cannabis. These qualities mean that consumers do not need to be concerned about anyone abusing CBD products or becoming addicted to it. There is great potential for misunderstanding of CBD and its effects. That is because it is a new compound for many people and comes from the same plant that THC derives from.

Research is still being done on whether and how CBD interacts with other antiseizure medications. This will be important since it will allow for more precise and effective use of CBD in treating epilepsy. Researchers believe CBD could raise the blood level of Banzel (rufinamide) and Topamax. It may decrease the blood level of Onfi (clobazam). This could have effects on seizure control and potentially cause side effects. CBD can potentially elevate liver enzymes when taken alongside other antiseizure medications. This can be a sign of liver injury, and medical attention should be sought immediately. Researchers find adding Epidiolex to a regimen can increase the chances of certain side effects. It might also decrease the number of side effects people experience.
Using CBD Without a Prescription

Epidiolex is only available by prescription. However, numerous companies produce over-the-counter CBD products. Some consumers have begun to use them as a supplemental seizure control. This trend will likely grow now that CBD has been made federally legal by the 2018 Farm Bill. More states are making CBD and hemp an important part of their economic planning.

The FDA does not regulate over-the-counter CBD or other cannabinoid products. So, they are largely untested unless companies pay for testing themselves voluntarily. The FDA warns people to be cautious since products can be mislabeled and overstate their potential benefits. Additionally, these products are not being tested by the government for quality and safety. People with epilepsy need to be especially cautious. Products may be mislabeled with dosages and could put consumers at risk of more seizures or other side effects.

One study from 2017 found that 26 percent of CBD products purchased online contained less CBD than companies claimed. These sorts of factors make it important to purchase only from transparent, trustworthy companies. Look for companies whose products are proven to be accurately labeled and safely processed.
What Do Studies on Epidiolex Show?

Studies on Epidiolex date back as far as from a few years ago helped the FDA to approve the medication on June 25, 2018. Epidiolex is produced by Greenwich Biosciences, the American arm of GW Pharmaceuticals. Epidiolex is designed to give consistent, easy-to-identify dosages. Epidiolex was studied in clinical trials using control groups. Some individuals were given placebos, while others received various doses of CBD. Researchers were not informed about which group received placebo group and which received CBD. These are typical examples of gold-standard studies. They are the best indication of whether treatments actually work.

In one study, 689 people with LGS or Dravet syndrome were treated with Epidiolex in both controlled and uncontrolled trials. Of those patients, 533 took Epidiolex for more than six months, while 391 were treated for over a year. In compassionate use and expanded access programs, 161 LGS or Dravet patients received Epidiolex. In addition, 109 of these patients were treated for more than six months. Each study participant was also taking one or more other medications to control their seizures.

Participants in controlled trials rarely had to stop using Epidiolex because of side effects. Usually, Epidiolex only caused side effects for those taking higher doses. Most often, the cause for stopping Epidiolex was symptoms of changes in liver function. Lethargy, sedation, and sleepiness were indications that led participants to stop taking CBD. This occurred in 3 percent of those taking the higher dosage. The side effects included decreased appetite, changes in liver function, diarrhea, and sleepiness. Weakness, fatigue, rashes, sleep problems, insomnia, and risk of infections were also reported.

Studies show that CBD with traditional seizure medications reduced drop seizures in LGS patients. Others showed that Epidiolex was useful in treating people with difficult-to-treat seizures caused by Dravet syndrome. CBD showed some indications of being associated with a higher frequency of adverse effects, often at higher doses. Several CBD clinical trials are ongoing or actively recruiting participants. Researchers are looking at using Epidiolex to treat Sturge-Weber Syndrome and Tuberous Sclerosis Complex.
Health Insurance and CBD

Because CBD is a new therapy for patients with epilepsy, some people may have difficulty with health insurance coverage. Some may even deal with the unavailability of medication. Because medical marijuana products are new, and some providers hesitate to pay for them, patients can feel lost about where to turn for help. Patients should consult their doctors for documentation to get approval for insurance coverage. Otherwise, they can get help finding a source that can help fill the prescription.
How to Travel with CBD Products

Traveling with CBD used to be more difficult than it is now. This is largely because some states have legalized CBD products while others had not. Hemp and hemp-derived products were still considered Schedule I cannabis at the federal level. There was no uniform approach to medical hemp products. Thanks to the 2018 Farm Bill, this is no longer the case. CBD products are legal on a federal level throughout the United States.

Nevertheless, because CBD is a cannabis product, there are some prudent steps to take when traveling with it. Keep all paperwork with CBD products to show that they are legal and in compliance with federal law. This is especially important if using hemp flower or other raw plant products. These could be mistaken for high-THC cannabis, which is still illegal under federal law.
Should You Use CBD Products?

Anyone considering CBD for therapeutic reasons should learn the potential risks and benefits. Patients considering medical marijuana should also understand that it may not be the right fit for them, even if it works for other people. For some people, CBD is simply ineffective, while for others, it can cause side effects.

Patients with epilepsy who want to pursue medical marijuana should consult their physicians. About 30 percent of epilepsy patients have treatment-resistant epilepsy. This is despite conventional treatment options and medications. It makes sense that many patients are eager to find a better option and look to CBD oil as a potential fit. It is recommended that patients consult with a specialized epilepsy center for a thorough evaluation. This will ensure that other possible treatments of epilepsy are tried before using medical marijuana.

If you have any history of adverse reactions with cannabis, you should consider the potential pros and cons of using it. Make sure to tell your doctor if you have ever had any adverse reactions to cannabis in the past. They can consider this when making prescription decisions.
Can Medical Marijuana or CBD Replace Other Seizure Medications?

Patients should never stop taking medications without first checking with their health care providers. In some instances, study participants using CBD were able to be weaned off of other medications. This was under strict medical supervision and was not true for every participant. Proper medical supervision is necessary before ever considering ceasing a seizure medication. Like other medications, Epidiolex is not for every patient and may not work well for some. Physicians are in the position to decide whether medications are working well with their patients’ feedback.
What if My Health Care Provider Refuses to Prescribe Medical Cannabis or CBD?

Controlling seizures can, unfortunately, be a trial-and-error process. Some treatments that work well for certain patients do nothing for others or can even be harmful. Prescribing doctors consider patients’ overall health, current medication regimen, medical history, and seizure control. Health care providers are in the best position to figure out whether medical marijuana or CBD will bring more benefits than risks for your situation.

Your physician may not feel comfortable recommending medical cannabis. Do not alter your treatment plan without first alerting them. There is always the possibility of seeking a second opinion from another provider. Nevertheless, CBD should always be taken under the supervision of a medical professional. This helps patients keep better track of their symptoms, as well as helping doctors spot potential problems very early.

Acetazolamide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/main trade names
   1.6 Main manufacturers/main importers
   1.7 Presentation/formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailablity
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
9.0 CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)







    1. NAME

 

       1.1 Substance

 

           Acetazolamide

 

       1.2 Group

 

           ATC Code:  S01EC Carbonic anhydrase inhibitor

 

       1.3 Synonyms

 

           Acetamidothiadiazolesulfonamide

           Acetazolamid

           Acetazoleamide

           Acetozolamide

           Carbonic anhydrase inhibitor No. 6063

 

       1.4 Identification numbers

 

           1.4.1 CAS number

 

                  59-66-5

 

           1.4.2 Other numbers

 

                  RTECS:  AC8225000

 

       1.5 Main brand names/main trade names

 

           Acetamox; Ak-Zol; Apo-Acetazolamide; Atenezol; AZM-Tab; 

           Cidamex; Daranide; Dazamide; Defiltran; Dehydratin; Diacarb; 

           Diamox; 4-Diamox; Didoc; Diluran; Diuramid; Diureticum- 

           Holzinger; Diuriwas; Diutazol; Donmox; Duiramid; Edemox; 

           Eumicton; Fonurit; Glaupax; Glupax; MZM; Natrionex; Nephramid; 

           Nephramide; Neptazane; Phonurit; Storzolamide; Vetamox.

 

       1.6 Main manufacturers/main importers

 

           Lederle

 

       1.7 Presentation/formulation

 

           125 mg, 250 mg tablets

           

           500 mg sustained release capsules

           

           Intravenous injection 500 mg/5 cc

 

 

 

    2. SUMMARY

 

       2.1 Main risks and target organs

 

           Overdoses of diuretics are rare and problems most 

           frequently involve chronic overmedication or poor monitoring of 

           effects or drug-drug interactions that are not anticipated by 

           the clinician.  Main toxic effects are on the kidneys with 

           diuresis of water, sodium, potassium, and most importantly 

           bicarbonate with resultant dehydration.  More caution is 

           warranted with patients at higher risk for renal  abnormal 

           function including patients with any renal disease, diabetes 

           mellitus, exposure to nephrotoxic contrast agents and 

           borderline fluid and/or electrolyte status.

 

       2.2 Summary of clinical effects

 

           Patients with either acute or chronic overdosage with 

           acetazolamide may show signs of dehydration with thirst, 

           lethargy, confusion, poor skin turgor, and prolonged capillary 

           refill time, but may have a paradoxical continued diuresis. 

           Electrolyte abnormalities include hyponatremia, hypokalemia, 

           and a non-anion gap hyperchloremic metabolic acidosis in the 

           more than mild ingestion which may lead to further 

           deterioration in mental status, production of seizures, 

           electrocardiographic abnormalities, and arrhythmias.  Prior 

           renal insufficiency will lead to increased toxicity at a given 

           dose.  There are idiosyncratic reactions producing bone marrow 

           suppression with hepatic and renal insufficiency. 

           Acetazolamide may also precipitate in the renal tubules 

           producing calculi with renal colic.  Hypokalemia may lead to 

           muscular weakness, hyporeflexia, and hypochloremic metabolic 

           alkalosis.

           

           In chronic therapy, especially in geriatric patients, a chronic 

           metabolic acidosis may lead to a chronic compensatory 

           hyperventilation which increases pulmonary vascular resistance 

           and decreases left ventricular function.  This can be 

           especially significant in patients on concurrent beta-blocker 

           or calcium channel blocker therapy.  The ventricular 

           fibrillation threshold may then be reduced.

           

           Cardiac arrhythmias may occur due to potassium deficiency. 

           Abuse or overdose may result in pancreatitis.  Hyperglycemia, 

           hyperuricemia, and hyperlipidemia may occur with acute overdose 

           or in chronic use or abuse.  Hypersensitivity reactions such as 

           rash, photosensitivity, thrombocytopenia, and pancreatitis are 

           rare.

 

 

 

       2.3 Diagnosis

 

           Diagnosis should be considered in a patient that 

           demonstrates an apparently paradoxical alkaline urine in the 

           face of a metabolic acidosis or patients with unexplained 

           dehydration or hypokalemia (Spratt et al., 1982). 

           Acetazolamide levels are available at some centers but are 

           rarely useful in the acute setting.  Measurement of 

           electrolytes, urine pH, and blood gas analysis will help to 

           support the diagnosis.  Patients that may have access to 

           acetazolamide include climbers, and patients with glaucoma or 

           edematous states.

 

       2.4 First aid measures and management principles

 

           Since the complications of an overdose of strictly 

           acetazolamide are relatively rare, invasive or noxious 

           interventions such as syrup of ipecac or gastric lavage are 

           probably not warranted in most cases.  Gastrointestinal 

           decontamination with activated charcoal is probably warranted 

           if the patient presents within 1-2 hours post-ingestion, 

           especially in the face of serious underlying disease.

           

           Intervention should be targeted at replacing any fluid and 

           electrolyte abnormalities initially with intravenous isotonic 

           crystalloid solutions.  Obtaining serum electrolytes including 

           serum bicarbonate and urinalysis with urine pH is warranted 

           except in the most trivial ingestion.  Venous or arterial blood 

           gas measurement may be helpful in the severely or chronically 

           overdosed patient to better define the patient's acid-base 

           status.  Sodium bicarbonate infusion may be necessary if serum 

           pH is below 7.10 and does not respond to initial volume 

           resuscitation (Goldfrank et al, 1994).  A too rapid correction 

           may exacerbate electrolyte abnormalities.  For hypotension, 

           vigorous fluid hydration is necessary before using 

           vasopressors, and invasive monitoring with at least a central 

           venous pressure monitor is recommended.

 

    3. PHYSICO-CHEMICAL PROPERTIES

 

       3.1 Origin of the substance

 

           Acetazolamide is of synthetic origin.

 

       3.2 Chemical structure

 

           N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide; N-[5- 

           (aminosulfonyl)-1,3,4-thiadiazol-2-yl]-acetamide; 5-Acetamido- 

           1,3,4-thiadiazole-2-sulfonamide.

           

           Molecular weight: 222.2

           

           Molecular formula: C4H6N4O3S2

 

 

 

       3.3 Physical properties

 

           3.3.1 Properties of the substance

 

                  Acetazolamide exists as a white to faintly 

                  yellowish-white, odourless crystalline powder. 

                  Acetazolamide is very slightly soluble in water and only 

                  slightly soluble in ethanol (~750 g/l); it is 

                  practically insoluble in ether and chloroform.  The pH 

                  of a suspension 1g Acetazolamide in 50 ml water is 4.0 

                  to 6.0 (McEvoy, 1995).

                  

                  Acetazolamide has a melting point of about 260 °C, with 

                  decomposition (Moffat, 1986).

                  

                  The pKa values are 7.2 and 9.0 (Dollery, 1991).

 

           3.3.2 Properties of the locally available formulation

 

       3.4 Other characteristics

 

           3.4.1 Shelf-life of the substance

 

                  Solutions of acetazolamide are stable for one 

                  week after reconstitution, but it is recommended to use 

                  the solution within 24 hours (McEvoy, 1995).

 

           3.4.2 Shelf-life of the locally available formulation

 

                  To be completed by each center.

 

           3.4.3 Storage conditions

 

                  Acetazolamide tablets and extended-release 

                  capsules should be stored in a well-closed container at 

                  15 to 30°C.

 

           3.4.4 Bioavailablity

 

                  No data found.

 

           3.4.5 Specific properties and composition

 

                  No data found.

 

 

 

    4. USES

 

       4.1 Indications

 

           1. Preoperative management of closed-angle glaucoma, or as 

           an adjunct in the treatment of open-angle glaucoma.

           

           2. Abnormal retention of fluid: drug-induced oedema, obesity, 

           and congestive cardiac failure.

           

           3. Epilepsy

           

           4. Prevention or amelioration of acute high-altitude (mountain) 

           sickness when rapid ascent is necessary or in subjects who are 

           particularly susceptible to altitude sickness despite gradual 

           ascent.  However, this is not an approved indication for the 

           use of acetazolamide.

           

           5. Metabolic alkalaemia.

           

           6. Periodic paralysis

           (Dollery, 1991; McEvoy, 1995; Reynolds, 1993).

 

       4.2 Therapeutic dosage

 

           4.2.1  Adults

 

                  Glaucoma

                  

                  In the treatment of glaucoma the usual dose is 250 to 

                  1000 mg by mouth daily, in divided doses for amounts 

                  over 250 mg daily, or as a controlled release 

                  preparation.

                  

                  When the patient with glaucoma is unable to take oral 

                  medicine, 500 mg of acetazolamide may be administered IV 

                  or IM in adults (McEvoy, 1995).

                  

                  Abnormal retention of fluid

                  

                  For congestive heart failure, toxaemia and oedema the 

                  dose is 250-375 mg once daily in the morning.  Response 

                  may decrease with time and it may be helpful to omit the 

                  drug every third day, or to use alternate day 

                  dosage.

                  

                  For obesity the dose is 250-375 mg daily, which may be 

                  used on alternate weeks. (Dollery, 1991)

                  

                  Epilepsy

                  

 

 

 

                  Acetazolamide used in the treatment of epilepsy is 

                  administered in doses of 250 to 1000 mg daily in divided 

                  doses for amounts over 250 mg daily (Reynolds, 

                  1993).

                  

                  High-altitude sickness

                  

                  For the treatment of mountain sickness the usual dose is 

                  500 to 1000 mg daily.

                  

                  Metabolic alkalaemia

                  

                  In patients with metabolic alkalaemia acetazolamide 2.5 

                  to 5 mg per kg body-weight is administered intravenously 

                  (Berthelsen et al. as quoted in Reynolds, 1993)

 

           4.2.2  Children

 

                  Glaucoma and epilepsy

                  

                  A suggested dose for children for glaucoma or epilepsy 

                  is 8 to 30 mg per kg daily (Reynolds, 1993).  In acute 

                  glaucoma in children, 5 to 10 mg/kg may be administered 

                  IM or IV every 6 hours (McEvoy, 1995).

                  

                  Abnormal retention of fluid

                  

                  As a diuretic in children, an acetazolamide dosage of 

                  5 mg/kg or 150 mg/m2 may be administered orally or IV 

                  once daily in the morning (McEvoy, 1995).

 

       4.3 Contraindications

 

           1. Renal hyperchloraemic acidosis.

           

           2. Addison's disease and all types of suprarenal gland 

           failure.

           

           3. Conditions where there is known depletion of sodium and 

           potassium (at least until this is treated).

           

           4. Long-term administration is contraindicated in patients with 

           chronic closed angle-closure glaucoma.

           

           5. Known sensitivity to sulfonamides.

           (Dollery, 1991).

           

           6. Acetazolamide should not be used to alkalinize urine 

           following salicylate overdose since it may worsen metabolic 

           acidosis (Ellenhorn, 1988).

 

 

 

    5. ROUTES OF ENTRY

 

       5.1 Oral

 

           Acetazolamide is administered orally as tablets or 

       controlled release capsules.

 

       5.2 Inhalation

 

           Unknown

 

       5.3 Dermal

 

           Unknown

 

       5.4 Eye

 

           Unknown

 

       5.5 Parenteral

 

           When oral acetazolamide administration is impractical, 

           similar doses of acetazolamide sodium may be given by 

           intramuscular or preferably by intravenous injection.

 

       5.6 Others

 

           Unknown

 

    6. KINETICS

 

       6.1 Absorption by route of exposure

 

           Acetazolamide is well absorbed from the gastrointestinal 

           tract. Following oral administration of 500 mg of acetazolamide 

           as tablets, peak plasma concentrations are achieved within 1-3 

           hours. Low concentrations of acetazolamide are present in 

           plasma 24 hours after the drug is given.

 

       6.2 Distribution by route of exposure

 

           Acetazolamide is distributed throughout body tissues; it 

           concentrates principally in erythrocytes, plasma and kidneys 

           and to a lesser extent in liver, muscles, eyes and the central 

           nervous system. Acetazolamide does not accumulate in tissues. 

           The drug crosses the placenta in unknown  quantities (Wade, 

           1993).

           

           Acetazolamide is tightly bound to carbonic anhydrase and high 

           concentrations are present in tissues containing this enzyme 

           such as erythrocytes and the renal cortex (Reynolds, 1993).

           

           There is a small amount of irreversible binding to red cells. 

           It is 70 to 90% bound to plasma protein (Dollery, 1991).

           

 

 

 

           The volume of distribution of acetazolamide is 0.2 L/kg 

           (Dollery, 1991).

 

       6.3 Biological half-life by route of exposure

 

           Different sources have quoted different plasma half-life 

           values for acetazolamide as follows 3 to 6 hours according to 

           Reynolds (1993) whilst Dollery (1991) quotes the plasma half 

           life range as 6 to 9 hours with a mean plasma half-life of 8 

           hours.

 

       6.4 Metabolism

 

           Acetazolamide is not metabolized (Dollery, 1991)

 

       6.5 Elimination by route of exposure

 

           Acetazolamide is excreted unchanged by the kidneys via 

           tubular secretion and passive reabsorption. After 

           administration of the oral tablets 70-100% (average 90%) of the 

           dose is excreted in urine within 24-hours; 47% of the dose is 

           excreted within 24 hours following administration of the 

           controlled release tablets.

           

           There is no evidence of enterohepatic circulation although 

           small amounts of unchanged drug are eliminated in the bile 

           (Dollery, 1991).

 

    7. PHARMACOLOGY AND TOXICOLOGY

 

       7.1 Mode of action

 

           7.1.1 Toxicodynamics

 

                  Metabolic acidosis may occur with long term 

                  acetazolamide therapy due to reduced bicarbonate 

                  concentrations, and in some instances, elevated plasma 

                  chloride concentrations.

                  

                  Renal calculi have occurred, possibly due to the reduced 

                  excretion of citrate combined with unchanged or 

                  increased calcium excretion.

 

           7.1.2 Pharmacodynamics

 

                  Acetazolamide is a carbonic anhydrase inhibitor. 

                  Acetazolamide reduces the formation of hydrogen and 

                  bicarbonate ions from carbon dioxide and water by 

                  noncompetitive, reversible inhibition of the enzyme 

                  carbonic anhydrase, thereby reducing the availability of 

                  these ions for active transport into secretions.

                  

 

 

 

                  In the eye acetazolamide reduces the formation of 

                  aqueous humor so that intraocular pressure in both 

                  normal and glaucomatous eyes is reduced.

                  

                  In the kidney the inhibition of carbonic anhydrase 

                  causes a reduction in hydrogen ion concentration in the 

                  renal tubules so that there is as increased excretion of 

                  bicarbonate and, to a lesser extent, sodium and 

                  potassium. Potassium loss is particularly high during 

                  acute administration. As the reabsorption of water is 

                  reduced, the volume of urine  is increased, and the pH 

                  of the urine becomes alkaline.  The excretion  of 

                  lithium is increased whereas the excretion of ammonia, 

                  acidity, citrate and uric acid is decreased.

                  

                  The anticonvulsant activity of acetazolamide has been 

                  theorised to be caused by the production of metabolic 

                  acidosis. However, it has been postulated that a direct 

                  effect on carbonic anhydrase in the brain may result in 

                  increased carbon dioxide tension, which has been 

                  demonstrated to retard neuronal conduction; an 

                  adrenergic mechanism may be involved (McEvoy, 1995).

                  

                  For acute mountain sickness, possible mechanisms of 

                  action include increased respiratory drive secondary to 

                  induction of metabolic acidosis, and therapeutic effects 

                  through diuresis (USP DI, 1995).

 

       7.2 Toxicity

 

           7.2.1 Human data

 

                  7.2.1.1 Adults

 

                           One patient died of cholestatic 

                           jaundice after taking 13 g of acetazolamide in 

                           26 days. In one patient, fatal bone marrow 

                           depression with leukopenia, thrombocytopenia, 

                           and anemia occurred after therapy with 500 mg 

                           of acetazolamide twice daily for 14 weeks. One 

                           case of renal failure (anuria) occurred in a 

                           patient after taking 500 mg of acetazolamide 

                           twice daily for 2 weeks (McEvoy, 1995).

                           

                           According to Dollery (1991) intentional 

                           overdose has not been reported. Drowsiness and 

                           disorientation have been reported when daily 

                           doses of 1 g and 5 g have been given to 

                           patients with hepatic failure (Dollery, 

                           1991).

 

 

 

                  7.2.1.2 Children

 

                           Unknown

 

           7.2.2 Relevant animal data

 

                  Numerous animal studies have demonstrated that 

                  the toxicity of acetazolamide was very low in the 

                  species studied (mouse, dog, rat, monkey). In the mouse, 

                  the LD50 is 3000 to 6000 mg/kg (Dollery, 1991)

 

           7.2.3 Relevant in vitro data

 

                  Not relevant

 

       7.3 Carcinogenicity

 

           No data available

 

       7.4 Teratogenicity

 

           There have been no reports of congenital defects despite 

           past widespread use though one women on 750 mg per day for 

           glaucoma during the 1st and 2nd trimester had a baby with a 

           sacrococcygeal teratoma but no causal link could be made 

           (Briggs et al, 1994).

           

           Teratogenicity tests in rats and mice showed the absence of 

           fourth and fifth digits from the right forelimb in the 

           offspring of rats and mice that received 0.6% acetazolamide in 

           the diet during pregnancy (Layton and Trelstad, 1965, and 

           Holmes and Trelstad, 1979, as quoted by Dollery, 1991). There 

           were no apparent lessions in the newborn of rabbits and monkeys 

           (Scott et al, 1981, as quoted by Dollery, 1991).

           

           The drug crosses the placenta in unknown quantities (Reynolds, 

           1993).

 

       7.5 Mutagenicity

 

           No data available

 

       7.6 Interactions

 

           Potentially hazardous interactions

           

           The effects of folic acid antagonists, oral hypoglycaemic 

           agents and oral anticoagulants may be increased by 

           acetazolamide.

           

           The urinary antiseptic effect of methenamine may be prevented 

           by acetazolamide by keeping the urine alkaline. The 

           alkalinization  of the urine by acetazolamide can reduce the 

           urinary excretion of many weak bases (including amphetamine, 

 

 

 

           quinine, quinidine, and diethylcarbamazine) and thus enhance 

           their pharmacological effects. In one patient taking phenytoin 

           and acetazolamide drug-induced osteomalacia was reported 

           (Davidson, 1975, Rawlins, 1978, Richens, 1977, and Mallov, 

           1977, as quoted by Dollery, 1991).

           

           Potentially useful interactions

           

           Acetazolamide can aid the penetration of weakly acidic 

           substances across the blood/cerebrospinal fluid barrier by 

           diffusion. Acetazolamide and other carbonic anhydrase 

           inhibitors increase the effects of mercurial diuretics 

           (Dollery, 1991).

 

       7.7 Main adverse effects

 

           The incidence and severity of many adverse reactions to 

           acetazolamide are dose related and usually respond to a 

           lowering of the dosage or withdrawal of the drug.

           

           Potentially life-threatening effects

           

           Acetazolamide is a sulfonamide derivative, and some adverse 

           effects similar to those of sulfonamides have been reported. 

           The more serious effects include blood disorders, skin toxicity 

           and renal stone formation. Stevens-Johnson syndrome has not 

           been reported (Rubenstein, 1975, as quoted by Dollery, 

           1991).

           

           Symptomatic adverse effects

           

           Flushing, thirst, headache, drowsiness, dizziness, fatigue, 

           irritability, excitement, paresthesias, ataxia, hyperpnoea and 

           gastrointestinal disturbances have all been reported (Dollery, 

           1991).

           

           Interference with clinical pathology tests

           

           Sulfonamides may give false negative or decreased values for 

           urinary phenolsulfonphthalein and phenol red elimination values 

           for urinary protein, serum non-protein and for serum uric acid 

           (Dollery, 1991).

 

 

 

    9.0 CLINICAL EFFECTS

 

       9.1 Acute poisoning

 

           9.1.1 Ingestion

 

                  Oral ingestion is the usual means of exposure 

                  outside of a health care facility.  The clinical effects 

                  are those described in Section 2.2.

 

           9.1.2 Inhalation

 

                  Not relevant.

 

           9.1.3 Skin exposure

 

                  There is no appreciable dermal 

                  absorption.

 

           9.1.4 Eye contact

 

                  There is no significant absorption or local 

                  irritation.

 

           9.1.5 Parenteral exposure

 

                  Acetazolamide is used intravenously in acute 

                  volume overload states or in acute glaucoma but would 

                  not be available outside of a health care facility.  The 

                  clinical effects are those described in Section 

                  2.2.

 

           9.1.6 Other

 

                  Not relevant.

 

       9.2 Chronic poisoning

 

           9.2.1 Ingestion

 

                  As in acute poisoning.

 

           9.2.2 Inhalation

 

                  Not relevant.

 

           9.2.3 Skin exposure

 

                  As in acute poisoning.

 

           9.2.4 Eye contact

 

                  As in acute poisoning.

 

 

 

           9.2.5 Parenteral exposure

 

                  As in acute poisoning.

 

           9.2.6 Other

 

                  Not relevant.

 

       9.3 Course, prognosis, cause of death

 

           The great majority of acute overdoses especially in 

           otherwise healthy individuals are benign and with simple 

           symptomatic care should have an excellent outcome.  Patients 

           that are on chronic therapy and presenting with complications 

           thereof may have a worse prognosis especially if not suspected 

           by the clinician.  Long-term therapy with diuretics must be 

           closely monitored.  Patients on long-term therapy who present 

           with acute problems should be specifically evaluated for volume 

           status and electrolyte and acid-base abnormalities including 

           metabolic acidosis. Patients that present with arrhythmias or 

           seizures while on diuretics should be rapidly evaluated for 

           hyponatremia, hypokalemia, and hypomagnesemia.  Patients that 

           present with unexplained fluid or electrolyte abnormalities 

           should be evaluated for possible diuretic abuse.  Prognosis 

           should also be excellent in these patients if potential 

           abnormalities are rapidly evaluated and appropriately 

           treated.

           

           Acetazolamide overdoses should  be evaluated according to the 

           extent of volume depletion, the degree of electrolyte 

           abnormality or acid-base disturbance, and the severity of the 

           patient's underlying medical condition(s) and not according to 

           the amount ingested.

           

           Deaths, though rare, do occur, not directly from the drug, but 

           complications in its use or abuse, namely arrhythmias and 

           seizures from electrolyte abnormalities or cardiac or renal 

           dysfunction secondary to volume depletion, or from severe 

           metabolic acidosis.

 

       9.4 Systematic description of clinical effects

 

           9.4.1  Cardiovascular

 

                  Arrhythmias may result from hypokalemia but are 

                  usually not life-threatening unless digoxin is also 

                  being administered and are self-limited with potassium 

                  replenishment.  Myocardial function may be impaired due 

                  to hypovolemia in patients with marginal function who 

                  require high ventricular loading pressures.

                  

 

 

 

                  Chronic use may result in metabolic acidosis with a 

                  compensatory hyperventilation that can lead to increased 

                  pulmonary vascular resistance which is usually 

                  reversible with discontinuation of the 

                  medication.

 

           9.4.3  Neurological

 

                  9.4.3.1  CNS

 

                           Toxicity may be manifested as lethargy 

                           and generalized weakness due to dehydration. 

                           There may be seizures due to hyponatremia. 

                           With chronic use, paresthesias and somnolence 

                           are frequently reported (Goodman et al., 1990). 

                           Headache, confusion, depression, irritability, 

                           nervousness, vertigo, dizziness and ataxia have 

                           been reported (McEvoy, 1995).

 

                  9.4.3.2  Peripheral nervous system

 

                           May demonstrate hyporeflexia due to 

                           hypokalemia.

 

                  9.4.3.3  Autonomic nervous system

 

                           There are no known effects.

 

                  9.4.3.4  Skeletal and smooth muscle

 

                           There may be muscle weakness in both 

                           skeletal and smooth muscle due to hypokalemia 

                           and/or hypomagnesemia.  Tremor and flaccid 

                           paralysis have been reported (McEvoy, 

                           1995).

 

           9.4.4  Gastrointestinal

 

                  Gastrointestinal disturbances including anorexia, 

                  nausea, vomiting, diarrhea, constipation, and abdominal 

                  distension may occur (McEvoy, 1995).  Chronic use or 

                  abuse may result in pancreatitis which may be immune- 

                  mediated.

 

           9.4.5  Hepatic

 

                  Liver dysfunction has been reported as an 

                  idiosyncratic reaction.  A case of cholestatic jaundice 

                  was reported after ingestion of 500 mg/day for 26 days 

                  (Ellenhorn, 1988).

 

 

 

           9.4.6  Urinary

 

                  9.4.6.1  Renal

 

                           Incorrect or unmonitored use may 

                           exacerbate underlying renal insufficiency due 

                           to a multitude of conditions including diabetes 

                           mellitus, chronic hypertension, cystic kidney 

                           disease, collagen vascular disease, or gout. 

                           Acetazolamide may cause nephrolithiasis and 

                           renal colic (Ellenhorn, 1988).  Dysuria and 

                           crystalluria have been reported (McEvoy, 

                           1995).

 

                  9.4.6.2  Other

 

                           May lead to urinary incontinence in 

                           the elderly and urinary retention in patients 

                           with prostatism.

 

           9.4.7  Endocrine and reproductive systems

 

                  Hyperglycemia may result with acute or chronic 

                  use or overdose and is usually self-limited.

 

           9.4.8  Dermatological

 

                  No effects reported except allergic skin 

                  rashes.

 

           9.4.9  Eye, ear, nose, throat: local effects

 

                  Acetazolamide is used to lower IOP in acute 

                  glaucoma and also as a maintenance anti-glaucoma agent 

                  and it works by inhibiting carbonic anhydrase in the 

                  ciliary body.  Myopia has been reported and generally 

                  subsides with cessation of therapy (McEvoy, 

                  1995).

 

           9.4.10 Haematological

 

                  There have been several case reports of fatal 

                  aplastic anemia, and isolated agranulocytosis or 

                  thrombocytopenia (Kristinsson, 1966).

 

           9.4.11 Immunological

 

                  None known

 

 

 

           9.4.12 Metabolic

 

                  9.4.12.1 Acid-base disturbances

 

                           Chronic use has resulted in a 

                           hyperchloremic/hypokalemic metabolic acidosis 

                           and can be seen to a lesser extent in an acute 

                           ingestion.  41% of 27 elderly patients on 

                           chronic therapy had moderate to severe acidosis 

                           with serum pH less than 7.29  (Heller et al., 

                           1985).

 

                  9.4.12.2 Fluid and electrolyte disturbances

 

                           Acute or chronic use or abuse can 

                           result in dehydration due to free water and 

                           electrolyte loss.  Hyponatremia, hypokalemia, 

                           and hyperchloremia with bicarbonate loss may 

                           occur.  To a lesser degree and usually on a 

                           more chronic basis, significant hypomagnesemia 

                           and hypocalcemia may result.

 

                  9.4.12.3 Others

 

                           Hyperuricemia and hyperlipidemia may 

                           result following chronic use.  Patients with 

                           cirrhosis have experienced disorientation 

                           possibly due to elevation of ammonia levels 

                           with carbonic anhydrase inhibitors (McEvoy, 

                           1995).

 

           9.4.13 Allergic reactions

 

                  There have been several reports of skin rash and 

                  serum sickness hypersensivity in patients on chronic 

                  therapy (Kristinsson, 1966).  Acetazolamide is a 

                  sulfonamide derivative and shares the incidence of 

                  hypersensitivity reactions (McEvoy, 1995).  There are 

                  rare true allergic reactions reported to 

                  acetazolamide.

 

           9.4.14 Other clinical effects

 

                  The resulting hypokalemia may exacerbate 

                  underlying digoxin toxicity. There is a major potential 

                  interaction with salicylates with documented cases with 

                  significant increases in baseline salicylate levels when 

                  acetazolamide was initiated in several elderly patients 

                  (Sweeney et al, 1986).  The toxicity would also be 

                  exacerbated by metabolic acidosis induced by 

                  acetazolamide, which will increase the CNS salicylate 

                  level and resultant toxicity at a given salicylate serum 

                  level.

 

 

 

           9.4.15 Special risks

 

                  As noted above special risks with furosemide use 

                  or overdose exist in patients with pre-existing renal 

                  disease or fluid and/or electrolyte abnormalities. 

                  Acetazolamide is secreted in breast milk but in one case 

                  a nursing infant exposed for one week showed no ill 

                  results  after receiving an estimated 0.6 mg/day 

                  (approximately 0.06% of the maternal dose) (Briggs et 

                  al, 1994).

 

       9.5 Other

 

           None identified.

 

    10. MANAGEMENT

 

        10.1 General principles

 

             Since diuretic overdoses are usually benign, aggressive 

             decontamination procedures are not warranted.  Treatment is 

             symptomatic in nature and is directed at correcting any fluid 

             and/or electrolyte abnormalities.  More aggressive management 

             may be necessary in the patient with underlying abnormalities 

             including renal insufficiency, fluid and/or electrolyte 

             abnormalities, myocardial dysfunction, or taking other 

             potentially toxic medications such as digoxin or an 

             aminoglycoside antibiotic.  Treatment aggressiveness must be 

             targeted to the severity of apparent toxicity and the 

             underlying chronicity thereof.

 

        10.2 Relevant laboratory analyses

 

             10.2.1 Sample collection

 

                    Levels of diuretics are rarely available and 

                    clinically useful, with the possible exception in 

                    cases of alleged use or abuse in patients that present 

                    with unexplained fluid and/or electrolyte 

                    abnormalities or in suspected Munchausen or 

                    Munchausen-by-proxy patients.  There are acetazolamide 

                    levels available at some research centers.  There does 

                    not appear to be any additional benefit in glaucoma 

                    therapy with levels greater than 4.2 mg/ml and this is 

                    usually achieved at a dose of 63 mg four times a day 

                    at steady state (Friedland et al, 1977).

 

             10.2.2 Biomedical analysis

 

                    Analysis should be targeted to the expected 

                    electrolyte abnormalities including sodium, potassium, 

                    chloride, and bicarbonate measurements in the mildly 

                    to moderately ill patient.  Blood gas analysis may be 

                    necessary in the more severely ill patient or when one 

 

 

 

                    needs to more precisely define the acid-base 

                    disturbance that may be present.  In more chronic use 

                    or abuse, magnesium and calcium levels may be 

                    necessary to define their depletion and need for 

                    replenishment.  If drug abuse of any kind is 

                    suspected, a general urine drug screen may  be 

                    indicated.

 

             10.2.3 Toxicological analysis

 

                    Analysis would only be necessary as described 

                    above.  See Section 8 for additional detail.

 

             10.2.4 Other investigations

 

                    None relevant.

 

        10.3 Life supportive procedures and symptomatic/specific treatment

 

             Life supportive measures are usually not necessary and 

             may only be needed in potentially life-threatening 

             arrhythmias seen with hypokalemia (especially with concurrent 

             digoxin use) and with seizures secondary to hyponatremia, 

             both fairly rare complications.  Symptomatic treatment is 

             directed at fluid/electrolyte repletion, initially with 

             intravenous isotonic crystalloid solutions.  Depending on the 

             severity of volume depletion, this can be administered 

             initially as rapid boluses in the range of 1 - 2 L in the 

             adult patient or 10 - 20 mL/kg in the pediatric patient. 

             Further repletion should be based on clinical response to the 

             first bolus and definitive blood chemistry analysis.  Care 

             must be taken in bolusing patients with underlying renal or 

             cardiac insufficiency that may make them more prone to fluid 

             overload and pulmonary edema. 

             

             In cases of severe hyponatremia resulting in seizures, 

             attention must be made to assess the patient's airway, 

             breathing, and circulation status.  Seizure treatment should 

             follow standard guidelines.

             

             Arrhythmias associated with hypokalemia usually are not 

             malignant and will respond to judicious potassium 

             replacement.  If arrhythmias are malignant in nature and 

             while replenishing potassium, the usual ventricular 

             antiarrhythmic agents are utilized.  In the chronic use or 

             abuse of diuretics, hypomagnesemia may contribute to 

             ventricular arrhythmias, especially torsade de pointe, and 

             replacement therapy in an urgent manner may terminate these 

             arrhythmias without resorting to potentially detrimental 

             medications.  The dose would be magnesium sulfate 2 - 4 g 

             intravenously diluted to 100 - 250 mL over 15 - 30 minutes 

             (40 - 80 mg/kg for pediatric patients, suitably 

             diluted).

 

 

 

        10.4 Decontamination

 

             Since these ingestions are usually benign or are 

             associated with hypovolemia, specific measures such as 

             inducing vomiting or administering cathartics are 

             contraindicated.  If the patient presents early, certainly 

             less than 1 hour after ingestion, with a large ingestion or 

             with underlying cardiac, renal, or hepatic insufficiency, 

             then a dose of activated charcoal is probably indicated. 

             Certainly, in an otherwise normal child with a limited acute 

             ingestion, no GI decontamination is warranted.

 

        10.5 Elimination

 

             There is no role for enhanced elimination, but a single 

             patient study with dialysis-dependent renal failure given one 

             500 mg dose of acetazolamide pre-dialysis showed an average 

             clearance of 22 mL/minute despite its high RBC distribution 

             (Vaziri et al, 1980).

 

        10.6 Antidote treatment

 

             10.6.1 Adults

 

                    There is no antidote for any of the 

                    diuretics.

 

             10.6.2 Children

 

                    There is no antidote for any of the 

                    diuretics.

 

        10.7 Management discussion

 

             Acetazolamide ingestions are usually benign and serious 

             complications rare.  Treatment usually is limited to 

             supportive and symptomatic care.

 

    11. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             A 74 year-old woman on chronic acetazolamide therapy, 

             500 mg bid, for her glaucoma presented with abdominal pain, 

             anorexia, fatigue, and a 9 kg weight loss over 3 weeks.  Her 

             heart rate was 140 per minute.  Serum electrolytes were 

             sodium 138 mEq/L, potassium 3.8 mEq/L, chloride 118 mEq/L, 

             and bicarbonate 15 mEq/L.  Arterial blood gases measurements 

             were: pH of 7.36, pO2 93 mmHg, and pCO2 26 mmHg.  Her status 

             improved markedly with withdrawal of acetazolamide (Clark and 

             Vestal, 1984).

 

 

 

        11.2 Internally extracted data on cases

 

             None available.

 

        11.3 Internal cases

 

             None available.

 

    12. ADDITIONAL INFORMATION

 

        12.1 Availability of antidotes

 

             There are no specific antidotes.

 

        12.2 Specific preventive measures

 

             There are no specific preventive measures except 

             careful monitoring of patients on chronic therapy and 

             avoiding known drug interactions.

 

        12.3 Other

 

             Not relevant.

 

    13. REFERENCES

 

        AHA (American Heart Association) (1992).  Guidelines for 

        cardiopulmonary resuscitation and emergency cardiac care.  JAMA. 

        268:2171 - 2302.

        

        Antihypertensive drugs.  In:  Ellenhorn MJ & Barceloux DG, eds. 

        Medical toxicology: diagnosis and treatment of human poisoning. 

        New York, Elsevier, pp. 279-280.

        

        Barkin RM, Rosen P, eds. (1990):  Emergency pediatrics, 3rd ed. 

        St. Louis, Mosby.

        

        Briggs GG, Freeman RK, Yaffe SJ (1994).  Drugs in pregnancy and 

        lactation, 3rd ed.  Baltimore, Williams &Wilkins, pp. 6-7.

        

        Clark BG, Vestal RE (1984). Adverse drug reactions in the elderly: 

        Case studies.  Geriatrics 39(12):53-66.

        

        Dollery CT ed. (1991). Therapeutic drugs Edinburgh, Churchill 

        Livingstone.

        

        Ellenhorn MJ, Barceloux DG (1988). Medical Toxicology : Diagnosis 

        and Treatment of Human Poisoning. New York : Elsevier.

        

        Friedland BR, Mallonee J, Anderson DR (1977).  Short-term dose 

        response characteristics of acetazolamide in man.  Arch Ophthalmol 

        95:1809-12.

        

 

 

 

        Goodman L, Gilman AG, Rall TW, Nies AS, Taylor P, eds. (1985). 

        The pharmacological basis of therapeutics, 7th ed.  New York, 

        Macmillan.  pp.716-8.

        

        Heller I, Halevy J, Cohen S, et al. (1985).  Significant metabolic 

        acidosis induced by acetazolamide:  not a rare complication.  Arch 

        Intern Med 145:1815-1817.

        

        Kristinsson A (1966).  Fatal reaction to acetazolamide.  Brit J 

        Ophthal.  51:348-9.

        

        Lewin NA (1994).  Antihypertensive agents.  In:  Goldfrank LR, 

        Weisman RS, Flomenbaum NE, Howland MA, Lewin NA, Hoffman RS. 

        Goldfrank's toxicologic emergencies 5th ed.  Norwalk, Conn., 

        Appleton & Lange, pp. 708.

        

        Reynolds JEF, ed. (1993).  Martindale: The Extra Pharmacopoeia. 

        Ass. editors Perfitt K, Parsons AN, Sweetman SC. London, The 

        Pharmaceutical Press.

        

        McEvoy GK ed. (1995).  American Hospital Formulary Service, Drug 

        information.  Bethesda, MD, American Society of Hospital 

        Pharmacists.

        

        Moffat AC(1986) Clarke's Isolation and identification of drugs in 

        pharmaceuticals, body fluids, and post-mortem material. 2nd ed. 

        (consulting editors Jackson JV, Moss MS, Widdop B) London, 

        Pharmaceutical Press.

        

        Spratt DI, Pont A (1982).  The clinical features of covert 

        diuretic use.  West J Med.  137:331-335.

        

        Sweeney KR, Chapron DJ, Brandt JL, Gomolin IH, Feig PU, Kramer PA 

        (1986).  Toxic interaction between acetazolamide and salicylate: 

        case reports and a pharmacokinetic explanation.  Clin Pharmacol 

        Ther.  40(5):518-24.

        

        USP DI (1995).  United States Pharmacopeia. 15th edition, 

        Rockville, MD, The United States Pharmacopeial Convention Inc., 

        Vol. 1, p 659.

        

        Vaziri ND&lt Saiki J, Barton CH, Rajudin M, Ness RL (1980). 

        Hemodialyzability of acetazolamide.  Southern Medical Journal. 

        73(4):422-3.

        

        Woo OF (1994).  Diuretics.  In:  Olson KR, ed.  Poisoning and 

        overdose handbook. Norwalk, Conn., Appleton & Lange, pp. 157- 

        158.

 

 

 

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), 

    COMPLETE ADDRESS(ES)

 

    Authors:

    

        Craig R. Warden, MD

        Jefferey L. Burgess, MD

        Washington Poison Center

        155 NE 100th St., Suite 400

    

    Reviewer:

    

        PIM panel, October 1995

    

    Initial Date:

    

        10 October 1995

 

    

Carbamazepine
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method(s)
         8.2.2.4 Advanced quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    CARBAMAZEPINE

    International Programme on Chemical Safety
    Poisons Information Monograph 100
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Carbamazepine

        1.2  Group

             Nervous system, antiepileptics, antiepileptics,
             carboxamide derivatives.

        1.3  Synonyms

             G 32883

        1.4  Identification numbers

             1.4.1  CAS number

                    298-46-4

             1.4.2  Other numbers

                    ATC code: NO3AF

        1.5  Main brand names, main trade names

             Biston, Calepsin, Convulsine, Epitol, Finlepsin,
             Hermolepsin, Karbamazepine, Lexin, Mazepine, Neuritol,
             Neurotol, Neurotop, Nordotol, Servimazepine, Sirtal,
             Stazepine, Tegretal, Tegretol, Telesmin, Temporol, Teril,
             Timonil, Trimonil Retard (Index Nominum, 1987).

        1.6  Main manufacturers, main importers

             Geigy (importer):      Argentine, Australia, Belgium,
                                    Canada, Denmark, France,
                                    Italy, Netherlands, Norway,
                                    Portugal, South Africa, Spain,
                                    Switzerland, UK, USA.
    
             Spofa:          Prague, Czech Republic
    
             Protea:         Glebe, NSW 2037, Australia
    

             Arzneitmittelwerk:  8122 Radebeul, Dresden,
                                 Germany 
    
             Lääke:          20101 Abo, Finland 
    
             Fujinawa:       Tokyo, Japan
    
             ICN:            Montreal, Quebec, Canada
    
             Eczacoibasoi:   Istanbul, Turkey

             Farmos Group:   20101, Turku, Finland
    
             Servipharm:     4002, Basel, Switzerland
    
             Polfa:          Warszawa, Poland
    
             Orion:          00510, Helsinki, Finland
    
             Taro:           Haifa, Israel
    
             Desitin:        2000 Hamburg, Germany
    
             (Index Nominum, 1992/93; Reynolds, 1996)

    2.  SUMMARY

        2.1  Main risks and target organs

             The principle toxic effects of  carbamazepine are
             depression in level of consciousness, convulsions and ECG
             changes. 

        2.2  Summary of clinical effects

             Cardiovascular tachycardia, hypotension, conduction
             disorders.
    
             Respiratory:  central respiratory depression.
    
             Eyes:  mydriasis, nystagmus.
    
             Neurological: depressed level of consciousness, ataxia,
             initial hyperreflexia followed by hyporeflexia,
             ophisthotonus, agitation, disorientation, tremor, involuntary
             movements, convulsions.
    
             Gastrointestinal: nausea and vomiting

        2.3  Diagnosis

             The diagnosis should be considered in any patient with
             access to carbamazepine who presents with a depressed level

             of consciousness.  The presence of seizure activity or ECG
             changes makes the diagnosis more likely.  The diagnosis is
             confirmed in laboratory by measurement of  toxic serum
             carbamazepine levels.

        2.4  First aid measures and management principles

             Management is supportive.  Particular attention is
             directed towards maintenance of the airway and ventilation
             and control of seizures.  Other clinical features that may
             require treatment include hypotension, hypothermia and
             hyponatraemia.
    
             The administration of oral activated charcoal to prevent
             furhter absorption is indicated once the airway is secured. 
             Repeat doses of activated charcoal are effective in enhancing
             elimination of carbamazepine.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic.

        3.2  Chemical structure

             Carbamazepine is an iminostilbene derivative that is
             related chemically to the tricyclic antidepressants and is
             structurally similar to phenytoin.
    
             Chemical name: 5H-Dibenz[b,f]azepine-5-carboxamide;
             5-carbamoyl-5H-dibenz[b,f]azepine
    
             Molecular formula of carbamazepine: C15H12N2O.
    
             Molecular weight: 236.26.

        3.3  Physical properties

             3.3.1  Colour

                    White to yellowish-white

             3.3.2  State/form

                    Crystal

             3.3.3  Description

                    Almost odourless, carbamazepine can either have
                    no taste or be slightly bitter.  It is practically
                    insoluble in water and ether but soluble in acetone,

                    alcohol, carbon tetrachloride, chloroform,
                    dimethylformamide dioxane, and propylene glycol
    
                    Melting point: 190 to 193°C.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No data available.

             3.4.2  Storage conditions

                    Store in airtight containers, below 40°C and,
                    preferably, between 15 and 30°C, and away from light
                    (Budavari, 1996).

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Carbamazepine has both antiepileptic and
                    psychotropic properties.  Accepted indications
                    include:
    
                    Epilepsy: Generalized tonic-clonic (grand mal) and
                    partial (focal) seizures.
    
                    Pain syndromes: Trigeminal neuralgia and
                    glossopharyngeal neuralgia.
    
                    Manic depressive illness unresponsive to lithium. 
    
                    (Reynolds, 1996)

        4.2  Therapeutic dosage

             4.2.1  Adults

                    The dose of carbamazepine should be adjusted
                    according to the needs of each patient.  The
                    therapeutic plasma concentration is 4 to 12 mg/L (20
                    to 50 mmol/L).  The total daily dose should preferably
                    be given as three or four divided doses.
    
                    Epilepsy: the initial oral dose is 200 mg twice a day,
                    increased by 200 mg at weekly intervals until the

                    patient responds.  The maintenance dose is 800 mg to
                    1200 mg/day, maximum 1600 mg/day.
    
                    Neuralgia: the initial dose is 100 mg twice a day,
                    with an additional 200 mg every other day until pain
                    is relieved.  The maintenance dose is 200-1200 mg
                    daily, maximum 1600 mg/day.
    
                    Psychosis: initial doses are 400-600 mg per day, to a
                    maximum of 1.6 g/day as needed and tolerated.
    
                    (Reynolds, 1996).

             4.2.2  Children

                    The safety and efficacy of carbamazepine have
                    not been established in children less than 
                    6-years-old.  Some doctors give an initial dosage of 
                    5 mg/kg daily, which may be increased to 10 to 20 
                    mg/kg daily; the following doses can be used as
                    guidelines:
    
                    less than 1 year old:   100 to 200 mg/day
                    1 to 5 years old:       200 to 400 mg/day
                    5 to 10 years old:      400 to 600 mg/day
                    10 to 15 years old:     600 to 1000 mg/day
    
                    The dosage should not exceed 1 g/day (Reynolds, 1996)

        4.3  Contraindications

             Hypersensitivity to carbamazepine
             Atrioventricular conduction defects (unless paced)
             Aplastic anaemia
             Acute intermittent porphyria
    
             Caution should be exercised in administering carbamazepine to
             patients with history of cardiac, hepatic, haematologic or
             renal disease or with raised intraocular pressure.
    
             Carbamazepine should not be given with monoamine oxidase
             inhibitors or within two weeks of its cessation.
             (Reynolds, 1996; Morant & Ruppaner, 1997).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Carbamazepine is given orally in tablet or syrup form.  
             Carbamazepine intoxication occurs from ingestion.

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             Not relevant.

        5.4  Eye

             Not relevant.

        5.5  Parenteral

             No data available.

        5.6  Other

             Rectal.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Absorption of carbamazepine from the gastrointestinal
             tract is slow and erratic but almost complete. Oral
             absorption is more rapid on a full stomach and slower from
             tablets than from solution.
    
             Peak plasma concentrations usually occur within 4 to 12 hours
             of oral aministration.  However, they may be delayed up to 
             24 hours after overdose.

        6.2  Distribution by route of exposure

             Carbamazepine is 76% bound to plasma proteins.  It is
             rapidly and uniformly distributed throughout the body.
    
             Carbamazepine epoxide, the principal active metabolite, is
             50% bound to plasma proteins (Rane et al., 1976).  It is
             probably subject to enterohepatic circulation (Laffey &
             Guzzardi, 1983).
    
             Carbamazepine crosses the blood-brain barrier and the
             placenta, accumulates in fetal tissues, and is distributed
             into breast milk at concentrations about 60% those of
             maternal plasma.  The drug has been detected in cerebrospinal
             fluid in concentrations approximately 15% those of serum.
    
             The volume of distribution is 0.79 to 1.4 L/kg increasing
             after long-term treatment to 0.96 to 2.07 L/kg (Westenberg et
             al., 1978).

        6.3  Biological half-life by route of exposure

             Carbamazepine induces its own metabolism, so that the
             plasma half-life ranges from 18 to 60 hours following a
             single dose, and from 10 to 35 hours during chronic therapy. 
             The half-life is shorter in children than in adults.

        6.4  Metabolism

             Carbamazepine can induce its own metabolism.  It is
             metabolized in the liver to an epoxide and several other
             metabolites.  A major metabolic pathway is oxidation by
             microsomal enzymes to form carbamazepine 10, 11 epoxide. This
             is an active compound and is almost completely metabolized to
             an inactive metabolite, trans-10,11-dihydroxy-10,11-
             dihydrocarbamazepine (trans-carbamazepine-diol), and excreted
             in the urine mainly in an unconjugated form.
    
             Carbamazepine is also inactivated by conjugation and
             hydroxylation.

        6.5  Elimination by route of exposure

             Carbamazepine and its metabolites are excreted in the
             urine.  After oral administration, 72% of the dose is
             excreted in the urine and 28% is eliminated in the faeces. 
             Only about 1 to 3% of the drug is excreted unchanged in the
             urine.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Signs of toxicity appear at plasma
                    concentrations above the upper limit of the
                    therapeutic level (12 mg/L or 50 µmol/L) and are due
                    to the effects on the central nervous system (Salcman
                    & Pippenger, 1975), gastrointestinal irritation
                    (Lehrman & Bauman, 1981), arrhythmogenic properties
                    (Beerman et al., 1975) and its anti-diuretic action
                    (Stevens, 1977).

             7.1.2  Pharmacodynamics

                    In cats, carbamazepine depresses thalamic
                    potential and bulbar and polysynaptic reflexes. Its
                    capacity to increase discharges of noradrenergic
                    neurones may contribute to its anti-epileptic actions
                    (Rall & Schleifer, 1985). Although the effects of
                    carbamazepine in animals and humans resemble those of

                    phenytoin, there are several important differences. 
                    For example, carbamazepine is more effective than
                    phenytoin in reducing stimulus-induced discharges in
                    the amygdala of stimulated rats.
    
                    The mechanisms responsible for these effects are not
                    clearly understood.  Carbamazepine seems to act by
                    reducing polysynaptic responses and blocking
                    post-tetanic potentiation (Drug Facts & Comparisons,
                    1985).
    
                    Its efficacy in neuralgia may result from the
                    reduction of excitatory synaptic transmission in the
                    spinal trigeminal nucleus because it increases the
                    latency of trigeminal neuronal response and decreases
                    the number of neuronal discharges.  Carbamazepine
                    10,11-epoxide, the major metabolite of carbamazepine,
                    also has considerable activity against neuralgia.
    
                    The antidiuretic effects of carbamazepine are a
                    consequence of  reduced plasma concentrations of
                    anti-diuretic hormone.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Of 22 adults requiring admission to
                             hospital following carbamazepine overdose,
                             the mean ingestion was 12 g (range 1.6 to 45
                             g).  All survived.  (Seymour, 1993).

                    7.2.1.2  Children

                             Children appear more likely to
                             suffer seizures and less likely to develop
                             electrocardiographic abnormalities (Bridge &
                             Norton, 1994).

             7.2.2  Relevant animal data

                    In animals, the lethal concentrations (oral LD50) are:
    
                    Mice:  3750 mg/kg; Rats:  4025 mg/kg
                    (Budavari, 1996.

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             Carbamazepine in doses of 25, 75, and 250 mg was given
             to Sprague-Dawley rats for two years. It caused a 
             dose-related increase in the incidence of hepatocellular 
             tumours in female rats and benign interstitial cell adenomas
             in the testes of males. The significance of these findings
             for humans is not known (PDR, 1988). There have been no 
             reports of tumorigenic effects in humans.

        7.4  Teratogenicity

             Carbamazepine is classified as category "C".  That is to
             say, studies in animals have revealed adverse effects on the
             fetus but there are no controlled studies in women.  Minor
             malformations such as those seen with fetal hydantoin
             syndrome have been observed with carbamazepine monotherapy. 
             However, carbamazepine has been recommended as the drug of
             choice in women at risk of pregnancy who require
             anticonvulsant therapy for the first time (Briggs et al.,
             1986).

        7.5  Mutagenicity

             Bacterial and mammalian mutagenicity studies using
             carbamazepine have shown no evidence of mutagenicity.

        7.6  Interactions

             Antibacterials
    
             Co-administration of isoniazid or erythromycin can cause
             significant increases in serum carbamazepine concentrations
             and lead to toxicity (Valsalan & Cooper, 1982; Wright et al.,
             1982; Wong et al., 1983; Mitsch, 1989).
    
             Antidepressants
    
             Co-adminstration of fluoxetine or fluvoxamine may result in
             reduced serum carbamazepine concentrations (Pearson, 1990;
             Fritz et al., 1991).  Serotonin syndrome has been reported
             with co-administration of carbamazepine and fluoxetine
             (Brœsen & Kragh-Sœrensen, 1993).  Severe neurotoxicity has
             been associated with co-administration of carbamazepine and
             lithium (Andrus, 1984; Chaudry & Waters, 1983).  
    
             Carbamazepine is chemically related to the tricyclic
             antidepressants and should not be given to patients who are
             sensitive to these drugs.
    

             Antiepileptics
    
             Phenytoin lowers serum carbamazepine by induction of
             metabolism (Christiansen & Dam, 1973).  Carbamazepine may in
             turn lower serum phenytoin concentrations (Hansen et al.,
             1971).  Phenobarbitone reduces serum concentrations of
             carbamazepine without loss of seizure control (Cereghino et
             al., 1975).
    
             Benzodiazepines
    
             Long-term carbamazepine therapy may result in enhanced
             metabolism of benzodiazepines due to enzyme induction
             (Dhillon & Richens, 1981; Lai et al., 1978).
    
             Calcium channel blockers
    
             Verapamil and diltiazem can inhibit carbamazepine metabolism
             to such an extent so as to result in clinical neurotoxicity
             (Macphee et al., 1986; Brodie & Macphee, 1986).

        7.7  Main adverse effects

             The adverse effects that occur most frequently during
             early treatment are dizziness, drowsiness, lightheadedness,
             unsteadiness, ataxia, nystagmus, nausea, and vomiting.  Their
             severity and incidence may be minimised by starting therapy
             with a low dose which is then gradually increased.
    
             The most severe adverse reactions involve the haemopoietic
             system, the skin, and the cardiovascular system.  They
             are:

             Haemopoietic system
             Leucocytosis, leucopenia, agranulocytosis, eosinophilia,
             purpura, aplastic anaemia, and thrombocytopenia.  These
             reactions are rare but can be serious.  Early detection of
             haematological toxicity is very important because aplastic
             anaemia and thrombocytopenia can be fatal. 
    
             Skin
    
             Pruritic and erythematous rashes, urticaria, Stevens-Johnson
             syndrome, exfoliative dermatitis, erythema multiforme or
             erythema nodosum, photosensitivity reactions, alterations in
             pigmentation, and aggravation of systemic lupus
             erythematous.
    
             Alopecia, diaphoresis, and toxic epidermal necrolysis may
             also occur.
    

             Cardiovascular system
    
             Congestive heart failure, oedema, aggravation of
             hypertension, hypotension, syncope and collapse, primary and
             recurrent thrombophlebitis, aggravation of coronary artery
             disease, arrhythmias and AV block, hyponatraemia and water
             intoxication.
    
             Other
    
             Genitourinary, metabolic, hepatic, and other reactions are
             rare.  They include lymphadenopathy, urinary frequency, acute
             urinary retention, albuminuria, glycosuria, elevated blood
             urea nitrogen level, microscopic deposits in the urine,
             impotence, cholestatic and hepatocellular jaundice, fever and
             chills, myalgia and arthralgia, leg cramps, conjunctivitis,
             and paraesthesiae. 
    
             (Reynolds, 1996)

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological analyses and their interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple qualitative test(s)

                    8.2.1.2  Advanced qualitative confirmation test(s)

                    8.2.1.3  Simple quantitative method(s)

                    8.2.1.4  Advanced quantitative method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple qualitative test(s)

                    8.2.2.2  Advanced qualitative confirmation test(s)

                    8.2.2.3  Simple quantitative method(s)

                    8.2.2.4  Advanced quantitative method(s)

                    8.2.2.5  Other dedicated method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Plasma carbamazepine concentration. 
                             This should be repeated at regular intervals
                             until it is falling.
    
                             Serum electrolytes.
                             Renal function tests.

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

                    Arterial blood gases in the ventilated patient
                    or where pulmonary aspiration is suspected.

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

                    In general the peak plasma carbamazepine
                    concentration correlates well with the clinical
                    severity of the poisoning.  The peak concentration may
                    be delayed up to 30 hours.  A single plasma
                    carbamazepine concentration may not correlate very
                    well with the severity of intoxication.
    
                    Therapeutic plasma levels of carbamazepine are from 4
                    to 10 mg/L.  Acute ingestion of greater than 10 mg/kg
                    can produce a plasma level above this range.
    
                    Ataxia and nystagmus may occur with levels greater
                    than 12 mg/L
    
                    In one series of adult admissions, a peak plasma
                    carbamazepine concentration above 170 mmol/L (40 mg/L)
                    was associate with an increased risk of serious
                    complications such as coma, seizures, respiratory
                    failure and cardiac conduction defects.  In those
                    patients with a peak concentration less than  170
                    mcmol/L, only one was comatose and none had any of the
                    other severe symptoms (Hojer et al., 1993).
    
                    Peak plasma carbamazepine concentrations have been
                    reported as ranging from 13.5 to 57.7 mg/L (57 to 244
                    mmol/L) in symptomatic children (Macnab et al., 1993). 
                    In ten severely poisoning children (coma, convulsions,
                    hypotension and respiratory depression), the mean
                    plasma carbamazepine concentration was 50 mg/L (213
                    mmol/L) with a range of from 333.7 to 80.9 mg/L (143
                    to 343 mmol/L) ( Tibbals, 1992).

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

             A chest x-ray in indicated where there is coma or
             convulsions have occurred to look for evidence of pulmonary
             aspiration.

        8.5  Overall Interpretation of all toxicological analyses and
             toxicological investigations

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The first signs of acute intoxication begin 1
                    to 3 hours after an overdose but may be delayed;
                    presenting symptoms usually include disturbances of
                    the central nervous system, and cardiovascular and,
                    less frequently, anticholinergic signs and symptoms.

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Not relevant.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Effects of chronic intoxication include: 
                    dizziness, drowsiness, and disturbances of cerebellar
                    and oculomotor function (ataxia, nystagmus, and
                    diplopia), cardiac arrhythmias, congestive heart
                    failure (rarely), bone marrow failure including
                    aplastic anaemia, cholestatic and hepatocellular
                    jaundice, dermatological reactions, 
                    tubulo-interstitial nephritis, water retention, and
                    hyponatraemia.

             9.2.2  Inhalation

                    Not relevant.

             9.2.3  Skin exposure

                    Not relevant.

             9.2.4  Eye contact

                    Not relevant.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Following overdose, peak plasma carbamazepine
             concentrations and clinical effects are usually delayed by 4
             to 8 hours and may be delayed up to 24 hours.  The degree of
             CNS depression is characteristically "cyclical" with sudden
             improvements and deteriorations.
    
             Severe intoxication is characterised by one or more of the
             following features: coma, seizures, hypotension, or cardiac
             conduction defects.
    
             Moderate intoxication is characterized by a depression in the
             level of consciousness not required intubation and without
             other severe effects.
    
             Minor intoxications may be asymptomatic or exhibit the
             following features: minor drowsiness, nystagmus, ataxia or
             dysarthria.
    
             The prognosis for carbamazepine poisoning is usually good
             even for severe cases provided that appropriate supportive
             care is instituted in a timely fashion.  Where death does
             occur, it is not usually a direct result of carbamazepine
             poisoning but secondary to being pulmonary aspiration of
             gastric contents occuring during convulsions (Bates et al.,
             1997).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    After acute ingestion, sinus tachycardia is
                    relatively common.  Minor ECG abnormalities, including
                    prolongation of the PR, QRS and QT intervals, are less
                    common, do not correlate with serum carbamazepine
                    concentration and rarely result in clinically
                    significant dysrhythmias.  Mild self-limiting
                    hypotension may be observed (Apfelbaum et al., 1995). 
                    Minor ECG abnormalities may also occur in the context
                    of chronic carbamazepine therapy.

             9.4.2  Respiratory

                    Severe acute intoxication leads to coma with
                    associated respiratory depression.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             The most prominent feature of
                             carbamazepine toxicity is depression in the
                             level of consciousness.  In one series, this
                             was observed in 100% of cases (Seymour,
                             1993).  Fluctuation in the level of
                             consciousness with sudden deterioration or
                             improvement is said to be characteristic and
                             may reflect irregular absorption or
                             enterohepatic circulation of carbamazepine
                             (Durelli et al., 1989)  Other observed
                             neurological features include paradoxical
                             seizures, mydriasis, abnormal muscle tone and
                             tendon reflexes, ataxia, nystagmus and
                             ophthalmoplegia (Seymour 1993).
    
                             Chronic carbamazepine intoxication can result
                             in headaches, diplopia and ataxia.

                    9.4.3.2  Peripheral nervous system

                             No significant effects.

                    9.4.3.3  Autonomic nervous system

                             Antimuscarinic effects especially
                             sinus tachycardia are frequently
                             observed.

                    9.4.3.4  Skeletal and smooth muscle

                             No significant effects.

             9.4.4  Gastrointestinal

                    Nausea and vomiting are common features of
                    acute toxicity.  Acute pancreatitis is described
                    following overdose (Tsao & Wright, 1993). 
    
                    Chronic ingestion can cause dry mouth, gastric
                    distress, abdominal pain, nausea, vomiting, and
                    anorexia.

             9.4.5  Hepatic

                    Transient hepatic dysfunction is described
                    following acute overdose (Seymour, 1993).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Acute intoxication can cause urinary
                             retention.

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    High concentrations of carbamazepine can
                    stimulate vasopression secretion and lead to
                    hyponatraemia (Syndrome of inappropriate antidiuretic
                    hormone secretion - SIADH) (Gandelman, 1994). 

             9.4.8  Dermatological

                    No significant effects.

             9.4.9  Eye, ear, nose, throat: local effects

                    No significant effects

             9.4.10 Haematological

                    No significant effects with acute poisoning.
                    Dose-related leukopenia has been reported as a chronic
                    effect.

             9.4.11 Immunological

                    No significant effects.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No significant effects.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hyponatraemia

                    9.4.12.3 Others

                             Hypothermia is reported after acute
                             overdose (Weaver et al., 1988).

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy: Carbamazepine is classified as
                    category "C".  That is to say, studies in animals have
                    revealed adverse effects on the fetus but there are no
                    controlled studies in women.  Minor malformations such
                    as those seen with fetal hydantoin syndrome have been
                    observed with carbamazepine monotherapy.  However,
                    carbamazepine has been recommended as the drug of
                    choice in women at risk of pregnancy who require
                    anticonvulsant therapy for the first time (Briggs et
                    al, 1986).
    
                    Breast-feeding: Carbamazepine's safety when used
                    during lactation has not been established.  The
                    concentration of carbamazepine in the milk is
                    approximately 60% of maternal plasma concentration. 
                    Either breast-feeding or carbamazepine should be
                    discontinued, depending on the importance of the drug
                    for the woman (Reynolds, 1996).
    
                    Porphyria: A study in rats showed that carbamazepine
                    should be regarded as potentially hazardous in people
                    who have hereditary hepatic porphyria (Reynolds,1989).

        9.5  Other

             No data available.

             9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The management of carbamazepine toxicity is essentially
             supportive. In severe cases, this may require endotracheal
             intubation and ventilation.

        10.2 Life supportive procedures and symptomatic/specific treatment

             The major threat to life is from a decreased level of
             consciousness and inadequate ventilation.
    
             The patient should be immediately assessed for adequacy of
             airway, breathing and circulation, and level of
             consciousness. The airway should be secured by endotracheal
             intubation if necessary. Supplemental oxygen should be
             provided. Intravenous access should be established. Vital
             signs, level of consciousness and cardiac rhythm should be
             carefully monitored.
    
             Seizures, hypotension, hyponatraemia, hypothermia should be
             managed according to standard guidelines.

        10.3 Decontamination

             Administer oral or nasogastric activated charcoal as
             soon as possible once the airway is deemed adequate or
             secured.

        10.4 Enhanced elimination

             Repeat-dose activated charcoal is the method of choice
             to enhance elimination of carbamazepine. A dose of 25 to 50 g
             of activated charcoal should be adminstered by nasogastric
             tube every 3 to 4 hours until clinical improvement occurs.
             
    
             Although charcoal haemoperfusion has been used to enhance the
             elimination of carbamazepine, repeat-dose actived charcoal
             appears to be at least as effective and is a much less
             invasive therapy (Vale, 1992).  It is important to note that,
             although repeat dose activated charcoal has been should to
             significantly enhance the elimination of carbamazepine, this
             has not been shown to associated with a more rapid clinical
             recovery (Wason et al., 1992)

        10.5 Antidote treatment

             10.5.1 Adults

                    There is no antidote.

             10.5.2 Children

                    There is no antidote.

        10.6 Management discussion

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A 23-year-old woman with epilepsy developed superficial
             coma, tachycardia, hypothermia, irregular respiration and
             dilated pupils after she ingested 16,000 mg carbamazepine. 
             Gastric lavage was performed.  However, 45 hours after she
             was admitted to hospital, her coma deepened and her
             respiration became more irregular.  Delayed absorption of
             carbamazepine from the gut, with an increase in serum
             carbamazepine concentration, probably accounts for these
             findings.  Following treatment with activated charcoal,
             sodium sulphate, forced diuresis (with sorbitol and
             mannitol), and metoclopramide, she recovered 100 hours after
             hospital admission (De Zeeuw et al., 1979).
    
             A 21-year-old man developed coma, respiratory depression,
             increased central venous pressure, hypotension and nodal
             tachycardia after he ingested 40 000 mg carbamazepine, with
             an unknown amount of lithium citrate.  Gastric lavage was
             successful and he was given IV fluids, diazepam, and
             phenobarbital.  Forty-five hours after ingestion, he
             developed fixed mydriasis and hypotonia.  He was treated with
             corticosteroids, diuretics, and hyperventilation, and 16
             hours later his pupils reacted increasingly to light.  He was
             extubated 24 hours later, and 2 days later he was conscious
             (Wernberg et al., 1982).
    
             A 23-month-old healthy boy (13.5 kg body weight) developed an
             unsteady gait after he ingested 2000 mg carbamazepine (148
             mg/kg) and was admitted to hospital 3 hours later.  His vital
             signs were normal but he was lethargic and ataxic and his
             pupils were moderately dilated.  He was given ipecac syrup
             but when he vomited, his vomitus did not contain pill
             fragments.  He was then given activated charcoal and
             magnesium sulphate.  He went into a deep coma 9 hours
             post-ingestion.  Fifteen hours after ingestion his vital
             signs were: blood pressure, 110/76 mmHg; pulse, 108 bpm;

             respiration, 24/minute; and temperature 36.4°C.  He was given
             multiple doses of activated charcoal and sodium sulphate. 
             Twenty-six hours after ingestion he had 3 episodes of
             tonic-clonic generalized seizures that were treated with
             diazepam 5 mg intravenous (IV).  The patient recovered
             completely in a few days, and there were no sequelae six
             months later (Deng et al., 1986).
    
             A 41-year-old woman was given erythromycin stearate (500 mg
             every 6 hours) while she was being treated with carbamazepine
             and phenobarbital (100 mg, 4 times a day).  This combination
             caused carbamazepine toxicity, with inappropriate ADH
             secretion, dizziness, nystagmus, and ataxia.  One week after
             receiving erythromycin, her blood levels increased from 13.3
             mg/L to 28.2 mg/L.  Twenty-four hours after all medication
             was stopped, her carbamazepine levels fell to 5.9 mg/L. 
             Carbamazepine and phenobarbital were then resumed, and her
             carbamazepine levels rose to 10.8 mg/L after 24 hours and to
             11.3 mg/L after three weeks (Carranco et al., 1985).
    
             A 22-year-old healthy male ingested an overdose of
             carbamazepine.  He had an initial period of restlessness and
             aggression.  He then became stuporous and was admitted to
             hospital in a coma.  His vital signs were normal.  Gastric
             lavage was performed and he was given 30 g sodium sulphate
             and a suspension of 50 g activated charcoal.  Haemoperfusion
             was performed for 4 hours, reducing the half-life and
             successfully enhancing the elimination of carbamazepine
             (Groot et al., 1984).
    
             A 45-year-old epileptic woman who had been receiving
             long-term therapy with carbamazepine, valproic acid, and
             phenytoin, ingested a carbamazepine overdose.  When she
             arrived at hospital, she was stuporous and had motor
             restlessness.  Her heart rate was 90 bpm, blood pressure
             140/80 mmHg, and temperature 35.0°C.  Eight hours later she
             was in a coma, her blood pressure was 90/50 mmHg, and her
             temperature 34.3°C.  Gastric lavage was performed and she was
             given activated charcoal and sodium sulphate.  Haemoperfusion
             for 4 hours, slowly decreased the plasma concentration of
             carbamazepine. Her condition steadily improved (Groot et al.,
             1984).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Therapy with carbamazepine should begin at low doses
             and be increased gradually until the patient responds.
    

             Special care should be taken when carbamazepine is
             administered in addition to other anticonvulsant therapy, or
             when the patient requires other medications because drug
             interactions can occur.

        12.2 Other

             No data available.

    13. REFERENCES

        Abrantes J & Marques Penha J (1986).  Therapeutic arsenal in
        clinical toxicology, Emergência Médica, II (6): 9-17 (in
        Portuguese).
    
        Andrus PF (1984) Lithium and carbamazepine.  J Clin Psychiatry
        45:525
    
        Bates N, Edwards N, Roper J & Volans G (eds) (1997)  Paediatric
        Toxicology.  Handbook of Poisoning in Children.  Macmillan
        Reference Ltd., London, U.K.
    
        Beerman B, Edhag O, Vallin H (1975).  Advanced heart block
        aggravated by carbamazepine, Br Heart J 37: 668.
    
        Borges A (1986).  The use of ipecac syrup and activated charcoal
        in toxicology, Emergência Médica, II (6): 4-7 (in Portuguese).
    
        Briggs GG, Freeman RM & Yaffe  SJ (1986).  Drugs in Pregnancy and
        Lactation.  2nd Ed Williams & Wilkins, Baltimore, Maryland.
    
        Brodie MJ & Macphee GJA (1986)  Carbamazepine neurotoxicity
        precipitated by diltiazem.  Brit Med J 292:1170-1.
    
        Brœsen K & Kragh-Sœrensen P (1993) Concomitant intake of
        nortriptyline and carbamazepine.   Ther Drug Monit 15:258-60.
    
        Budavari S (ed) (1996)  The Merck Index.  An encyclopedia of
        chemicals, drugs and biologicals. 12th Ed.  Merck & Co. Inc.
        Whitehouse Station, New Jersey.
    
        Carranco E, Kareus J, Shenley C et al. (1985).  Carbamazepine
        toxicity induced by concurrent erythromycin therapy. Arch Neurol.
        42: 187 - 188.
    
        Cereghino JJ et al.  (1975)  The efficacy of carbamazepine
        combination in epilepsy.  Clin Pharmacol Ther 18:733-41.
    
        Chaudry RP & Waters BGH (1983)  Lithium and carbamazepine
        interaction: possible neurotoxicity.  J Clin Psychiatry 44:30.
    

        De Zeeuw RA, Westenberg HGM, Klein E van der, Gimbrere JSF 
        (1979).  An unusual case of Carbamazepine Poisoning with a
        near-fatal relapse after two days. Clinical Toxicology l4:
        263-269. 
    
        Deng JF, Shipe Jr JR, Donowitz L & Spyker DA (1986). 
        Carbamazepine Toxicity:  Comparison of measurement of drug levels
        by HPLC and Emit and Model of carbamazepine Kinetics. Journal of
        Toxicology and Clinical Toxicology 24: 281- 294.
    
        Dhillon S & Richens A (1981)  Pharmacokinetics of diazepam in
        epileptic patients and normal volunteers following intravenous
        administration.  Brit J Clin Pharmacol 12:841-4.
    
        Drug Facts and Comparisons (1985).  Philadelphia, JB Lippincott
        Company.
    
        Durelli L, Massazza V & Cavallo R (1989)  Carbamazepine toxicity
        and poisoning.  Incidence, clinical features and managment.  Med
        Toxicol Adv Drug Experience 4:95-107.
    
        Fritz J et al. (1991) Interaction between carbamazepine and
        fluvoxamine.  Acta Psychiatr Scand 84:583-4.
    
        Gandelman MS (1994)  Review of carbamazepine-induced
        hyponatraemia.  Prog Neuropsychopharmacol Biol Psychiatry 
        18:211-33.
    
        Groot G, Heijst ANP & Maes RAA (1984).  Charcoal Haemoperfusion in
        the treatment of two cases of acute carbamazepine poisoning.
        Journal of Toxicology and Clinical Toxicology 22: 349-362.
    
        Hansen JM et al. (1971)  Carbamazepine-induced acceleration of
        diphenylhydantoin and warfarin metabolism in man. Clin Pharmacol
        Ther 12:539-43.
    
        Hojer J, Malmlund HO & Berg A (1993)  Clinical features in 28
        consecutive cases of laboratory confirmed massive poisoning with
        carbamazepine alone.  J Toxicol Clin Toxicol 31:449-58.
    
        Index Nominum (1992/93).  Repertoire des Substances
        médicamenteuses, Zurich, Centre Scientifique de la Société Suisse
        de Pharmacie.
    
        Laffey SH & Guzzardi LJ (1983).  "Phenytoin and other
        anticonvulsants" in Haddad LM & Winchester JF ed. Clinical
        Management of Poisoning and Drug Overdose. USA, Saunders  Co.
    
        Lai AA et al. (1978)  Time course of interaction between
        carbamazepine and clonazepam in normal man. Clin Pharmacol Ther
        24:316-23.
    

        Lehrman SN, Bauman ML (198l).  Carbamazepine overdose. Am J Dis
        Child 135: 768.
        London, Pharmaceutical Press, 368-372.
    
        Macnab WJ et al. (1993)  Carbamazepine poisoning in children. 
        Pediatr Emerg Care 9:195-8.
    
        Macphee GJA et al.  (1986)  Verapamil potentiates carbamazepine
        neurotoxicity: a clinically important inhibitory interaction. 
        Lancet i:700-3.
    
        Mitsch RA (1989)  Carbamazepine toxicity precipitated by
        intravenous erythromycin.  Drug Intell Clin Pharm 23:878-9.
    
        Morant J & Ruppaner H (1997) Compendium Suisse des Médicaments,
        18eme ed, Documed, Bâle, CH.
    
        PDR - Physicians' Desk Reference (1988), USA Medical Economics
        Company.
    
        Pearson HJ (1990) Interaction of fluoxetine with carbamazepine.  J
        Clin Psychiatry 51:126.
    
        Rall TW & Schleifer LS (1985).  Drugs effective in the therapy of
        the Epilepsies - Iminostilbenes, in: Goodman and Gilman's The
        Pharmacological Basis of Therapeutics. New York, MacMillan
        Publishing Co., Inc.
    
        Rane A, Hojer B, Wilson JT (1976).  Kinetics of carbamazepine and
        its 10,11-epoxide metabolite in children.  Clin Pharmacol Ther 19:
        276-283.
    
        Reynolds JEF (ed) (1996) Martindale, The Extra Pharmacopoeia,
        31st edition
    
        Rosa FW (1991). Spina bifida in infants of women treated with
        carbamazepine during pregnancy. New Engl. J Med. 324: 
        674 - 677.
    
        Salcman M, Pippenger CE (1975).  Acute carbamazepine
        encephalopathy. J Am Med Assoc 231: 915.
    
        Stevens WP (1977).  Water intoxication due to carbamazepine, Br
        Med J 1: 754.
    
        Tibbals J (1992) Acute toxic reation to carbamazepine: clinical
        effects and serum concentrations.  J Pediatr 121:295-9.
    
        Tsao CY & Wright FS (1993) Acute chemical pancreatitis associated
        with carbamazepine intoxication.  Epilepsia 34:174-6.
    

        Valsalan VC & Cooper GL (1982)  Carbamazepine intoxication caused
        by interaction with isoniazid.  Br Med J 285:261-2.
    
        Weaver DF, Camfield P & Frazer A (1988)  Massive carbamazepine
        overdose: clinical and pharmacologic observation in five episodes. 
        Neurology 38:755-9.
    
        Wernberg M, Peterson TK & Kristensar HK (1982).  Carbamazepine
        poisoning. Ugeskt Laeg l43: 619-620 (in German).
    
        Westenberg HGM, Klein E van der, Oei TT, Zeeuw RA de (1978). 
        Kinetics of carbamazepine and carbamazepine epoxide determined by
        use of plasma and saliva.  Clin Pharmacol Ther 23: 320-328.
    
        Wong YY et al.  (1983)  Effect of erythomycin on carbamazepine
        kinetics.  Clin Pharmacol Ther 33:460-4.
    
        Wright JM et al.  (1982) Isoniazid-induced carbamazepine toxicity
        and vice versa.  N Engl J Med 307:1325-7.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Authors:    Arlinda Borges, J. Bivar Abrantes, J. Marques Penha,
                    P. Paiva Parada, M. Teresa Teixeira, Teresa M. Pinto
                    Centro de Informaçao Antivenénos
                    Instituto Nacional de Emergencia Médica
                    Rua Infante D Pedro, 8
                    1700 Lisbon
                    Portugal
    
                    Tel:     7930503
                    Fax:     7937124
                    Telex:   13304 SNALP P
    
        Date:       February 1988
    
        Reviewer:   Dr J. Pronczuk
                    CIAT, 7° piso
                    Hospital de Clinicas
                    Av. Italia s/n
                    Montevideo
                    Uruguay
    
        Date:       July 1988
    
        Peer
        review:     Adelaide, Australia, April 1991
    
        Update:     Dr R. Fernando, June 1993
    

        Update/edit: Dr M.O. Rambourg-Schepens & Dr L. Murray
    
        Date:        November 1999
    


    
Clobazam
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    Clobazam

    International Programme on Chemical Safety
    Poisons Information Monograph 921
    Pharmaceutical

    This monograph does not contain all of the sections completed. This
    mongraph is harmonised with the Group monograph on Benzodiazepines
    (PIM G008).

    1.  NAME

        1.1  Substance

             Clobazam

        1.2  Group

             ATC classification index

             Psycholeptics (N05)/  Anxiolytics (N05B)/
             Benzodiazepine derivatives (N05BA)

        1.3  Synonyms

             H-4723; HR-376; LM-2717

        1.4  Identification numbers

             1.4.1  CAS number

                    22316-47-8

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Central nervous system, causing depression of
             respiration and consciousness.

        2.2  Summary of clinical effects

             Central nervous system (CNS) depression and coma, or
             paradoxical excitation, but deaths are rare when
             benzodiazepines are taken alone. Deep coma and other
             manifestations of severe CNS depression are rare. Sedation,
             somnolence, diplopia, dysarthria, ataxia and intellectual

             impairment are the most common adverse effects of
             benzodiazepines. Overdose in adults frequently involves co-
             ingestion of other CNS depressants, which act synergistically
             to increase toxicity. Elderly and very young children are
             more susceptible to the CNS depressant action. Intravenous
             administration of even therapeutic doses of benzodiazepines
             may produce apnoea and hypotension.
             Dependence may develop with regular use of benzodiazepines,
             even in therapeutic doses for short periods. If
             benzodiazepines are discontinued abruptly after regular use,
             withdrawal symptoms may develop.  The amnesia produced by
             benzodiazepines can have medico-legal consequences.

        2.3  Diagnosis

             The clinical diagnosis is based upon the history of
             benzodiazepine overdose and the presence of the clinical
             signs of benzodiazepine intoxication.
             Benzodiazepines can be detected or measured in blood and
             urine using standard analytical methods. This information may
             confirm the diagnosis but is not useful in the clinical
             management of the patient.
             A clinical response to flumazenil, a specific benzodiazepine
             antagonist, also confirms the diagnosis of benzodiazepine
             overdose, but administration of this drug is rarely
             justified.

        2.4  First aid measures and management principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly involve co-
             ingestion of other CNS depressants and other drugs. Activated
             charcoal normally provides adequate gastrointestinal
             decontamination. Gastric lavage is not routinely indicated.
             Emesis is contraindicated. The use of flumazenil is reserved
             for cases with severe respiratory or cardiovascular
             complications and should not replace the basic management of
             the airway and respiration. The routine use of flumazenil is
             contraindicated because of potential complications, including
             seizures.  Renal and extracorporeal methods of enhanced
             elimination are not effective.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical Name:
             7-Chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-
             -2,4(3H)-dione
    

             Molecular Formula: C16H13ClN2O2
    
             Molecular Weight: 300.7

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Very slightly soluble in water; soluble in
                    alcohol and in methyl alcohol. A 1% suspension in
                    water has a pH of 5.5 to 7.5 (Reynolds, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

    4.  USES

        4.1  Indications
             4.1.1  Indications
             4.1.2  Description
        4.2  Therapeutic dosage
             4.2.1  Adults
             4.2.2  Children
        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral
        5.2  Inhalation
        5.3  Dermal
        5.4  Eye
        5.5  Parenteral
        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure
        6.2  Distribution by route of exposure
        6.3  Biological half-life by route of exposure
        6.4  Metabolism
        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action
             7.1.1  Toxicodynamics
             7.1.2  Pharmacodynamics
        7.2  Toxicity
             7.2.1  Human data
                    7.2.1.1  Adults
                    7.2.1.2  Children
             7.2.2  Relevant animal data
             7.2.3  Relevant in vitro data
        7.3  Carcinogenicity
        7.4  Teratogenicity
        7.5  Mutagenicity
        7.6  Interactions
        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
                    8.1.1.1  Toxicological analyses
                    8.1.1.2  Biomedical analyses
                    8.1.1.3  Arterial blood gas analysis
                    8.1.1.4  Haematological analyses
                    8.1.1.5  Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
                    8.1.2.1  Toxicological analyses
                    8.1.2.2  Biomedical analyses
                    8.1.2.3  Arterial blood gas analysis
                    8.1.2.4  Haematological analyses
                    8.1.2.5  Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
                    8.1.3.1  Toxicological analyses
                    8.1.3.2  Biomedical analyses
                    8.1.3.3  Arterial blood gas analysis
                    8.1.3.4  Haematological analyses
                    8.1.3.5  Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
                    8.2.1.1  Simple Qualitative Test(s)
                    8.2.1.2  Advanced Qualitative Confirmation Test(s)
                    8.2.1.3  Simple Quantitative Method(s)
                    8.2.1.4  Advanced Quantitative Method(s)
             8.2.2  Tests for biological specimens
                    8.2.2.1  Simple Qualitative Test(s)
                    8.2.2.2  Advanced Qualitative Confirmation Test(s)
                    8.2.2.3  Simple Quantitative Method(s)
                    8.2.2.4  Advanced Quantitative Method(s)
                    8.2.2.5  Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
                    8.3.1.1  Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.3  Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"
             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             For toxicological analyses: whole blood 10 mL; urine 25 mL
             and gastric contents 25 mL.
    
             Biomedical analysis
             Blood gases, serum electrolytes, blood glucose and hepatic
             enzymes when necessary in severe cases.
    
             Toxicological analysis
             Qualitative testing for benzodiazepines is helpful to confirm
             their presence, but quantitative levels are not clinically
             useful. More advanced analyses are not necessary for the
             treatment of the poisoned patient due the lack of correlation
             between blood concentrations and clinical severity (Jatlow et
             al., 1979; MacCormick et al., 1985; Minder, 1989).
    
             TLC and EMIT: These provide data on the presence of
             benzodiazepines, their metabolites and possible associations
             with other drugs.
    
             GC or HPLC: These permit identification and quantification of
             the benzodiazepine which caused the poisoning and its
             metabolites in blood and urine.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The onset of impairment of consciousness is
                    relatively rapid in benzodiazepine poisoning.  Onset
                    is more rapid following larger doses and with agents
                    of shorter duration of action. The most common and
                    initial symptom is somnolence.  This may progress to
                    coma Grade I or Grade II (see below) following very
                    large ingestions.
    
                    Reed Classification of Coma (Reed et al., 1952)
    
                    Coma Grade I:   Depressed level of consciousness,
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade III: Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes absent. Vital
                                    signs intact
    
                    Coma Grade IV:  Coma grade III plus respiratory and
                                    circulatory collapse

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    Overdose by the intravenous route results in
                    symptoms similar to those associated with ingestion,
                    but they appear immediately after the infusion, and
                    the progression of central nervous system (CNS)
                    depression is more rapid. Acute intentional poisoning

                    by this route is uncommon and most cases are
                    iatrogenic. Rapid intravenous infusion may cause
                    hypotension, respiratory depression and
                    apnoea.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxic effects associated with chronic exposure
                    are secondary to the presence of the drug and
                    metabolites and include depressed mental status,
                    ataxia, vertigo, dizziness, fatigue, impaired motor
                    co-ordination, confusion, disorientation and
                    anterograde amnesia. Paradoxical effects of
                    psychomotor excitation, delirium and aggressiveness
                    also occur. These chronic effects are more common in
                    the elderly, children and patients with renal or
                    hepatic disease.
    
                    Administration of therapeutic doses of benzodiazepines
                    for 6 weeks or longer can result in physical
                    dependence, characterized by a withdrawal syndrome
                    when the drug is discontinued. With larger doses, the
                    physical dependence develops more rapidly.

             9.2.2  Inhalation

                    No data.

             9.2.3  Skin exposure

                    No data.

             9.2.4  Eye contact

                    No data.

             9.2.5  Parenteral exposure

                    The chronic parenteral administration of
                    benzodiazepines may produce thrombophlebitis and
                    tissue irritation, in addition to the usual symptoms
                    (Greenblat & Koch-Weser, 1973).

             9.2.6  Other

                    No data.

        9.3  Course, prognosis, cause of death

             Benzodiazepines are relatively safe drugs even in
             overdose. The clinical course is determined by the
             progression of the neurological symptoms. Deep coma or other
             manifestations of severe central nervous system (CNS)
             depression are rare with benzodiazepines alone.  Concomitant
             ingestion of other CNS depressants may result in a more
             severe CNS depression of longer duration.
    
             The therapeutic index of the benzodiazepines is high and the
             mortality rate associated with poisoning due to
             benzodiazepines alone is very low. Complications in severe
             poisoning include respiratory depression and aspiration
             pneumonia. Death is due to respiratory arrest.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, bradycardia and tachycardia have
                    been reported with overdose (Greenblatt et al., 1977;
                    Meredith & Vale 1985). Hypotension is more frequent
                    when benzodiazepines are ingested in association with
                    other drugs (Hojer et al., 1989). Rapid intravenous
                    injection is also associated with hypotension.

             9.4.2  Respiratory

                    Respiratory depression may occur in
                    benzodiazepine overdose and the severity depends on
                    dose ingested, amount absorbed, type of benzodiazepine
                    and co-ingestants. Respiratory depression requiring
                    ventilatory support has occurred in benzodiazepine
                    overdoses (Sullivan, 1989; Hojer et al.,1989). The
                    dose-response for respiratory depression varies
                    between individuals.  Respiratory depression or
                    respiratory arrest may rarely occur with therapeutic
                    doses. Benzodiazepines may affect the control of
                    ventilation during sleep and may worsen sleep apnoea
                    or other sleep-related breathing disorders, especially
                    in patients with chronic obstructive pulmonary disease
                    or cardiac failure (Guilleminault, 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             CNS depression is less marked than
                             that produced by other CNS depressant agents
                             (Meredith & Vale, 1985). Even in large
                             overdoses, benzodiazepines usually produce
                             only mild symptoms and this distinguishes

                             them from other sedative-hypnotic agents.
                             Sedation, somnolence, weakness, diplopia,
                             dysarthria, ataxia and intellectual
                             impairment are the most common neurological
                             effects. The clinical effects of severe
                             poisoning are sleepiness, ataxia and coma
                             Grade I to Grade II (Reed). The presence of
                             more severe coma suggests the possibility of
                             co-ingested drugs. Certain of the newer
                             short-acting benzodiazepines (temazepam,
                             alprazolam and triazolam) have been
                             associated with several fatalities and it is
                             possible that they may have greater acute
                             toxicity (Forrest et al., 1986). The elderly
                             and very young children are more susceptible
                             to the CNS depressant action of
                             benzodiazepines.
                             The benzodiazepines may cause paradoxical CNS
                             effects, including excitement, delirium and
                             hallucinations. Triazolam has been reported
                             to produce delirium, toxic psychosis, memory
                             impairment and transient global amnesia
                             (Shader & Dimascio, 1970; Bixler et al,
                             1991). Flurazepam has been associated with
                             nightmares and hallucinations.
                             There are a few reports of extrapyramidal
                             symptoms and dyskinesias in patients taking
                             benzodiazepines (Kaplan & Murkafsky, 1978;
                             Sandyk, 1986).
                             The muscle relaxation caused by
                             benzodiazepines is of CNS origin and
                             manifests as dysarthria, incoordination and
                             difficulty standing and walking.

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

                    Oral benzodiazepine poisoning will produce
                    minimal effects on the gastrointestinal tract (GI)
                    tract but can occasionally cause nausea or vomiting
                    (Shader & Dimascio, 1970).

             9.4.5  Hepatic

                    A case of cholestatic jaundice due focal
                    hepatic necrosis was associated with the
                    administration of diazepam (Tedesco & Mills,
                    1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Vesical hypotonia and urinary
                             retention has been reported in association
                             with diazepam poisoning (Chadduck et al.,
                             1973).

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    Galactorrhoea with normal serum prolactin
                    concentrations has been noted in 4 women taking
                    benzodiazepines (Kleinberg et al., 1977).
                    Gynaecomastia has been reported in men taking high
                    doses of diazepam (Moerck & Majelung, 1979). Raised
                    serum concentrations of oestrodiol were observed in
                    men taking diazepam 10 to 20 mg daily for 2 weeks
                    (Arguelles & Rosner, 1975).

             9.4.8  Dermatological

                    Bullae have been reported following overdose
                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                    et al., 1990).
                    Allergic skin reactions were attributed to diazepam at
                    a rate of 0.4 per 1000 patients (Brigby,
                    1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    Brown opacification of the lens occurred in 2
                    patients who used diazepam for several years (Pau
                    Braune, 1985).

             9.4.10 Haematological

                    No data.

             9.4.11 Immunological

                    Allergic reaction as above (see 9.4.8).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    Hypersensitivity reactions including
                    anaphylaxis are very rare (Brigby, 1986). Reactions
                    have been attributed to the vehicle used for some
                    parenteral diazepam formulations (Huttel et al.,
                    1980). There is also a report of a type I
                    hypersensitivity reaction to a lipid emulsion of
                    diazepam (Deardon, 1987).

             9.4.14 Other clinical effects

                    Hypothermia was reported in 15% of cases in
                    one series. (Martin, 1985; Hojer et al.,
                    1989).

             9.4.15 Special risks

                    Pregnancy
                    Passage of benzodiazepines across the placenta depends
                    on the degree of protein binding in mother and fetus,
                    which is influenced by factors such as stage of
                    pregnancy and plasma concentrations of free fatty
                    acids in mother and fetus (Lee et al., 1982). Adverse
                    effects may persist in the neonate for several days
                    after birth because of immature drug metabolising
                    enzymes. Competition between diazepam and bilirubin
                    for protein binding sites could result in
                    hyperbilirubinemia in the neonate (Notarianni,
                    1990).
                    The abuse of benzodiazepines by pregnant women can
                    cause withdrawal syndrome in the neonate. The
                    administration of benzodiazepines during childbirth
                    can produce hypotonia, hyporeflexia, hypothermia and
                    respiratory depression in the newborn.
                    Benzodiazepines have been used in pregnant patients
                    and early reports associated diazepam and
                    chlordiazepoxide with some fetal malformations, but
                    these were not supported by later studies (Laegreid et
                    al., 1987; McElhatton, 1994).
    

                    Breast feeding
                    Benzodiazepines are excreted in breast milk in
                    significant amounts and may result in lethargy and
                    poor feeding in neonates.  Benzodiazepines should be
                    avoided in nursing mothers (Brodie, 1981; Reynolds,
                    1996).

        9.5  Other

             Dependence and withdrawal
             Benzodiazepines have a significant potential for abuse and
             can cause physical and psychological dependence. Abrupt
             cessation after prolonged use causes a withdrawal syndrome
             (Ashton, 1989). The mechanism of dependence is probably
             related to functional deficiency of GABA activity.
             Withdrawal symptoms include anxiety, insomnia, headache,
             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
             weakness, perspiration, irritability, hypersensitivity to
             visual and auditory stimuli, palpitations, tachycardia and
             postural hypotension. In severe and rare cases of withdrawal
             from high doses, patients may develop affective disorders or
             motor dysfunction: seizures, psychosis, agitation, confusion,
             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
             Reynolds, 1996).
             The time of onset of the withdrawal syndrome depends on the
             half-life of the drug and its active metabolites; the
             symptoms occur earlier and may be more severe with short-
             acting benzodiazepines. Others risk factors for withdrawal
             syndrome include prolonged use of the drug, higher dosage and
             abrupt cessation of the drug.
    
             Abuse
             Benzodiazepines, particularly temazepam, have been abused
             both orally and intravenously (Stark et al., 1987; Woods,
             1987; Funderburk et al, 1988)
    
             Criminal uses
             The amnesic effects of benzodiazepines have been used for
             criminal purposes with medicolegal consequences (Ferner,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly include other
             drugs and other CNS depressants. Activated charcoal normally
             provides adequate gastrointestinal decontamination. Gastric
             lavage is not routinely indicated. Emesis is contraindicated.

             The use of flumazenil is reserved for cases with severe
             respiratory or cardiovascular complications and should not
             replace the basic management of the airway and respiration.
             Renal and extracorporeal elimination methods are not
             effective.
        10.2 Life supportive procedures and symptomatic/specific treatment

             The patient should be evaluated to determine adequacy
             of airway, breathing and circulation. Continue clinical
             observation until evidence of toxicity has resolved.
             Intravenous access should be available for administration of
             fluid. Endotracheal intubation, assisted ventilation and
             supplemental oxygen may be required on rare occasions, more
             commonly when benzodiazepines are ingested in large amounts
             or with other CNS depressants.

        10.3 Decontamination

             Gastric lavage is not routinely indicated following
             benzodiazepine overdose. Emesis is contraindicated because of
             the potential for CNS depression. Activated charcoal can be
             given orally.

        10.4 Enhanced elimination

             Methods of enhancing elimination are not
             indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Flumazenil, a specific benzodiazepine
                    antagonist at central GABA-ergic receptors is
                    available. Although it effectively reverses the CNS
                    effects of benzodiazepine overdose, its use in
                    clinical practice is rarely indicated.
                    Use of Flumazenil is specifically contraindicated when
                    there is history of co-ingestion of tricyclic
                    antidepressants or other drugs capable of producing
                    seizures (including aminophylline and cocaine),
                    benzodiazepine dependence, or in patients taking
                    benzodiazepines as an anticonvulsant agent. In such
                    situations, administration of Flumazenil may
                    precipitate seizures (Lopez, 1990; Mordel et al.,
                    1992).
                    Adverse effects associated with Flumazenil include
                    hypertension, tachycardia, anxiety, nausea, vomiting
                    and benzodiazepine withdrawal syndrome.
                    The initial intravenous dose of 0.3 to 1.0 mg may be
                    followed by further doses if necessary. The absence of
                    clinical response to 2 mg of flumazenil within 5 to 10

                    minutes indicates that benzodiazepine poisoning is not
                    the major cause of CNS depression or coma.
                    The patient regains consciousness within 15 to 30
                    seconds after injection of flumazenil, but since it is
                    metabolised more rapidly than the benzodiazepines,
                    recurrence of toxicity and CNS depression can occur
                    and the patient should be carefully monitored after
                    initial response to flumazenil therapy.  If toxicity
                    recurs, further bolus doses may be administered or an
                    infusion commenced at a dose of 0.3 to 1.0 mg/hour
                    (Meredith et al., 1993).

             10.5.2 Children

                    The initial intravenous dose of 0.1 mg should
                    be repeated each minute until the child is awake.
                    Continuous intravenous infusion should be administered
                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                    1993).

        10.6 Management discussion

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. Flumazenil is the specific
             antagonist of the effects of benzodiazepines, but the routine
             use for the treatment of benzodiazepine overdosage is not
             recommended. The use of Flumazenil should only be considered
             where severe CNS depression is observed. This situation
             rarely occurs, except in cases of mixed ingestion. The
             administration of flumazenil may improve respiratory and
             cardiovascular function enough to decrease the need for
             intubation and mechanical ventilation, but should never
             replace basic management principles.
             Flumazenil is an imidazobenzodiazepine and has been shown to
             reverse the sedative, anti-convulsant and muscle-relaxant
             effects of benzodiazepines. In controlled clinical trials,
             flumazenil significantly antagonizes benzodiazepine-induced
             coma arising from anaesthesia or acute overdose. However, the
             use of flumazenil has not been shown to reduce mortality or
             sequelae in such cases.
             The administration of flumazenil is more effective in
             reversing the effects of benzodiazepines when they are the
             only drugs producing CNS toxicity. Flumazenil does not
             reverse the CNS depressant effects of non-benzodiazepine
             drugs, including alcohol. The diagnostic use of flumazenil in
             patients presenting with coma of unknown origin can be
             justified by its high therapeutic index and the fact that
             this may limit the use of other diagnostic procedures (CT
             scan, lumbar puncture, etc).
             Flumazenil is a relatively expensive drug and this may also
             influence its use, especially in areas with limited
             resources.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

    13. REFERENCES

        Arguelles AE, & Rosner J. (1975) Diazepam and plasma
        testosterone levels. Lancet, ii: 607.
    
        Ashton CH (1989) Drug-induced stupor and coma: some physical signs
        and their pharmacological basis. Adverse drug React Acute
        Poisoning Rev, 8: 1-59.
    
        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
        (1991) Next-day memory impairment with triazolam use. Lancet, 337:
        827-831.
    
        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
        3358-63.
    
        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
        descyclopropylmethyl-prazepam in whole-blood, plasma and milk
        after administration of prazepam to humans. Biopharm Drug Dispos,
        2: 59-68.
    
        Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with
        diazepam. J Urol, 109: 1005-1007.
    
        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
        Anaesth, 59: 391.
    
        Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell
        Clin Pharm, 15: 487.
    
        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.
    
        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
        Press, Oxford.
    
        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
        temazepam overdoses (letter). Lancet, 2: 226.
    
        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
        lorazepam and diazepam: an evaluation in "recreational" drug
        users. Drug Alcohol Depend, 22: 215-222.
    

        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
        benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513.
    
        Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J
        Med, 88 (suppl 3A): 25S - 28S.
    
        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990)
        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.
    
        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
        poisoning: experience of 702 admissions to an intensive care unit
        during a 14-year period. J Intern Med, 226: 117-122.
    
        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
        mediated reactions to diazepam with Cremophor as solvent. Br J
        Anaesth, 52: 77-9.
    
        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
        Psychiatry, 134: 477-479.
    
        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
        associated with low dose benzodiazepine treatment. Am J
        Psychiatry, 135: 1558-1559.
    
        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
        235 cases. N Eng J Med 296: 589-600.
    
        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
        children exposed to benzodiazepines in utero. Lancet, 1:108-
        109.
    
        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
        protein binding of diazepam in maternal and foetal serum during
        pregnancy. Br J Clin Pharmacol, 14: 551-4.
    
        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
        after a benzodiazepine antagonist. Crit Care Med, 18:1480-
        1481.
    
        Martin SM (1985) The effect of diazepam on body temperature change
        in humans during cold exposure. J Clin Pharmacol, 25: 611-613.
    
        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
        clinical findings and serum concentrations in two cases. J Clin
        Psychiatr, 46:247-248.
    
        McElhatton PR. (1994) The effects of benzodiazepines use during
        pregnancy and lactation. Reprod Toxicol, 8: 461-75.
    
        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
        dantrolene as antidotes, 1st ed. Cambridge University Press,
        Cambridge.
    

        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
        agents. Adverse Drug React Acute Poison Rev, 4: 83-122.
    
        Minder EI (1989) Toxicity in a case of acute and massive overdose
        of chlordiazepoxide and its correlation to blood concentration.
        Clin Toxicol, 27: 117-127.
    
        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam
        abuse.Lancet, i: 1344-5.
    
        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
        after flumazenil administration in a case of combined
        benzodiazepine and tricyclic antidepressant overdose. Crit Care
        Med, 12: 1733-1734.
    
        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
        and neonates. Clin Pharnacokinet, 18: 20-36.
    
        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
        Augenheilkd, 187: 219-20 (in German).
    
        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
        intoxication. A study of 300 cases based on a physiologic system
        of classification of the severity of intoxication. Ann Intern Med,
        37: 390-396.
    
        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
        Pharmaceutical Press, London, 699-744.
    
        Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med
        J, 3: 28-29.
    
        Sandyk R (1986) Orofacial diskynesias associated with lorazepam
        therapy. Clin Pharm, 5: 419-21.
    
        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
        ed. Willians & Wilkins, Baltimore.
    
        Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter).
        Lancet, 2:802-803.
    
        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
        support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-
        452.
    
        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
        470-2.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:           Dr Ligia Fruchtengarten
                          Poison Control Centre of Sao Paulo  -  Brazil
                          Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          FAX / Phone:   55  11  2755311
                          E-mail:   lfruchtengarten@originet.com.br
    
        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          Centro de Controle de Intoxicaçoes de Sao Paulo
                          Av Francisco de Paula Quintanilha Ribeiro, 860
                          04330 - 020   Sao Paulo  -  SP  -  Brazil.
    
        Date:             July 1997
    
        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                          September 1997.
                          R. Ferner, L. Murray (Chairperson), M-O.
                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                          Nolf, A.Borges.
    
        Review 1998:      Lindsay Murray
                          Queen Elizabeth II Medical Centre
                          Perth, Western Australia.
    
        Editor:           Dr M.Ruse, April 1998
    


    


INTOX Home Page
Clonazepam
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    Clonazepam

    International Programme on Chemical Safety
    Poisons Information Monograph 326
    Pharmaceutical

    This monograph does not contain all of the sections completed. This
    mongraph is harmonised with the Group monograph on Benzodiazepines
    (PIM G008).

    1.  NAME

        1.1  Substance

             Clonazepam

        1.2  Group

             ATC classification index

             Psycholeptics (N05)/  Anxiolytics (N05B)/
             Benzodiazepine derivatives (N05BA)

        1.3  Synonyms

             Clonazepamum; Ro-5-4023

        1.4  Identification numbers

             1.4.1  CAS number

                    1622-61-3

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Central nervous system, causing depression of
             respiration and consciousness.

        2.2  Summary of clinical effects

             Central nervous system (CNS) depression and coma, or
             paradoxical excitation, but deaths are rare when
             benzodiazepines are taken alone. Deep coma and other
             manifestations of severe CNS depression are rare. Sedation,
             somnolence, diplopia, dysarthria, ataxia and intellectual

             impairment are the most common adverse effects of
             benzodiazepines. Overdose in adults frequently involves co-
             ingestion of other CNS depressants, which act synergistically
             to increase toxicity. Elderly and very young children are
             more susceptible to the CNS depressant action. Intravenous
             administration of even therapeutic doses of benzodiazepines
             may produce apnoea and hypotension.
             Dependence may develop with regular use of benzodiazepines,
             even in therapeutic doses for short periods. If
             benzodiazepines are discontinued abruptly after regular use,
             withdrawal symptoms may develop.  The amnesia produced by
             benzodiazepines can have medico-legal consequences.

        2.3  Diagnosis

             The clinical diagnosis is based upon the history of
             benzodiazepine overdose and the presence of the clinical
             signs of benzodiazepine intoxication.
             Benzodiazepines can be detected or measured in blood and
             urine using standard analytical methods. This information may
             confirm the diagnosis but is not useful in the clinical
             management of the patient.
             A clinical response to flumazenil, a specific benzodiazepine
             antagonist, also confirms the diagnosis of benzodiazepine
             overdose, but administration of this drug is rarely
             justified.

        2.4  First aid measures and management principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly involve co-
             ingestion of other CNS depressants and other drugs. Activated
             charcoal normally provides adequate gastrointestinal
             decontamination. Gastric lavage is not routinely indicated.
             Emesis is contraindicated. The use of flumazenil is reserved
             for cases with severe respiratory or cardiovascular
             complications and should not replace the basic management of
             the airway and respiration. The routine use of flumazenil is
             contraindicated because of potential complications, including
             seizures.  Renal and extracorporeal methods of enhanced
             elimination are not effective.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical Name:
             5-(2-Chlorophenyl)-1,3-dihydro-7-nitro-1,4- -benzodiazepin-2-
             one
    

             Molecular Formula: C15H10ClN3O3
    
             Molecular Weight: 315.7

        3.3  Physical properties

             3.3.1  Colour

                    Light yellow

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Clonazepam has a faint odour. Practically
                    insoluble in water; slightly soluble in alcohol and in
                    methyl alcohol; sparingly soluble in acetone and in
                    chloroform; very slightly to slightly soluble in
                    ether.
                    (Reynolds, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

                    Store in airtight containers. Protect from
                    light (Reynolds, 1996).

    4.  USES

        4.1  Indications
             4.1.1  Indications
             4.1.2  Description
        4.2  Therapeutic dosage
             4.2.1  Adults
             4.2.2  Children
        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral
        5.2  Inhalation
        5.3  Dermal
        5.4  Eye
        5.5  Parenteral
        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure
        6.2  Distribution by route of exposure
        6.3  Biological half-life by route of exposure
        6.4  Metabolism
        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action
             7.1.1  Toxicodynamics
             7.1.2  Pharmacodynamics
        7.2  Toxicity
             7.2.1  Human data
                    7.2.1.1  Adults
                    7.2.1.2  Children
             7.2.2  Relevant animal data
             7.2.3  Relevant in vitro data
        7.3  Carcinogenicity
        7.4  Teratogenicity
        7.5  Mutagenicity
        7.6  Interactions
        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
                    8.1.1.1  Toxicological analyses
                    8.1.1.2  Biomedical analyses
                    8.1.1.3  Arterial blood gas analysis
                    8.1.1.4  Haematological analyses
                    8.1.1.5  Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
                    8.1.2.1  Toxicological analyses
                    8.1.2.2  Biomedical analyses
                    8.1.2.3  Arterial blood gas analysis
                    8.1.2.4  Haematological analyses
                    8.1.2.5  Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
                    8.1.3.1  Toxicological analyses
                    8.1.3.2  Biomedical analyses
                    8.1.3.3  Arterial blood gas analysis
                    8.1.3.4  Haematological analyses
                    8.1.3.5  Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
                    8.2.1.1  Simple Qualitative Test(s)
                    8.2.1.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.1.3  Simple Quantitative Method(s)
                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens
                    8.2.2.1  Simple Qualitative Test(s)
                    8.2.2.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.2.3  Simple Quantitative Method(s)
                    8.2.2.4  Advanced Quantitative Method(s)
                    8.2.2.5  Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
                    8.3.1.1  Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.3  Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"
             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and
             their interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             For toxicological analyses: whole blood 10 mL; urine 25 mL
             and gastric contents 25 mL.
    
             Biomedical analysis
             Blood gases, serum electrolytes, blood glucose and hepatic
             enzymes when necessary in severe cases.
    
             Toxicological analysis
             Qualitative testing for benzodiazepines is helpful to confirm
             their presence, but quantitative levels are not clinically
             useful. More advanced analyses are not necessary for the
             treatment of the poisoned patient due the lack of correlation
             between blood concentrations and clinical severity (Jatlow et
             al., 1979; MacCormick et al., 1985; Minder, 1989).
    
             TLC and EMIT: These provide data on the presence of
             benzodiazepines, their metabolites and possible associations
             with other drugs.
    

             GC or HPLC: These permit identification and quantification of
             the benzodiazepine which caused the poisoning and its
             metabolites in blood and urine.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The onset of impairment of consciousness is
                    relatively rapid in benzodiazepine poisoning.  Onset
                    is more rapid following larger doses and with agents
                    of shorter duration of action. The most common and
                    initial symptom is somnolence.  This may progress to
                    coma Grade I or Grade II (see below) following very
                    large ingestions.
    
                    Reed Classification of Coma (Reed et al., 1952)
    
                    Coma Grade I:   Depressed level of consciousness,
                                    response to  painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade III: Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes absent. Vital
                                    signs intact
    
                    Coma Grade IV:  Coma grade III plus respiratory and
                                    circulatory collapse

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    Overdose by the intravenous route results in
                    symptoms similar to those associated with ingestion,
                    but they appear immediately after the infusion, and
                    the progression of central nervous system (CNS)
                    depression is more rapid. Acute intentional poisoning
                    by this route is uncommon and most cases are
                    iatrogenic. Rapid intravenous infusion may cause
                    hypotension, respiratory depression and
                    apnoea.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxic effects associated with chronic exposure
                    are secondary to the presence of the drug and
                    metabolites and include depressed mental status,
                    ataxia, vertigo, dizziness, fatigue, impaired motor
                    co-ordination, confusion, disorientation and
                    anterograde amnesia. Paradoxical effects of
                    psychomotor excitation, delirium and aggressiveness
                    also occur. These chronic effects are more common in
                    the elderly, children and patients with renal or
                    hepatic disease.
    
                    Administration of therapeutic doses of benzodiazepines
                    for 6 weeks or longer can result in physical
                    dependence, characterized by a withdrawal syndrome
                    when the drug is discontinued. With larger doses, the
                    physical dependence develops more rapidly.

             9.2.2  Inhalation

                    No data.

             9.2.3  Skin exposure

                    No data.

             9.2.4  Eye contact

                    No data.

             9.2.5  Parenteral exposure

                    The chronic parenteral administration of
                    benzodiazepines may produce thrombophlebitis and
                    tissue irritation, in addition to the usual symptoms
                    (Greenblat & Koch-Weser, 1973).

             9.2.6  Other

                    No data.

        9.3  Course, prognosis, cause of death

             Benzodiazepines are relatively safe drugs even in
             overdose. The clinical course is determined by the
             progression of the neurological symptoms. Deep coma or other
             manifestations of severe central nervous system (CNS)
             depression are rare with benzodiazepines alone.  Concomitant
             ingestion of other CNS depressants may result in a more
             severe CNS depression of longer duration.

    
             The therapeutic index of the benzodiazepines is high and the
             mortality rate associated with poisoning due to
             benzodiazepines alone is very low. Complications in severe
             poisoning include respiratory depression and aspiration
             pneumonia. Death is due to respiratory arrest.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, bradycardia and tachycardia have
                    been reported with overdose (Greenblatt et al., 1977;
                    Meredith & Vale 1985). Hypotension is more frequent
                    when benzodiazepines are ingested in association with
                    other drugs (Hojer et al., 1989). Rapid intravenous
                    injection is also associated with hypotension.

             9.4.2  Respiratory

                    Respiratory depression may occur in
                    benzodiazepine overdose and the severity depends on
                    dose ingested, amount absorbed, type of benzodiazepine
                    and co-ingestants. Respiratory depression requiring
                    ventilatory support has occurred in benzodiazepine
                    overdoses (Sullivan, 1989; Hojer et al.,1989). The
                    dose-response for respiratory depression varies
                    between individuals.  Respiratory depression or
                    respiratory arrest may rarely occur with therapeutic
                    doses. Benzodiazepines may affect the control of
                    ventilation during sleep and may worsen sleep apnoea
                    or other sleep-related breathing disorders, especially
                    in patients with chronic obstructive pulmonary disease
                    or cardiac failure (Guilleminault, 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             CNS depression is less marked than
                             that produced by other CNS depressant agents
                             (Meredith & Vale, 1985). Even in large
                             overdoses, benzodiazepines usually produce
                             only mild symptoms and this distinguishes
                             them from other sedative-hypnotic agents.
                             Sedation, somnolence, weakness, diplopia,
                             dysarthria, ataxia and intellectual
                             impairment are the most common neurological
                             effects. The clinical effects of severe
                             poisoning are sleepiness, ataxia and coma
                             Grade I to Grade II (Reed). The presence of
                             more severe coma suggests the possibility of
                             co-ingested drugs. Certain of the newer
                             short-acting benzodiazepines (temazepam,
                             alprazolam and triazolam) have been
                             associated with several fatalities and it is
                             possible that they may have greater acute
                             toxicity (Forrest et al., 1986). The elderly
                             and very young children are more susceptible
                             to the CNS depressant action of
                             benzodiazepines.
                             The benzodiazepines may cause paradoxical CNS
                             effects, including excitement, delirium and
                             hallucinations. Triazolam has been reported
                             to produce delirium, toxic psychosis, memory
                             impairment and transient global amnesia
                             (Shader & Dimascio, 1970; Bixler et al,
                             1991). Flurazepam has been associated with
                             nightmares and hallucinations.
                             There are a few reports of extrapyramidal
                             symptoms and dyskinesias in patients taking
                             benzodiazepines (Kaplan & Murkafsky, 1978;
                             Sandyk, 1986).
                             The muscle relaxation caused by
                             benzodiazepines is of CNS origin and
                             manifests as dysarthria, incoordination and
                             difficulty standing and walking.

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

                    Oral benzodiazepine poisoning will produce
                    minimal effects on the gastrointestinal tract (GI)
                    tract but can occasionally cause nausea or vomiting
                    (Shader & Dimascio, 1970).

             9.4.5  Hepatic

                    A case of cholestatic jaundice due focal
                    hepatic necrosis was associated with the
                    administration of diazepam (Tedesco & Mills,
                    1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Vesical hypotonia and urinary
                             retention has been reported in association
                             with diazepam poisoning (Chadduck et al.,
                             1973).

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    Galactorrhoea with normal serum prolactin
                    concentrations has been noted in 4 women taking
                    benzodiazepines (Kleinberg et al., 1977).
                    Gynaecomastia has been reported in men taking high
                    doses of diazepam (Moerck & Majelung, 1979). Raised
                    serum concentrations of oestrodiol were observed in
                    men taking diazepam 10 to 20 mg daily for 2 weeks
                    (Arguelles & Rosner, 1975).

             9.4.8  Dermatological

                    Bullae have been reported following overdose
                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                    et al., 1990).
                    Allergic skin reactions were attributed to diazepam at
                    a rate of 0.4 per 1000 patients (Brigby,
                    1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    Brown opacification of the lens occurred in 2
                    patients who used diazepam for several years (Pau
                    Braune, 1985).

             9.4.10 Haematological

                    No data.

             9.4.11 Immunological

                    Allergic reaction as above (see 9.4.8).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No direct disturbances have been described.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    Hypersensitivity reactions including
                    anaphylaxis are very rare (Brigby, 1986). Reactions
                    have been attributed to the vehicle used for some
                    parenteral diazepam formulations (Huttel et al.,
                    1980). There is also a report of a type I
                    hypersensitivity reaction to a lipid emulsion of
                    diazepam (Deardon, 1987).

             9.4.14 Other clinical effects

                    Hypothermia was reported in 15% of cases in
                    one series. (Martin, 1985; Hojer et al.,
                    1989).

             9.4.15 Special risks

                    Pregnancy
                    Passage of benzodiazepines across the placenta depends
                    on the degree of protein binding in mother and fetus,
                    which is influenced by factors such as stage of
                    pregnancy and plasma concentrations of free fatty
                    acids in mother and fetus (Lee et al., 1982). Adverse
                    effects may persist in the neonate for several days
                    after birth because of immature drug metabolising
                    enzymes. Competition between diazepam and bilirubin

                    for protein binding sites could result in hyper-
                    bilirubinemia in the neonate (Notarianni, 1990).
                    The abuse of benzodiazepines by pregnant women can
                    cause withdrawal syndrome in the neonate. The
                    administration of benzodiazepines during childbirth
                    can produce hypotonia, hyporeflexia, hypothermia and
                    respiratory depression in the newborn.
                    Benzodiazepines have been used in pregnant patients
                    and early reports associated diazepam and
                    chlordiazepoxide with some fetal malformations, but
                    these were not supported by later studies (Laegreid et
                    al., 1987; McElhatton, 1994).
    
                    Breast feeding
                    Benzodiazepines are excreted in breast milk in
                    significant amounts and may result in lethargy and
                    poor feeding in neonates.  Benzodiazepines should be
                    avoided in nursing mothers (Brodie, 1981; Reynolds,
                    1996).

        9.5  Other

             Dependence and withdrawal
             Benzodiazepines have a significant potential for abuse and
             can cause physical and psychological dependence. Abrupt
             cessation after prolonged use causes a withdrawal syndrome
             (Ashton, 1989). The mechanism of dependence is probably
             related to functional deficiency of GABA activity.
             Withdrawal symptoms include anxiety, insomnia, headache,
             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
             weakness, perspiration, irritability, hypersensitivity to
             visual and auditory stimuli, palpitations, tachycardia and
             postural hypotension. In severe and rare cases of withdrawal
             from high doses, patients may develop affective disorders or
             motor dysfunction: seizures, psychosis, agitation, confusion,
             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
             Reynolds, 1996).
             The time of onset of the withdrawal syndrome depends on the
             half-life of the drug and its active metabolites; the
             symptoms occur earlier and may be more severe with short-
             acting benzodiazepines. Others risk factors for withdrawal
             syndrome include prolonged use of the drug, higher dosage and
             abrupt cessation of the drug.
             
             Abuse
             Benzodiazepines, particularly temazepam, have been abused
             both orally and intravenously (Stark et al., 1987; Woods,
             1987; Funderburk et al, 1988)
             
             Criminal uses
             The amnesic effects of benzodiazepines have been used for
             criminal purposes with medicolegal consequences (Ferner,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly include other
             drugs and other CNS depressants. Activated charcoal normally
             provides adequate gastrointestinal decontamination. Gastric
             lavage is not routinely indicated. Emesis is contraindicated.
             The use of flumazenil is reserved for cases with severe
             respiratory or cardiovascular complications and should not
             replace the basic management of the airway and respiration.
             Renal and extracorporeal elimination methods are not
             effective.

        10.2 Life supportive procedures and symptomatic/specific treatment

             The patient should be evaluated to determine adequacy
             of airway, breathing and circulation. Continue clinical
             observation until evidence of toxicity has resolved.
             Intravenous access should be available for administration of
             fluid. Endotracheal intubation, assisted ventilation and
             supplemental oxygen may be required on rare occasions, more
             commonly when benzodiazepines are ingested in large amounts
             or with other CNS depressants.

        10.3 Decontamination

             Gastric lavage is not routinely indicated following
             benzodiazepine overdose. Emesis is contraindicated because of
             the potential for CNS depression. Activated charcoal can be
             given orally.

        10.4 Enhanced elimination

             Methods of enhancing elimination are not
             indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Flumazenil, a specific benzodiazepine
                    antagonist at central GABA-ergic receptors is
                    available. Although it effectively reverses the CNS
                    effects of benzodiazepine overdose, its use in
                    clinical practice is rarely indicated.
                    Use of Flumazenil is specifically contraindicated when
                    there is history of co-ingestion of tricyclic
                    antidepressants or other drugs capable of producing

                    seizures (including aminophylline and cocaine),
                    benzodiazepine dependence, or in patients taking
                    benzodiazepines as an anticonvulsant agent. In such
                    situations, administration of Flumazenil may
                    precipitate seizures (Lopez, 1990; Mordel et al.,
                    1992).
                    Adverse effects associated with Flumazenil include
                    hypertension, tachycardia, anxiety, nausea, vomiting
                    and benzodiazepine withdrawal syndrome.
                    The initial intravenous dose of 0.3 to 1.0 mg may be
                    followed by further doses if necessary. The absence of
                    clinical response to 2 mg of flumazenil within 5 to 10
                    minutes indicates that benzodiazepine poisoning is not
                    the major cause of CNS depression or coma.
                    The patient regains consciousness within 15 to 30
                    seconds after injection of flumazenil, but since it is
                    metabolised more rapidly than the benzodiazepines,
                    recurrence of toxicity and CNS depression can occur
                    and the patient should be carefully monitored after
                    initial response to flumazenil therapy.  If toxicity
                    recurs, further bolus doses may be administered or an
                    infusion commenced at a dose of 0.3 to 1.0 mg/hour
                    (Meredith et al., 1993).

             10.5.2 Children

                    The initial intravenous dose of 0.1 mg should
                    be repeated each minute until the child is awake.
                    Continuous intravenous infusion should be administered
                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                    1993).

        10.6 Management discussion

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. Flumazenil is the specific
             antagonist of the effects of benzodiazepines, but the routine
             use for the treatment of benzodiazepine overdosage is not
             recommended. The use of Flumazenil should only be considered
             where severe CNS depression is observed. This situation
             rarely occurs, except in cases of mixed ingestion. The
             administration of flumazenil may improve respiratory and
             cardiovascular function enough to decrease the need for
             intubation and mechanical ventilation, but should never
             replace basic management principles.
             Flumazenil is an imidazobenzodiazepine and has been shown to
             reverse the sedative, anti-convulsant and muscle-relaxant
             effects of benzodiazepines. In controlled clinical trials,
             flumazenil significantly antagonizes benzodiazepine-induced
             coma arising from anaesthesia or acute overdose. However, the
             use of flumazenil has not been shown to reduce mortality or
             sequelae in such cases.

             The administration of flumazenil is more effective in
             reversing the effects of benzodiazepines when they are the
             only drugs producing CNS toxicity. Flumazenil does not
             reverse the CNS depressant effects of non-benzodiazepine
             drugs, including alcohol. The diagnostic use of flumazenil in
             patients presenting with coma of unknown origin can be
             justified by its high therapeutic index and the fact that
             this may limit the use of other diagnostic procedures (CT
             scan, lumbar puncture, etc).
             Flumazenil is a relatively expensive drug and this may also
             influence its use, especially in areas with limited
             resources.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

    13. REFERENCES

        Arguelles AE, & Rosner J. (1975) Diazepam and plasma
        testosterone levels. Lancet, ii: 607.
    
        Ashton CH (1989) Drug-induced stupor and coma: some physical signs
        and their pharmacological basis. Adverse drug React Acute
        Poisoning Rev, 8: 1-59.
    
        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
        (1991)  Next-day memory impairment with triazolam use.  Lancet,
        337: 827-831.
    
        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
        3358-63.
    
        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
        descyclopropylmethyl-prazepam in whole-blood, plasma and milk
        after administration of prazepam to humans. Biopharm Drug Dispos,
        2: 59-68.
    
        Chadduck WM, Loar CR & Denton IC. (1973)  Vesical hypotonicity
        with diazepam. J Urol, 109: 1005-1007.
    
        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
        Anaesth,  59: 391.
    
        Einarson TR (1981) Oxazepam withdrawal convulsions.  Drug Intell
        Clin Pharm, 15: 487.
    

        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.
    
        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
        Press, Oxford.
    
        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
        temazepam overdoses (letter).  Lancet, 2: 226.
    
        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
        lorazepam and diazepam:  an evaluation in "recreational" drug
        users.  Drug Alcohol Depend, 22: 215-222.
    
        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
        benzodiazepine derivatives.  Clin Pharm Ther,  21: 497-513.
    
        Guilleminault C. (1990)  Benzodiazepines, bresthing and sleep.  Am
        J Med, 88 (suppl 3A): 25S - 28S.
    
        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) 
        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.
    
        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
        poisoning: experience of 702 admissions to an intensive care unit
        during a 14-year period.  J Intern Med, 226: 117-122.
    
        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
        mediated reactions to diazepam with Cremophor as solvent. Br J
        Anaesth,  52:  77-9.
    
        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
        Psychiatry, 134: 477-479.
    
        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
        associated with low dose benzodiazepine treatment. Am J
        Psychiatry, 135: 1558-1559.
    
        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
        235 cases. N Eng J Med  296: 589-600.
    
        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
        children exposed to benzodiazepines in utero.  Lancet, 1:
        108-109.
    
        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
        protein binding of diazepam in maternal and foetal serum during
        pregnancy. Br J Clin Pharmacol, 14: 551-4.
    
        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
        after a benzodiazepine antagonist.  Crit Care Med, 18:
        1480-1481.
    

        Martin SM (1985) The effect of diazepam on body temperature change
        in humans during cold exposure. J Clin Pharmacol,   25: 611-613.
    
        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
        clinical findings and serum concentrations in two cases.  J Clin
        Psychiatr,  46:247-248.
    
        McElhatton PR. (1994) The effects of benzodiazepines use during
        pregnancy and lactation. Reprod Toxicol,  8: 461-75.
    
        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
        dantrolene as antidotes, 1st ed. Cambridge University Press,
        Cambridge.
    
        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
        agents. Adverse Drug React Acute Poison Rev,  4: 83-122.
    
        Minder EI (1989) Toxicity in a case of acute and massive overdose
        of chlordiazepoxide and its correlation to blood concentration. 
        Clin Toxicol,  27: 117-127.
    
        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam
        abuse.Lancet, i: 1344-5.
    
        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
        after flumazenil administration in a case of combined
        benzodiazepine and tricyclic antidepressant overdose. Crit Care
        Med,  12: 1733-1734.
    
        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
        and neonates. Clin Pharnacokinet, 18: 20-36.
    
        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
        Augenheilkd, 187: 219-20 (in German).
    
        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
        intoxication. A study of 300 cases based on a physiologic system
        of classification of the severity of intoxication. Ann Intern Med,
        37: 390-396.
    
        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
        Pharmaceutical Press, London, 699-744.
    
        Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med
        J,  3: 28-29.
    
        Sandyk R (1986) Orofacial diskynesias associated with lorazepam
        therapy. Clin Pharm,  5: 419-21.
    
        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
        ed. Willians & Wilkins, Baltimore.
    

        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).
        Lancet,  2:802-803.
    
        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:
        450-452.
    
        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
        470-2.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:           Dr Ligia Fruchtengarten
                          Poison Control Centre of Sao Paulo  -  Brazil
                          Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          FAX / Phone:   55  11  2755311
                          E-mail:   lfruchtengarten@originet.com.br
    
        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          Centro de Controle de Intoxicaçoes de Sao Paulo
                          Av Francisco de Paula Quintanilha Ribeiro, 860
                          04330 - 020   Sao Paulo  -  SP  -  Brazil.
    
        Date:             July 1997
    
        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                          September 1997.
                          R. Ferner, L. Murray (Chairperson), M-O.
                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                          Nolf, A.Borges.
    
        Review 1998:      Lindsay Murray
                          Queen Elizabeth II Medical Centre
                          Perth, Western Australia.
    
        Editor:           Dr M.Ruse, April 1998
    


    
Clorazepate dipotassium
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    Clorazepate dipotassium

    International Programme on Chemical Safety
    Poisons Information Monograph 327
    Pharmaceutical

    This monograph does not contain all of the sections completed. This
    mongraph is harmonised with the Group monograph on Benzodiazepines
    (PIM G008).

    1.  NAME

        1.1  Substance

             Clorazepate dipotassium

        1.2  Group

             ATC classification index

             Psycholeptics (N05)/  Anxiolytics (N05B)/
             Benzodiazepine derivatives (N05BA)

        1.3  Synonyms

             Abbott-35616; AH-3232; 4306-CB; Clorazepate Dipotassium;
             Dikalii Clorazepas; Dipotassium Clorazepate

        1.4  Identification numbers

             1.4.1  CAS number

                    57109-90-7

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             Central nervous system, causing depression of
             respiration and consciousness.

        2.2  Summary of clinical effects

             Central nervous system (CNS) depression and coma, or
             paradoxical excitation, but deaths are rare when
             benzodiazepines are taken alone. Deep coma and other
             manifestations of severe CNS depression are rare. Sedation,

             somnolence, diplopia, dysarthria, ataxia and intellectual
             impairment are the most common adverse effects of
             benzodiazepines. Overdose in adults frequently involves co-
             ingestion of other CNS depressants, which act synergistically
             to increase toxicity. Elderly and very young children are
             more susceptible to the CNS depressant action. Intravenous
             administration of even therapeutic doses of benzodiazepines
             may produce apnoea and hypotension.
             Dependence may develop with regular use of benzodiazepines,
             even in therapeutic doses for short periods. If
             benzodiazepines are discontinued abruptly after regular use,
             withdrawal symptoms may develop.  The amnesia produced by
             benzodiazepines can have medico-legal consequences.

        2.3  Diagnosis

             The clinical diagnosis is based upon the history of
             benzodiazepine overdose and the presence of the clinical
             signs of benzodiazepine intoxication.
             Benzodiazepines can be detected or measured in blood and
             urine using standard analytical methods. This information may
             confirm the diagnosis but is not useful in the clinical
             management of the patient.
             A clinical response to flumazenil, a specific benzodiazepine
             antagonist, also confirms the diagnosis of benzodiazepine
             overdose, but administration of this drug is rarely
             justified.

        2.4  First aid measures and management principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly involve co-
             ingestion of other CNS depressants and other drugs. Activated
             charcoal normally provides adequate gastrointestinal
             decontamination. Gastric lavage is not routinely indicated.
             Emesis is contraindicated. The use of flumazenil is reserved
             for cases with severe respiratory or cardiovascular
             complications and should not replace the basic management of
             the airway and respiration. The routine use of flumazenil is
             contraindicated because of potential complications, including
             seizures.  Renal and extracorporeal methods of enhanced
             elimination are not effective.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical Name:
             Potassium 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-
             benzodiazepine-3-carboxylate with potassium hydroxide.
    

             Molecular Formula: C16H11ClK2N2O4
    
             Molecular Weight: 408.9

        3.3  Physical properties

             3.3.1  Colour

                    White or light yellow

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    The crystals  darken on exposure to light.
                    Solutions in water or in alcohol are unstable and
                    should be used immediately.
                    British Pharmacopoeia solubilities are: freely soluble
                    or very soluble in water; very slightly soluble in
                    alcohol; practically insoluble in dichloromethane.
                    US Pharmacopoeia solubilities are: soluble in water,
                    but may precipitate from solution on standing;
                    slightly soluble in alcohol and in isopropyl alcohol;
                    practically insoluble in acetone, in chloroform, in
                    dichloromethane, and in ether.
                    (Reynolds, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

                    Store under nitrogen in airtight containers.
                    Protect from light.
                    (Reynolds, 1996).

    4.  USES

        4.1  Indications
             4.1.1  Indications
             4.1.2  Description
        4.2  Therapeutic dosage
             4.2.1  Adults
             4.2.2  Children
        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral
        5.2  Inhalation
        5.3  Dermal
        5.4  Eye
        5.5  Parenteral
        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure
        6.2  Distribution by route of exposure
        6.3  Biological half-life by route of exposure
        6.4  Metabolism
        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action
             7.1.1  Toxicodynamics
             7.1.2  Pharmacodynamics
        7.2  Toxicity
             7.2.1  Human data
                    7.2.1.1  Adults
                    7.2.1.2  Children
             7.2.2  Relevant animal data
             7.2.3  Relevant in vitro data
        7.3  Carcinogenicity
        7.4  Teratogenicity
        7.5  Mutagenicity
        7.6  Interactions
        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
                    8.1.1.1  Toxicological analyses
                    8.1.1.2  Biomedical analyses
                    8.1.1.3  Arterial blood gas analysis
                    8.1.1.4  Haematological analyses
                    8.1.1.5  Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
                    8.1.2.1  Toxicological analyses
                    8.1.2.2  Biomedical analyses
                    8.1.2.3  Arterial blood gas analysis
                    8.1.2.4  Haematological analyses
                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens
                    8.1.3.1  Toxicological analyses
                    8.1.3.2  Biomedical analyses
                    8.1.3.3  Arterial blood gas analysis
                    8.1.3.4  Haematological analyses
                    8.1.3.5  Other (unspecified) analyses
        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
                    8.2.1.1  Simple Qualitative Test(s)
                    8.2.1.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.1.3  Simple Quantitative Method(s)
                    8.2.1.4  Advanced Quantitative Method(s)
             8.2.2  Tests for biological specimens
                    8.2.2.1  Simple Qualitative Test(s)
                    8.2.2.2  Advanced Qualitative Confirmation  Test(s)
                    8.2.2.3  Simple Quantitative Method(s)
                    8.2.2.4  Advanced Quantitative Method(s)
                    8.2.2.5  Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
                    8.3.1.1  Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                    8.3.1.3  Other fluids
             8.3.2  Arterial blood gas analyses
             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"
             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
             For toxicological analyses: whole blood 10 mL; urine 25 mL
             and gastric contents 25 mL.
    
             Biomedical analysis
             Blood gases, serum electrolytes, blood glucose and hepatic
             enzymes when necessary in severe cases.
    

             Toxicological analysis
             Qualitative testing for benzodiazepines is helpful to confirm
             their presence, but quantitative levels are not clinically
             useful. More advanced analyses are not necessary for the
             treatment of the poisoned patient due the lack of correlation
             between blood concentrations and clinical severity (Jatlow et
             al., 1979; MacCormick et al., 1985; Minder, 1989).
    
             TLC and EMIT: These provide data on the presence of
             benzodiazepines, their metabolites and possible associations
             with other drugs.
    
             GC or HPLC: These permit identification and quantification of
             the benzodiazepine which caused the poisoning and its
             metabolites in blood and urine.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The onset of impairment of consciousness is
                    relatively rapid in benzodiazepine poisoning.  Onset
                    is more rapid following larger doses and with agents
                    of shorter duration of action. The most common and
                    initial symptom is somnolence.  This may progress to
                    coma Grade I or Grade II (see below) following very
                    large ingestions.
    
                    Reed Classification of Coma (Reed et al., 1952)
    
                    Coma Grade I:   Depressed level of consciousness,
                                    response to  painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade III: Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes absent. Vital
                                    signs intact
    
                    Coma Grade IV:  Coma grade III plus respiratory and
                                    circulatory collapse

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    Overdose by the intravenous route results in
                    symptoms similar to those associated with ingestion,
                    but they appear immediately after the infusion, and
                    the progression of central nervous system (CNS)
                    depression is more rapid. Acute intentional poisoning
                    by this route is uncommon and most cases are
                    iatrogenic. Rapid intravenous infusion may cause
                    hypotension, respiratory depression and
                    apnoea.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxic effects associated with chronic exposure
                    are secondary to the presence of the drug and
                    metabolites and include depressed mental status,
                    ataxia, vertigo, dizziness, fatigue, impaired motor
                    co-ordination, confusion, disorientation and
                    anterograde amnesia. Paradoxical effects of
                    psychomotor excitation, delirium and aggressiveness
                    also occur. These chronic effects are more common in
                    the elderly, children and patients with renal or
                    hepatic disease.
    
                    Administration of therapeutic doses of benzodiazepines
                    for 6 weeks or longer can result in physical
                    dependence, characterized by a withdrawal syndrome
                    when the drug is discontinued. With larger doses, the
                    physical dependence develops more rapidly.

             9.2.2  Inhalation

                    No data.

             9.2.3  Skin exposure

                    No data.

             9.2.4  Eye contact

                    No data.

             9.2.5  Parenteral exposure

                    The chronic parenteral administration of
                    benzodiazepines may produce thrombophlebitis and
                    tissue irritation, in addition to the usual symptoms
                    (Greenblat & Koch-Weser, 1973).

             9.2.6  Other

                    No data.

        9.3  Course, prognosis, cause of death

             Benzodiazepines are relatively safe drugs even in
             overdose. The clinical course is determined by the
             progression of the neurological symptoms. Deep coma or other
             manifestations of severe central nervous system (CNS)
             depression are rare with benzodiazepines alone.  Concomitant
             ingestion of other CNS depressants may result in a more
             severe CNS depression of longer duration.
    
             The therapeutic index of the benzodiazepines is high and the
             mortality rate associated with poisoning due to
             benzodiazepines alone is very low. Complications in severe
             poisoning include respiratory depression and aspiration
             pneumonia. Death is due to respiratory arrest.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, bradycardia and tachycardia have
                    been reported with overdose (Greenblatt et al., 1977;
                    Meredith & Vale 1985). Hypotension is more frequent
                    when benzodiazepines are ingested in association with
                    other drugs (Hojer et al., 1989). Rapid intravenous
                    injection is also associated with hypotension.

             9.4.2  Respiratory

                    Respiratory depression may occur in
                    benzodiazepine overdose and the severity depends on
                    dose ingested, amount absorbed, type of benzodiazepine
                    and co-ingestants. Respiratory depression requiring
                    ventilatory support has occurred in benzodiazepine
                    overdoses (Sullivan, 1989; Hojer et al., 1989). The
                    dose-response for respiratory depression varies
                    between individuals.  Respiratory depression or
                    respiratory arrest may rarely occur with therapeutic

                    doses. Benzodiazepines may affect the control of
                    ventilation during sleep and may worsen sleep apnoea
                    or other sleep-related breathing disorders, especially
                    in patients with chronic obstructive pulmonary disease
                    or cardiac failure (Guilleminault, 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             CNS depression is less marked than
                             that produced by other CNS depressant agents
                             (Meredith & Vale, 1985). Even in large
                             overdoses, benzodiazepines usually produce
                             only mild symptoms and this distinguishes
                             them from other sedative-hypnotic agents.
                             Sedation, somnolence, weakness, diplopia,
                             dysarthria, ataxia and intellectual
                             impairment are the most common neurological
                             effects. The clinical effects of severe
                             poisoning are sleepiness, ataxia and coma
                             Grade I to Grade II (Reed). The presence of
                             more severe coma suggests the possibility of
                             co-ingested drugs. Certain of the newer
                             short-acting benzodiazepines (temazepam,
                             alprazolam and triazolam) have been
                             associated with several fatalities and it is
                             possible that they may have greater acute
                             toxicity (Forrest et al., 1986). The elderly
                             and very young children are more susceptible
                             to the CNS depressant action of
                             benzodiazepines.
                             The benzodiazepines may cause paradoxical CNS
                             effects, including excitement, delirium and
                             hallucinations. Triazolam has been reported
                             to produce delirium, toxic psychosis, memory
                             impairment and transient global amnesia
                             (Shader & Dimascio, 1970; Bixler et al,
                             1991). Flurazepam has been associated with
                             nightmares and hallucinations.
                             There are a few reports of extrapyramidal
                             symptoms and dyskinesias in patients taking
                             benzodiazepines (Kaplan & Murkafsky, 1978;
                             Sandyk, 1986).
                             The muscle relaxation caused by
                             benzodiazepines is of CNS origin and
                             manifests as dysarthria, incoordination and
                             difficulty standing and walking.

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

                    Oral benzodiazepine poisoning will produce
                    minimal effects on the gastrointestinal tract (GI)
                    tract but can occasionally cause nausea or vomiting
                    (Shader & Dimascio, 1970).

             9.4.5  Hepatic

                    A case of cholestatic jaundice due focal
                    hepatic necrosis was associated with the
                    administration of diazepam (Tedesco & Mills,
                    1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Vesical hypotonia and urinary
                             retention has been reported in association
                             with diazepam poisoning (Chadduck et al.,
                             1973).

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    Galactorrhoea with normal serum prolactin
                    concentrations has been noted in 4 women taking
                    benzodiazepines (Kleinberg et al., 1977).
                    Gynaecomastia has been reported in men taking high
                    doses of diazepam (Moerck & Majelung, 1979). Raised
                    serum concentrations of oestrodiol were observed in
                    men taking diazepam 10 to 20 mg daily for 2 weeks
                    (Arguelles & Rosner, 1975).

             9.4.8  Dermatological

                    Bullae have been reported following overdose
                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                    et al., 1990).
                    Allergic skin reactions were attributed to diazepam at
                    a rate of 0.4 per 1000 patients (Brigby,
                    1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    Brown opacification of the lens occurred in 2
                    patients who used diazepam for several years (Pau
                    Braune, 1985).

             9.4.10 Haematological

                    No data.

             9.4.11 Immunological

                    Allergic reaction as above (see 9.4.8).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    Hypersensitivity reactions including
                    anaphylaxis are very rare (Brigby, 1986). Reactions
                    have been attributed to the vehicle used for some
                    parenteral diazepam formulations (Huttel et al.,
                    1980). There is also a report of a type I
                    hypersensitivity reaction to a lipid emulsion of
                    diazepam (Deardon, 1987).

             9.4.14 Other clinical effects

                    Hypothermia was reported in 15% of cases in
                    one series. (Martin, 1985; Hojer et al.,
                    1989).

             9.4.15 Special risks

                    Pregnancy
                    Passage of benzodiazepines across the placenta depends
                    on the degree of protein binding in mother and fetus,
                    which is influenced by factors such as stage of
                    pregnancy and plasma concentrations of free fatty
                    acids in mother and fetus (Lee et al., 1982). Adverse
                    effects may persist in the neonate for several days
                    after birth because of immature drug metabolising
                    enzymes. Competition between diazepam and bilirubin
                    for protein binding sites could result in
                    hyperbilirubinemia in the neonate (Notarianni,
                    1990).

                    The abuse of benzodiazepines by pregnant women can
                    cause withdrawal syndrome in the neonate. The
                    administration of benzodiazepines during childbirth
                    can produce hypotonia, hyporeflexia, hypothermia and
                    respiratory depression in the newborn.
                    Benzodiazepines have been used in pregnant patients
                    and early reports associated diazepam and
                    chlordiazepoxide with some fetal malformations, but
                    these were not supported by later studies (Laegreid et
                    al., 1987; McElhatton, 1994).
    
                    Breast feeding
                    Benzodiazepines are excreted in breast milk in
                    significant amounts and may result in lethargy and
                    poor feeding in neonates.  Benzodiazepines should be
                    avoided in nursing mothers (Brodie, 1981; Reynolds,
                    1996).

        9.5  Other

             Dependence and withdrawal
             Benzodiazepines have a significant potential for abuse and
             can cause physical and psychological dependence. Abrupt
             cessation after prolonged use causes a withdrawal syndrome
             (Ashton, 1989). The mechanism of dependence is probably
             related to functional deficiency of GABA activity.
             Withdrawal symptoms include anxiety, insomnia, headache,
             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
             weakness, perspiration, irritability, hypersensitivity to
             visual and auditory stimuli, palpitations, tachycardia and
             postural hypotension. In severe and rare cases of withdrawal
             from high doses, patients may develop affective disorders or
             motor dysfunction: seizures, psychosis, agitation, confusion,
             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
             Reynolds, 1996).
             The time of onset of the withdrawal syndrome depends on the
             half-life of the drug and its active metabolites; the
             symptoms occur earlier and may be more severe with short-
             acting benzodiazepines. Others risk factors for withdrawal
             syndrome include prolonged use of the drug, higher dosage and
             abrupt cessation of the drug.
    
             Abuse
             Benzodiazepines, particularly temazepam, have been abused
             both orally and intravenously (Stark et al., 1987; Woods,
             1987; Funderburk et al, 1988)
    
             Criminal uses
             The amnesic effects of benzodiazepines have been used for
             criminal purposes with medicolegal consequences (Ferner,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly include other
             drugs and other CNS depressants. Activated charcoal normally
             provides adequate gastrointestinal decontamination. Gastric
             lavage is not routinely indicated. Emesis is contraindicated.
             The use of flumazenil is reserved for cases with severe
             respiratory or cardiovascular complications and should not
             replace the basic management of the airway and respiration.
             Renal and extracorporeal elimination methods are not
             effective.

        10.2 Life supportive procedures and symptomatic/specific treatment

             The patient should be evaluated to determine adequacy
             of airway, breathing and circulation. Continue clinical
             observation until evidence of toxicity has resolved.
             Intravenous access should be available for administration of
             fluid. Endotracheal intubation, assisted ventilation and
             supplemental oxygen may be required on rare occasions, more
             commonly when benzodiazepines are ingested in large amounts
             or with other CNS depressants.

        10.3 Decontamination

             Gastric lavage is not routinely indicated following
             benzodiazepine overdose. Emesis is contraindicated because of
             the potential for CNS depression. Activated charcoal can be
             given orally.

        10.4 Enhanced elimination

             Methods of enhancing elimination are not indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Flumazenil, a specific benzodiazepine
                    antagonist at central GABA-ergic receptors is
                    available. Although it effectively reverses the CNS
                    effects of benzodiazepine overdose, its use in
                    clinical practice is rarely indicated.
                    Use of Flumazenil is specifically contraindicated when
                    there is history of co-ingestion of tricyclic
                    antidepressants or other drugs capable of producing
                    seizures (including aminophylline and cocaine),

                    benzodiazepine dependence, or in patients taking
                    benzodiazepines as an anticonvulsant agent. In such
                    situations, administration of Flumazenil may
                    precipitate seizures (Lopez, 1990; Mordel et al.,
                    1992).
                    Adverse effects associated with Flumazenil include
                    hypertension, tachycardia, anxiety, nausea, vomiting
                    and benzodiazepine withdrawal syndrome.
                    The initial intravenous dose of 0.3 to 1.0 mg may be
                    followed by further doses if necessary. The absence of
                    clinical response to 2 mg of flumazenil within 5 to 10
                    minutes indicates that  benzodiazepine poisoning is
                    not the major cause of  CNS depression or coma.
                    The patient regains consciousness within 15 to 30
                    seconds after injection of flumazenil, but since it is
                    metabolised more rapidly than the benzodiazepines,
                    recurrence of toxicity and CNS depression can occur
                    and the patient should be carefully monitored after
                    initial response to flumazenil therapy.  If toxicity
                    recurs, further bolus doses may be administered or an
                    infusion commenced at a dose of 0.3 to 1.0 mg/hour
                    (Meredith et al., 1993).

             10.5.2 Children

                    The initial intravenous dose of 0.1 mg should
                    be repeated each minute until the child is awake.
                    Continuous intravenous infusion should be administered
                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                    1993).
             10.6 Management discussion

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. Flumazenil is the specific
             antagonist of the effects of benzodiazepines, but the routine
             use for the treatment of benzodiazepine overdosage is not
             recommended. The use of Flumazenil should only be considered
             where severe CNS depression is observed. This situation
             rarely occurs, except in cases of mixed ingestion. The
             administration of flumazenil may improve respiratory and
             cardiovascular function enough to decrease the need for
             intubation and mechanical ventilation, but should never
             replace basic management principles.
             Flumazenil is an imidazobenzodiazepine and has been shown to
             reverse the sedative, anti-convulsant and muscle-relaxant
             effects of benzodiazepines. In controlled clinical trials,
             flumazenil significantly antagonizes benzodiazepine-induced
             coma arising from anaesthesia or acute overdose. However, the
             use of flumazenil has not been shown to reduce mortality or
             sequelae in such cases.

             The administration of flumazenil is more effective in
             reversing the effects of benzodiazepines when they are the
             only drugs producing CNS toxicity. Flumazenil does not
             reverse the CNS depressant effects of non-benzodiazepine
             drugs, including alcohol. The diagnostic use of flumazenil in
             patients presenting with coma of unknown origin can be
             justified by its high therapeutic index and the fact that
             this may limit the use of other diagnostic procedures (CT
             scan, lumbar puncture, etc).
             Flumazenil is a relatively expensive drug and this may also
             influence its use, especially in areas with limited
             resources.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

    13. REFERENCES

        Arguelles AE, & Rosner J. (1975) Diazepam and plasma
        testosterone levels. Lancet, ii: 607.
    
        Ashton CH (1989) Drug-induced stupor and coma: some physical signs
        and their pharmacological basis. Adverse drug React Acute
        Poisoning Rev, 8: 1-59.
    
        Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
        (1991)  Next-day memory impairment with triazolam use.  Lancet,
        337: 827-831.
    
        Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
        3358-63.
    
        Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
        descyclopropylmethyl-prazepam in whole-blood, plasma and milk
        after administration of prazepam to humans. Biopharm Drug Dispos,
        2: 59-68.
    
        Chadduck WM, Loar CR & Denton IC. (1973)  Vesical hypotonicity
        with diazepam. J Urol, 109: 1005-1007.
    
        Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
        Anaesth,  59: 391.
    
        Einarson TR (1981) Oxazepam withdrawal convulsions.  Drug Intell
        Clin Pharm, 15: 487.
    

        Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.
    
        Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
        Press, Oxford.
    
        Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
        temazepam overdoses (letter).  Lancet, 2: 226.
    
        Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
        Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
        lorazepam and diazepam:  an evaluation in "recreational" drug
        users.  Drug Alcohol Depend, 22: 215-222.
    
        Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
        benzodiazepine derivatives.  Clin Pharm Ther,  21: 497-513.
    
        Guilleminault C. (1990)  Benzodiazepines, bresthing and sleep.  Am
        J Med, 88 (suppl 3A): 25S - 28S.
    
        Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) 
        Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.
    
        Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
        poisoning: experience of 702 admissions to an intensive care unit
        during a 14-year period.  J Intern Med, 226: 117-122.
    
        Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
        mediated reactions to diazepam with Cremophor as solvent. Br J
        Anaesth,  52:  77-9.
    
        Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
        Psychiatry, 134: 477-479.
    
        Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
        associated with low dose benzodiazepine treatment. Am J
        Psychiatry, 135: 1558-1559.
    
        Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
        235 cases. N Eng J Med  296: 589-600.
    
        Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
        children exposed to benzodiazepines in utero.  Lancet, 1:
        108-109.
    
        Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
        protein binding of diazepam in maternal and foetal serum during
        pregnancy. Br J Clin Pharmacol, 14: 551-4.
    
        Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
        after a benzodiazepine antagonist.  Crit Care Med, 18:
        1480-1481.
    

        Martin SM (1985) The effect of diazepam on body temperature change
        in humans during cold exposure. J Clin Pharmacol,  25: 611-613.
    
        McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
        clinical findings and serum concentrations in two cases.  J Clin
        Psychiatr,  46:247-248.
    
        McElhatton PR. (1994) The effects of benzodiazepines use during
        pregnancy and lactation. Reprod Toxicol,  8: 461-75.
    
        Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
        Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
        dantrolene as antidotes, 1st ed. Cambridge University Press,
        Cambridge.
    
        Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
        agents. Adverse Drug React Acute Poison Rev,  4: 83-122.
    
        Minder EI (1989) Toxicity in a case of acute and massive overdose
        of chlordiazepoxide and its correlation to blood concentration. 
        Clin Toxicol,  27: 117-127.
    
        Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse.
        Lancet, i: 1344-5.
    
        Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
        after flumazenil administration in a case of combined
        benzodiazepine and tricyclic antidepressant overdose. Crit Care
        Med,  12: 1733-1734.
    
        Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
        and neonates. Clin Pharnacokinet, 18: 20-36.
    
        Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
        Augenheilkd, 187: 219-20 (in German).
    
        Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
        intoxication. A study of 300 cases based on a physiologic system
        of classification of the severity of intoxication. Ann Intern Med,
        37: 390-396.
    
        Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
        Pharmaceutical Press, London, 699-744.
    
        Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med
        J,  3: 28-29.
    
        Sandyk R (1986) Orofacial diskynesias associated with lorazepam
        therapy. Clin Pharm,  5: 419-21.
    
        Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
        ed. Willians & Wilkins, Baltimore.
    

        Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).
        Lancet,  2:802-803.
    
        Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
        support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:
        450-452.
    
        Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
        470-2.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:           Dr Ligia Fruchtengarten
                          Poison Control Centre of Sao Paulo  -  Brazil
                          Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          FAX / Phone:   55  11  2755311
                          E-mail:   lfruchtengarten@originet.com.br
    
        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          Centro de Controle de Intoxicaçoes de Sao Paulo
                          Av Francisco de Paula Quintanilha Ribeiro, 860
                          04330 - 020   Sao Paulo  -  SP  -  Brazil.
    
        Date:             July 1997
    
        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                          September 1997.
                          R. Ferner, L. Murray (Chairperson), M-O.
                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                          Nolf, A.Borges.
    
        Review 1998:      Lindsay Murray
                          Queen Elizabeth II Medical Centre
                          Perth, Western Australia.
    
        Editor:           Dr M.Ruse, April 1998
    


    
Phenytoin
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/main trade names
   1.6 Main manufacturers and/or importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biological analyses
         8.1.1.3 Arterial blood gas analyses
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gs analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological Analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Test(s) for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method(s)
         8.2.2.4 Advanced quantitative method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analyses
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other biological specimens
      8.3.2 Arterial blood gas analysis
      8.3.3 Haematological analyses
      8.3.4 Other (unspecified) analyses
      8.3.5 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Summary of the most essential biomedical and toxicological analyses in acute poisoning and their interpretation
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive system
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat, local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from litterature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
12. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADRRESS(ES)



    Phenytoin

    International Programme on Chemical Safety
    Poisons Information Monograph 416
    Pharmaceutical

    1.  NAME

         1.1  Substance

               Phenytoin

         1.2  Group

               (N03) Antiepileptics (N03A B02) Hydantoin derivatives

         1.3  Synonyms

               diphenylhydantoin; Fenitoina; Phenantoinum; Phenytoinum;
               5,5-Diphenylhydantoin; 5,5-Diphenylimidazoline-2,4-dione

         1.4  Identification numbers

               1.4.1  CAS number

                       57-41-0

               1.4.2  Other numbers

                       CAS number: phenytoin sodium: 630-93-3
                       ATC codes: N03AB52: phenytoin, combinations

         1.5  Main brand names/main trade names

               Dantoin, Dilantin, Diphenlyn, Phenyltoin, Divulsan,
               Novo-diphenyl, Phentoin sodium, Denyl sodium, Dilantin
               sodium, Diphentoin, Diphenylan sodium, Kessodanten,
               Elsanutin, Phentoin, Di-Hydan, Phenhydan

         1.6  Main manufacturers and/or importers

               Carrion, Parke Davis

    2.  SUMMARY

         2.1  Main risks and target organs

               The intoxication usually manifests as mild central
               nervous system effects. More severe manifestations may be
               seen following massive overdose but fatalities are extremely
               rare.

         2.2  Summary of clinical effects

               Onset of symptoms including lateral nystagmus, ataxia,
               and drowsiness occurs within 1 to 2 hours after ingestion and
               may persist for about 4 to 5 days.
               In more severe cases, horizontal nystagmus, coarse tremor and
               inability to walk may be observed.
               In very severe poisoning, conciousness is impaired but coma
               is rarely observed.

         2.3  Diagnosis

               Diagnosis of phenytoin poisoning is clinical and based
               on history of overdose and/or access to phenytoin and the
               presence of specific clinical features especially nystagmus,
               dysarthria and ataxia. The diagnosis may be confirmed in the
               laboratory by measurement of an elevated serum phenytoin
               level but the levels do not always correlate precisely with
               the clinical severity of the intoxication.

         2.4  First aid measures and management principles

               Careful supportive management, gut decontamination
               measures and patience for 3 to 5 days almost always result in
               a good clinical outcome.

    3.  PHYSICO-CHEMICAL PROPERTIES

         3.1  Origin of the substance

               Synthetic.

         3.2  Chemical structure

               Molecular formula:       phenytoin: C15 H12 N2 O2
                                        phenytoin sodium: C15 H11 N2 Na O2
    
               Molecular weight:        phenytoin: 252.3
                                        phenytoin sodium: 274.3
    
               Structural name(s):      Phenytoin: 5,5-Diphenylhydantoin;
                                        5,5-Diphenylimidazoline-2,4-dione.

         3.3  Physical properties

               3.3.1  Colour

                       White

               3.3.2  State/Form

                       solid-crystalline
                       solid-powder

               3.3.3  Description

                       Phenytoin:
                       Very slightly soluble in water, slightly soluble in
                       chloroform and ether, soluble 1 in 70 in alcohol.
                       Melting point: 295-298°C
                       (Reynolds, 1996; Budavari, 1996).
    
                       Phenytoin sodium:
                       Phenytoin sodium (synonyms): Diphenin; Phenytoinum
                       Natricum; Soluble phenytoin
    
                       Slightly hygroscopic; on exposure to air it gradually
                       absorbs carbon dioxide with the liberation of
                       phenytoin.
                       Odourless, tasteless.
                       Soluble in water; the solution is turbid unless pH is
                       adjusted to 11,7
                       Soluble in alcohol
                       Practically insoluble in chloroform, in ether and in
                       methylene chloride.
                       Note on incompatibility: The mixing of phenytoin
                       sodium with other drugs or its addition to infusion
                       solutions is not recommended because precipitation may
                       occur (Reynolds, 1996).

         3.4  Other characteristics

               3.4.1  Shelf-life of the substance

                       5 years at 20°C

               3.4.2  Storage conditions

                       In airtight containers.

    4.  USES

         4.1  Indications

               4.1.1  Indications

               4.1.2  Description

                       Anticonvulsant
                       Antiarrhythmic.

         4.2  Therapeutic dosage

               4.2.1  Adults

                       Anticonvulsant:
                       The dose should be individualised to optimise control
                       of convulsions.  Measurement of plasma concentrations
                       is useful: 10 to 20 µg / mL (40 to 80 µmol/L) will
                       achieve good control in the majority of cases. A small
                       group of patients may require and will tolerate serum
                       phenytoin concentrations greater than 20 µg/mL (80
                       µmol/L) (Levine & Chang, 1990).
                       The suggested initial dose is 100 mg thrice daily
                       progressively increased at intervals of a few days to
                       a maximum of 600 mg daily.
                       Because it may take a week to establish therapeutic
                       plasma concentrations, an initial loading dose of 12
                       to 15 mg/kg body weight divided into 2 or 3 doses may
                       be given over about 6 hours and then followed by 100
                       mg thrice daily.
                       In the treatment of status epilepticus, a loading dose
                       of 10 to 15 mg/kg body weight of phenytoin sodium may
                       be given as slow intravenous injection (not more than
                       50 mg per minute) (Reynolds, 1996). Cardiac rhythm and
                       blood pressure should be continuously monitored during
                       the infusion.
    
                       Antiarrhythmic:
                       Phenytoin is occasionally used in the treatment of
                       cardiac arrhythmias, particularly those associated
                       with digitalis intoxication; it is of little or no use
                       in cardiac arrhythmias caused by  acute or chronic
                       heart disease.
                       The usual dose is 3.5 to 5  mg/kg body weight
                       administered by slow intravenous injection at a rate
                       of not more than 50 mg per minute. This dose may be
                       repeated once if necessary (Reynolds, 1996). Cardiac
                       rhythm and blood pressure should be continuously
                       monitored during the infusion.

               4.2.2  Children

                       Anticonvulsant:
                       Suggested initial dose is 5 mg/kg body weight daily in
                       2 or 3 divided  doses. Suggested maintenance dose is 4
                       to 8 mg/kg body weight daily.
                       Status epilepticus: intravenous loading dose of from
                       10 to 20 mg/kg body-weight, at a rate not exceeding 1
                       to 3 mg/kg/mn. (Reynolds, 1996). Cardiac rhythm and
                       blood pressure should be continuously monitored during
                       the infusion.
    

                       Antiarrhythmic:
                       As for adults.

         4.3  Contraindications

               Acute intermittent porphyria, hypersensitivity.
               Intravenous injection in patients with sino-atrial cardiac
               block, second- or third degree atrio-ventricular block, sinus
               bradycardia and Adam-Stokes syndrome. Caution is indicated in
               patients with uremia, hypoalbuminaemia, liver function
               disorders, and viral hepatitis (Informatorium Medicamentorum,
               1995).

    5.  ROUTES OF EXPOSURE

         5.1  Oral

               Most common route

         5.2  Inhalation

               Not applicable

         5.3  Dermal

               Not applicable

         5.4  Eye

               Not applicable

         5.5  Parenteral

               Intravenously in status epilepticus.

         5.6  Other

               No data

    6.  KINETICS

         6.1  Absorption by route of exposure

               Phenytoin is slowly, but almost completely absorbed from
               the gastro-intestinal tract; the rate of absorption is
               variable and its bioavailability can differ markedly with
               different pharmaceutical formulations. Large doses are more
               slowly absorbed. In severe oral poisoning, gastro-intestinal
               absorption may continue up to 60 hours (Wilder et al., 1973).
               Administration of 100 mg orally to normal volunteers produced
               two peaks at 2.5 to 3.5 and 10 to 12 hours (Robinson et al.,
               1975).

         6.2  Distribution by route of exposure

               Phenytoin is widely distributed throughout the body and
               is extensively (87 to 93%) bound to protein. The apparent
               volume of distribution is about 0.5 to 0.8 L/kg (Gugler et
               al., 1976; Hvidberg & Dam, 1976). Plasma binding is almost
               exclusively to albumin; in individuals with normal plasma
               albumin concentration and in absence of displacing agents,
               phenytoin is about 90% plasma bound.

         6.3  Biological half-life by route of exposure

               Following oral administration of therapeutic doses,
               phenytoin has a very variable, dose-dependent half-life. The
               range for a therapeutic dose is from 8 to 60 hours with an
               average of from 20 to 30 hours (Robinson et al., 1975;
               Hvidberg & Dam, 1976). In overdose in adults the range is
               from 24 to 230 hours (Holcomb et al., 1972; Gill et al.,
               1978; Albertson et al., 1981).

         6.4  Metabolism

               Phenytoin is extensively metabolised in the liver to 5-
               (4-hydroxyphenyl)-5 phenyl-hydantoin, which is inactive. This
               para hydroxylation of phenytoin is carried out by cytochrome
               P450 2C9 (Veronese et al., 1991, 1993). This enzyme also
               hydroxylates tolbutamide (Doecke et al., 1991), and warfarin
               (Rettie et al., 1992; Kaminski et al., 1993). This explains
               the interaction with these substances.
               The p-hydroxylated phenytoin is in turn conjugated to its
               glucuronide. Phenytoin hydroxylation is capacity-limited
               because of the saturable enzyme systems in the liver. At
               therapeutic doses, metabolism is nonlinear (first-order
               kinetics), while at toxic doses the metabolism is linear
               (zero-order kinetics) (Ellenhorn & Barceloux, 1988; Reynolds,
               1996).
               The p-hydroxylated phenytoin can be oxidised to 3,4-
               dihydroxyphenyl-phenylhydantoin, the catechol metabolite of
               phenytoin, and further to the 3-O-methylated catechol
               metabolite of phenytoin. These metabolites of phenytoin are
               of possible toxicological interest (Edeki & Brase, 1995).
               Phenytoin is more rapidly metabolised in children. (McEvoy,
               1995)
               The rate of metabolism appears to be subject to genetic
               polymorphism (Reynolds, 1996).
               Phenytoin undergoes entero-hepatic recycling (Reynolds,
               1996).

         6.5  Elimination by route of exposure

               The total systemic clearance of phenytoin from plasma is
               5.9 mL/minute/kg. (Gilman et al., 1990).
               Phenytoin is mainly excreted in the urine as its hydroxylated
               metabolite (23 to 70%), either free or in conjugated form
               (5%). About 4% is excreted unchanged, in the urine and 5% in
               the faeces. (Parker et al., 1970).
               Small amounts are excreted in the milk.

    7.  PHARMACOLOGY AND TOXICOLOGY

         7.1  Mode of action

               7.1.1  Toxicodynamics

                       Phenytoin is eliminated mainly through para-
                       hydroxylation by a cytochrome P450 system. The
                       metabolic pathway is subject to saturable kinetics in
                       overdose, allowing accumulation of free phenytoin.
                       Even at therapeutic doses, accumulation of free
                       phenytoin is possible in: hypoalbuminaemia, chronic
                       renal failure, hepatic dysfunction, hereditary
                       insufficient para-hydroxylation (Kutt et al., 1964;
                       Vasko et al., 1980; de Wolff, 1983), and inhibition of
                       phenytoin metabolism by other drugs.

               7.1.2  Pharmacodynamics

                       Phenytoin binds to specific site on voltage-
                       dependent sodium channels and is thought to exert its
                       anticonvulsant effect by suppressing the sustained
                       repetitive firing of neurons by inhibiting sodium flux
                       through these voltage dependent channels (Francis &
                       Burnham, 1992). Phenytoin stabilises membranes,
                       protecting the sodium pump in the brain and in the
                       heart. It limits the development of maximal convulsive
                       activity and reduces the spread of convulsive activity
                       from a discharging focus without influencing the focus
                       itself. (Reynolds, 1982, 1996)
                       Phenytoin has antiarrhythmic properties similar to
                       those of quinidine or procainamide.  Although
                       phenytoin has minimal effect on the electrical
                       excitability of cardiac muscle, it decreases the force
                       of contraction, depresses pacemaker action and
                       improves atrioventricular conduction. It also prolongs
                       the effective refractory period relative to the action
                       potential duration (Mc Evoy, 1995).

         7.2  Toxicity

               7.2.1  Human data

                       7.2.1.1  Adults

                                 Ingestion of 4,5 g has been reported
                                 to produce transient coma. However, 25 g has
                                 been tolerated without serious depression
                                 (Gosselin et al., 1976).

                       7.2.1.2  Children

                                 Fatal outcome has been reported in a
                                 7-year-old who ingested 2 g (Gosselin et al.,
                                 1976), in a 4 year old child who ingested
                                 forty 50 mg tablets and in a 16 year old girl
                                 who ingested an unknown amount (Laubscher,
                                 1966).

               7.2.2  Relevant animal data

                       Phenytoin has high acute toxicity:
                       LD50 (oral) mouse: 150 mg/kg
                       LD50 (intravenous) rat: 101 mg/kg
                       LD50 (intravenous) rabbit: 125 mg/kg
                       (Sax & Lewis, 1989; ANDIS, 1994).

               7.2.3  Relevant in vitro data

                       Not relevant

         7.3  Carcinogenicity

               Malignancies, including neuroblastoma, in children whose
               mothers were on phenytoin during pregnancy have been reported
               (McEvoy, 1995).

         7.4  Teratogenicity

               Phenytoin is classed as a teratogen risk factor D
               (Positive evidence of human fetal risk, but the benefits from
               use in pregnant women may be acceptable despite the
               risk).
               The epileptic pregnant woman taking phenytoin, either alone
               or in combination with other anticonvulsants, has a two to
               three times greater risk of delivering a child with
               congenital defects. It is not known if this increased risk is
               due to antiepileptic drugs, the disease itself, genetic
               factors, or a combination of these, although some evidence
               indicates that drugs are the causative factor.

               A recognisable pattern of malformations, known as the fetal
               hydantoin syndrome has been described and includes
               craniofacial and limb abnormalities, cleft lip, impaired
               growth, and congenital heart defects. (Briggs, 1994).

         7.5  Mutagenicity

               No data available.

         7.6  Interactions

               Drug interactions with phenytoin are numerous. They may
               be classified, according to mechanism, in the following
               way:
    
               Drugs displacing phenytoin plasma protein binding sites
               Azapropazone (Geaney et al., 1983)
               Diazoxide (Roe et al., 1975)
               Heparin (Schulz et al., 1983)
               Ibuprofen (Bachman et al., 1986)
               Phenylbutazone (Lunde et al., 1970)
               Salicylic acid (Lunde et al., 1970; Fraser et al., 1980;
               Paxton, 1980; Leonard et al., 1981)
               Sulfadimethoxine (Hansen et al., 1979)
               Sulfafurazole (Lunde et al., 1970)
               Sulfamethizole (Hansen et al., 1979; Lumholz et al.,
               1975)
               Sulfamethoxydiazine (Hansen et al., 1979)
               Sulfamethoxypyridazine (Hansen et al., 1979)
               Tolbutamide (Wesseling & Mols-Thurkow, 1975)
               Valproic acid (Patsalos & Lascelles, 1977; Monks et al.,
               1978; Dahlqvist et al., 1979; Bruni et al., 1980; Monks &
               Richens, 1980; Perucca et al., 1980; Sanson et al., 1980)
    
               Decreased total and unbound plasma phenytoin concentration
               caused by increased metabolism
               Folic acid (Viukari, 1968; Furlanot et al., 1978; Berg et
               al., 1983)
               Dexamethasone (Wong, 1985)
               Phenobarbital (Cucinell et al., 1965; Kutt et al., 1969;
               Browne et al., 1988a)
               Diazepam (Vajda et al., 1971; Richens & Houghton, 1975)
               Rifampicin (Kay et al., 1985)
               Methadone (Tong et al., 1981)
               Nitrofurantoin (Heipert & Pilz, 1978)
               Oestrogens and progestagens
    
               Increased unbound fraction of phenytoin secondary to reduced
               intrinsic metabolism
               Anticonvulsants:
               Valproic acid (Patsalos & Lascelles, 1977; Wilder et al.,
               1978; Bruni et al., 1980; Sanson et al., 1980; Perucca,
               1984)

               Carbamazepine (Hansen et al., 1971; Zielinski et al., 1985;
               Browne et al., 1988b)
               Sulthiame (Hansen et al., 1968; Houghton & Richens, 1974)
               Clobazam (Zifkin et al., 1991)
    
               Antithrombotics:
               Coumarin derivatives (Skovsted et al., 1976; Panegyres &
               Rischbieth, 1991; Abad-Santos et al., 1995)
               Triclodine (Rindone et al., 1996)
    
               Antituberculous drugs:
               Isoniazid and PAS (Kutt et al., 1970; Walubo & Aboo,
               1995)
    
               H2 antagonists:
               Cimetidine (Neuvonen et al., 1981; Levine et al., 1985;
               Sambol et al., 1989)
               Ranitidine (Bramhall & Levine, 1988)
               Omeprazole (Gugler & Jensen, 1985)
    
               Non-steroidal anti-inflammatory agents:
               Azapropazone (Roberts et al., 1981; Geany et al., 1983)
               Phenylbutazone (Andreasen et al., 1973; Neuvonen et al.,
               1979)
               Ibuprofen (Sandyk, 1982)
    
               Antiinfective agents:
               Metronidazole (Jensen & Gugler, 1985; Blyden et al.,
               1988)
               Chloramphenicol (Christensen & Skovsted, 1969; Ballek et al.,
               1973; Cosh et al., 1987)
    
               Antimycotics:
               Miconazole (Rolan et al., 1983)
               Fluconazole (Cadle et al., 1994)
    
               Psychoactive drugs:
               Fluoxetine (Jalil, 1992)
               Risperidone (Sanderson, 1996)
    
               Miscellaneous:
               Amiodarone (Gore et al., 1984; Shackleford & Watson, 1987;
               Ahmad, 1995)
               Allopurinol (Yokochi et al., 1982)
               Disulfiram

         7.7  Main adverse effects

               Anticonvulsant hypersensitivity syndrome is a
               potentially fatal drug reaction with cutaneous and systemic
               manifestations (incidence 1: 1000 to 1: 10.000). The findings
               are:
    

               Fever (90-100%)
               Dermatological (90%): erythema, papulous rash. In some cases
               erythroderma and even a lethal epidermal necrolysis has been
               reported.
               Lymphadenopathy (70%): lymphoma and depressed immunological
               function have been reported.
               Hepatitis (50-60%): hepatitis may develop in severe liver
               failure and death.
               Haematological (50%): leucocytosis with atypical lymphocytes,
               eosinophilia, and agranulocytosis.
               Connective tissues: coarsening of facial features, enlargment
               of the lips, gingival hyperplasia, hypertrichosis, Peyronie's
               disease.
               (Physician's Desk Reference, 1995)

    8.  TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

         8.1  Material sampling plan
               8.1.1  Sampling and specimen collection
                       8.1.1.1  Toxicological analyses
                       8.1.1.2  Biological analyses
                       8.1.1.3  Arterial blood gas analyses
                       8.1.1.4  Haematological analyses
                       8.1.1.5  Other (unspecified) analyses
               8.1.2  Storage of laboratory samples and specimens
                       8.1.2.1  Toxicological analyses
                       8.1.2.2  Biomedical analyses
                       8.1.2.3  Arterial blood gs analysis
                       8.1.2.4  Haematological analyses
                       8.1.2.5  Other (unspecified) analyses
               8.1.3  Transport of laboratory samples and specimens
                       8.1.3.1  Toxicological analyses
                       8.1.3.2  Biomedical analyses
                       8.1.3.3  Arterial blood gas analysis
                       8.1.3.4  Haematological Analyses
                       8.1.3.5  Other (unspecified) analyses
         8.2  Toxicological analyses and their interpretation
               8.2.1  Tests on toxic ingredient(s) of material
                       8.2.1.1  Simple qualitative test(s)
                       8.2.1.2  Advanced qualitative confirmation test(s)
                       8.2.1.3  Simple quantitative method(s)
                       8.2.1.4  Advanced quantitative method(s)
               8.2.2  Test(s) for biological specimens
                       8.2.2.1  Simple qualitative test(s)
                       8.2.2.2  Advanced qualitative confirmation test(s)
                       8.2.2.3  Simple quantitative method(s)
                       8.2.2.4  Advanced quantitative method(s)
               8.2.3  Interpretation of toxicological analyses
         8.3  Biomedical investigations and their interpretation
               8.3.1  Biochemical analyses

                       8.3.1.1  Blood, plasma or serum
                                 "Basic analyses"
                                 "Dedicated analyses"
                                 "Optional analyses"
                       8.3.1.2  Urine
                                 "Basic analyses"
                                 "Dedicated analyses"
                                 "Dedicated analyses"
                                 Optional analyses"
                       8.3.1.3  Other biological specimens

               8.3.2  Arterial blood gas analysis

                       Decrease of blood pH causes reduced protein
                       binding of phenytoin resulting in higher tissue
                       levels.

               8.3.3  Haematological analyses
                       "Basic analyses"
                       "Dedicated analyses"
                       "Optional analyses"
               8.3.4  Other (unspecified) analyses
               8.3.5  Interpretation of biomedical investigations

         8.4  Other biomedical (diagnostic) investigations and their
               interpretation

         8.5  Summary of the most essential biomedical and toxicological
               analyses in acute poisoning and their interpretation

               Interpretation of toxicological tests: total
               phenytoin:
    
               Serum concentration      Signs and Symptoms
               10 - 20 (g/mL)           therapeutic range (Troupin 1984a, b)
    
               20 - 30  (g/mL)          horizontal nystagmus on lateral gaze,
                                        ataxia, and drowsiness (Riker et al.
                                        1978)
    
               30 - 40  (g/mL)          vertical nystagmus, slurred speech
                                        ataxia, lurching gait, coarse tremors
    
               50 - 70 (g/mL)           fatalities recorded (Subik & Robinson
                                        1982)
    
               Interpretation of toxicological tests: free phenytoin
    
               1.5 - 3.5 (g/mL)         minor signs of intoxication (Wilson et
                                        al. 1979)
    
               > 5 (g/mL)               toxic effects (Booker & Darcey 1973)

    9.  CLINICAL EFFECTS

         9.1  Acute poisoning

               9.1.1  Ingestion

                       Onset of symptoms and signs, principally
                       involving the central nervous system, occurs within
                       hours of acute overdose (Ellenhorn & Barceloux, 1988;
                       Curtis et al., 1989). These manifestations of toxicity
                       may last many days and, in general, correlate with
                       serum phenytoin concentrations. The earliest
                       manifestations of toxicity following overdose are
                       nystagmus on lateral gaze, ataxia and drowsiness. With
                       more severe intoxication, vertical nystagmus,
                       dysarthria, progressive ataxia to the point of
                       inability to walk, hyperreflexia and impaired level of
                       consciousness are observed. Coma and/or respiratory
                       depression is rarely observed and should prompt
                       consideration of an alternative diagnosis. Paradoxical
                       seizures have been reported in severe phenytoin
                       intoxication but are extremely rare (Stilman & Masdeu,
                       1985).

               9.1.2  Inhalation

                       Not relevant

               9.1.3  Skin exposure

                       Not relevant

               9.1.4  Eye contact

                       Not relevant

               9.1.5  Parenteral exposure

                       Fatalities have been reported following
                       intravenous administration of phenytoin to elderly
                       patients with cardiac arrhythmias (Gellerman &
                       Martinez, 1967; Unger & Sklaroff, 1967; Zoneraich et
                       al., 1976; Earnest et al., 1983).
                       These complications appear more likely when
                       intravenous phenytoin is administered at a rapid rate
                       (Earnest et al., 1983) and have been attributed to the
                       solvent propylene glycol rather than to the phenytoin
                       itself (Louis et al., 1967; Gross et al., 1979;
                       Randazzo et al., 1995). The risk of hypotension and
                       arrythmia is minimal when intravenous phenytoin is
                       used as an anticonvulsant and administered at the
                       recommended rate. In a series of 164 patients who
                       received intravenous phenytoin loading following

                       presentation with acute convulsions, the incidence of
                       hypotension was approximately 5%, and the incidence of
                       apnea and cardiac arrhythmias was 0% (Binder et al.,
                       1996).

               9.1.6  Other

                       No data available

         9.2  Chronic poisoning

               9.2.1  Ingestion

                       The same as in acute poisoning.

               9.2.2  Inhalation

                       Not relevant.

               9.2.3  Skin exposure

                       Not relevant

               9.2.4  Eye contact

                       Not relevant

               9.2.5  Parenteral exposure

                       Not relevant

               9.2.6  Other

                       No data available.

         9.3  Course, prognosis, cause of death

               Normally the clinical course is one of gradual
               resolution of the signs and symptoms of intoxication leading
               to complete recovery.
               Death is rare after phenytoin overdose. It has been reported
               in association with administration of intravenous phenytoin
               for treatment of cardiac arrhythmias in elderly people
               (Gellerman & Martinez, 1967; Unger & Sklaroff, 1967;
               Zoneraich et al., 1976), and rarely from coma and hypotension
               following oral overdose in children (see section 11 for
               details).

         9.4  Systematic description of clinical effects

               9.4.1  Cardiovascular

                       Intravenous phenytoin has been reported to
                       cause depression of cardiac conduction, ventricular
                       fibrillation and heart block in elderly people treated
                       for cardiac arrhythmias (Gellerman & Martinez, 1967;
                       Unger & Sklaroff, 1967; Zoneraich et al., 1976).
                       Intravenous phenytoin is irritant and may cause
                       phlebitis (Jamerson et al., 1994).

               9.4.2  Respiratory

                       No data available.

               9.4.3  Neurological

                       9.4.3.1  CNS

                                 Nystagmus, ataxia, dysarthria,
                                 drowsiness, coarse resting tremor, ankle
                                 clonus, brisk deep tendon reflexes. In severe
                                 poisoning, the patient becomes obtund,
                                 confused and disoriented. Coma and
                                 respiratory depression are unusual.

                       9.4.3.2  Peripheral nervous system

                                 No data available.

                       9.4.3.3  Autonomic nervous system

                                 No data available

                       9.4.3.4  Skeletal and smooth muscle

                                 No data available.

               9.4.4  Gastrointestinal

                       No data available.

               9.4.5  Hepatic

                       A phenytoin hypersensitivity syndrome occurs
                       and is characterised by hepatitis. Overall mortality
                       rate when liver is involved is between 18% and 40%
                       (Harinasula & Zimmerman 1968; Dhar et al., 1974;
                       Parker & Shearer, 1979; Ting et al., 1982; Smythe &
                       Umstead, 1989; Howard et al., 1991,). The hepatitis is
                       usually anicteric (Pezzimenti & Hahn, 1970). Icterus
                       portends a poorer prognosis (Chaiken et al., 1950;

                       Dhar et al., 1974; Parker & Shearer, 1979).
                       Hepatomegaly with or without splenomegaly may be
                       present. The elevated hepatic transaminases, which may
                       be in the thousands of international units, can
                       continue to rise after phenytoin is discontinued (Ting
                       et al., 1982; Howard et al., 1991). Phenytoin-induced
                       chronic hepatitis has been reported (Roy et al.,
                       1993).

               9.4.6  Urinary

                       9.4.6.1  Renal

                                 No data available.

                       9.4.6.2  Other

                                 No data available.

               9.4.7  Endocrine and reproductive system

                       Phenytoin can induce hyperglycemia by
                       inhibiting the release of insulin (Belton et al.,
                       1965; Kizer et al., 1970; Levin et al., 1970; Holcomb
                       et al., 1972; Britton & Schwinghammer, 1980; Carter et
                       al., 1981). However, hypoglycemia has been reported in
                       a patient treated with phenytoin for 19 years who
                       ingested 20 g phenytoin together with 225 mg
                       zopiclone. This hypoglycemic episode was attributed to
                       phenytoin and may be due either to an escape from the
                       inhibitory effects of phenytoin on insulin secretion
                       or an increased sensitivity of the tissues to insulin
                       (Manto et al., 1996).

               9.4.8  Dermatological

                       In the Anticonvulsant Hypersensitivity
                       Syndrome, the cutaneous eruption begins as a patchy
                       macular erythema that evolves into a dusky, pink-
                       red,confluent, papular rash that usually is pruritic.
                       The upper trunk, face, and upper extremities are
                       affected first, with later involvement of the lower
                       extremities. In some cases erythroderma ensues.
                       Patients have periorbital and facial edema (Vittirio &
                       Muglia, 1995).
                       Epidermal necrolysis (even lethal) has been reported
                       (Gately & Lam, 1979; Janinis et al., 1993; Hunt,
                       1995).

               9.4.9  Eye, ear, nose, throat, local effects

                       No data available.

               9.4.10 Haematological

                       A number of adverse haematological effects
                       have been reported. These are not observed following
                       acute overdose.
                       The haematological abnormalities reported include
                       leucocytosis with atypical lymphocytes, eosinophilia
                       (Ray-Chaudhuri et al., 1989), leucopenia (Choen &
                       Bovasso, 1973) and agranulocytosis (Tsan et al., 1976;
                       Rawanduzy et al., 1993).
                       The marrow toxicity of anticonvulsants, which may be
                       more likely when used in combination (e.g. primidone),
                       is recognised. There may be three mechanisms of
                       toxicity. Firstly, primidone and phenytoin both cause
                       folate deficiency and a megaloblastic anaemia.
                       Secondly, an immune mechanism with a phenytoin-
                       dependent antigranulocyte antibody may cause
                       leucopenia, which resolves on discontinuing therapy.
                       Finally, phenytoin may cause a direct toxic effect
                       with pancytopenia and agranulocytosis (Laurenson et
                       al., 1994).
                       Subnormal serum-folate concentrations were found in
                       patients with chronic epilepsy treated with phenytoin
                       (Horwitz et al., 1968; Maxwell et al., 1972). It was
                       suggested that folate deficiency resulted from
                       accelerated metabolism of folate consequent upon
                       induction of liver enzymes by
                       anticonvulsants.

               9.4.11 Immunological

                       It seems likely that an aetiological
                       relationship exists between phenytoin treatment and
                       lymphoma. There is evidence of depressed immunological
                       function in patients given phenytoin (Brandt & Nilson,
                       1976; Rodriguez-Garcia et al., 1991; Ishizaka et al.,
                       1992; Kondo et al., 1994; Abbondazo et al.,
                       1995).

               9.4.12 Metabolic

                       9.4.12.1 Acid-base disturbances

                                 No data available.

                       9.4.12.2 Fluid and electrolyte disturbances

                                 No data available

                       9.4.12.3 Others

                                 No data available.

               9.4.13 Allergic reactions

                       Anticonvulsant hypersensitivity syndrome is a
                       potentially fatal drug reaction with cutaneous and
                       systemic manifestations (incidence one in 1000 to one
                       in 10 000 exposures) to the arene oxide producing
                       anticonvulsants: phenytoin, carbamazepine, and
                       phenobarbital sodium. The features include fever 
                       (90-100%), rash (90%), lympheadenopathy (70%), 
                       periorbital or facial edema (25%), hepatitis (50-60%),
                       haematologic abnormalities (50%), myalgia, arthralgia
                       (21%) and pharyngitis (10%). The reaction may be
                       genetically determined (Vittorio & Muglia,
                       1995).

               9.4.14 Other clinical effects

                       Not relevant.

         9.5  Other

               Connective tissues: coarsening of facial features,
               enlargment of the lips, gingival hyperplasia, hypertrichosis,
               Peyronie's disease (Dahlloef et al., 1991; Hassell & Hefti,
               1991; Bredfeldt, 1992; Natelli, 1992; Thomason et al., 1992;
               Seymour, 1993; Tigaran, 1994; McLoughlin et al., 1995; Perlik
               et al., 1995).

         9.6  Summary

    10. MANAGEMENT

         10.1 General principles

               Toxicity is rarely fatal and is treated by the
               institution of general supportive care and the
               discontinuation of phenytoin.

         10.2 Life supportive procedures and symptomatic/specific treatment

               Make a proper assessment of airway, breathing,
               circulation and neurological status of the patient.
               Maintain a clear airway.
               Administer oxygen if indicated.
               Open and maintain an intravenous route. Administer
               intravenous fluids.
               Monitor vital signs. It is not necessary to monitor the
               cardiac rhythm except in very severe cases.

         10.3 Decontamination

               Administer activated charcoal following acute overdose
               (not necessary for cases of chronic toxicity).

         10.4 Elimination

               Forced diuresis, haemodialysis and haemoperfusion are
               all ineffective (Jacobsen et al., 1986).

         10.5 Antidote treatment

               10.5.1 Adults

                       Not applicable.

               10.5.2 Children

                       Not applicable.

         10.6 Management discussion

               No data available.

    11. ILLUSTRATIVE CASES

         11.1 Case reports from litterature

               A 70-year old man with chronic lung disease for many
               years and angina pectoris for six months was admitted to the
               hospital because of increasing congestive heart failure
               despite digoxin and diuretic therapy. On admission the
               patient manifested evidence of some left-sided congestive
               heart failure wih tricuspid regurgitation. The ECG revealed
               regular sinus rhythm. The patient responded well to bed rest,
               oxygen, antibiotics, bronchodilators, and expectorants. 
               Maintenance dose of digoxin was continued. Two days after
               admission, he suddenly experienced pulmonary edema and atrial
               flutter with a ventricular response of 150. Phenytoin 250 mg,
               was given intravenously over a period of three minutes. The
               atrial flutter persisted, but with a high degree of atrio-
               ventricular block, followed by asystole three minutes after
               the completion of phenytoin. All attempts at resuscitation
               failed (Unger & Sklaroff, 1967).
    
               A 4 year-old girl was well until midway through the afternoon
               when her parents noted that her behaviour was abnormal. The
               next day, it was learned that she had accidentally ingested
               forty 50-mg tablets of phenytoin which has been prescribed
               for an older sister. The patient was hyperactive and ataxic.
               She appeared to have particular difficulty in keeping her
               head erect. Her pupils were miotic. Shortly thereafter she
               complained of epigastric pain and generalized pruritus. She
               had delusions and was difficult to manage. Her temperature
               was normal. Her condition changed little until that evening
               when she became progressively lethargic and was thereupon
               admitted to the hospital. The ataxia worsened, the patient
               became gradually less responsive, and her pupils were
               alternately miotic and dilated. By the following morning she

               was semicomatose. Several times that day and the following
               day, she vomited small mounts of pink material. The patient
               repeatedly opened her eyes and appeared to be afraid and then
               lapsed back into general unresponsiveness. Shortly after, the
               blood pressure became unrecordable. At 80 hours after the
               onset of symptoms there was an irreversible brain damage. A
               blood sample, drawn 24 hours after the onset of symptoms,
               revealed a phenytoin level of 94 mg/L (Laubscher, 1966).
    
               A 15-year-old boy ingested 19,5 g phenytoin sodium (15 g
               verifiable, equivalent to 392 mg/kg body weight)
               approximately four hours before emergency department
               presentation. He demonstrated the following signs: vomiting,
               obtundation responsive only to painful stimuli, reactive to
               light midposition pupils, brisk deep tendon reflexes,
               choreoathetoid movements, and irregular and shallow
               respirations. Treatment included nasotracheal intubation,
               gastric lavage, and activated charcoal. His clinical
               condition improved over the 7 following days, with periods of
               combativeness and agitation requiring the administration of
               diazepam, and responsiveness only to pain, alternately. The
               patient demonstrated no hypotension or cardiac arrhythmia.
               Peak phenytoin plasma level was 100,8 œg/mL. (Mellick et al.,
               1989).

    12. ADDITIONAL INFORMATION

         12.1 Specific preventive measures

               No data available

         12.2 Other

               No data available

    13. REFERENCES

         Abad-Santos F, Carcas AJ, Capitan C, Frias J (1995)
         Retroperitoneal haematoma in a patient treated with acenocoumarol,
         phenytoin and paroxetine. Clin Lab Haematol 17: 195-197
    
         Abbondazo SL, Irey NS, Frizzera G (1995) Dilantin-associated
         lymphadenopathy. Spectrum of histopathologic patterns. Am J Surg
         Pathol 19: 675-686
    
         Ahmad S (1995) Amiodarone and phenytoin interaction. J Am Geriat
         Soc 43: 1449-1450
    
         Albertson TE, Fisher CE Jr, Shragg TA (1981) A prolonged severe
         intoxication after ingestion of phenytoin and phenobarbital. West
         J Med 135: 418-422
    

         Andreasen PB, Froland A, Skovsted L, Andersen SA, Hauge M (1973)
         Diphenylhydantoin half-life in man and its inhibition by
         phenylbutazone: the role of genetic factors. Acta Medica
         Scandinavica 193: 561-564
    
         Australian National Drug Information Service (ANDIS) (1984)
         Profile on Phenytoin. Canberra, Commonwealth Department of Health
         and Family services, pp 1-21
    
         Bachmann KA, Schwarz JI, Forny RB, Jaurugui L, Sulivan TJ (1986)
         Inability of ibuprofen to alter single dose phenytoin disposition.
         Br J Clin Pharmacol 21: 165-169
    
         Baehler RW, Work J, Smith W et al.(1980) Charcoal hemoperfusion in
         the therapy for methosuximide and phenytoin overdose. Arch Intern
         Med 140: 1466-1468
    
         Ballek RE, Reidenberg MM, Orr L (1973) Inhibition of
         diphenylhydantoin metabolism by chloramphenicol Lancet I: 150
    
         Baylis EM, Crowley JM, Preece JM, Sylvester PE, Marks V (1971)
         Influence of folic acid on blood-phenytoin levels. Lancet I: 
         62-64
    
         Belton NR, Etheridge JE, Millichap JG (1965) Effects of
         convulsions and anticonvulsants on blood sugar in rabbits.
         Epilepsia 6: 243-249
    
         Berg MJ, Fischer LJ, Rivey MP, Vern BA, Lantz RK (1983) Phenytoin
         and folic acid interaction: a preliminary report. Therap Drug
         Monit 5: 389-394
    
         Binder L, Trujillo J, Parker D, Cuetter A (1996) Association of
         intravenous phenytoin toxicity with demographic, clinical, and
         dosing parameters. Am J Emergency Med 14: 398-401
    
         Blyden GT, Scavone JM, Greenblatt DJ ((1988) Metronidazole impairs
         clearance of phenytoin but not of alprazolam or lorazepam. J Clin
         Pharmacol 28: 240-245
    
         Bollini P, Riva R, Albani F, Ida N, Cacciara L (1983) Decreased
         phenytoin level during antineoplastic therapy. Epilepsia 24: 
         75-78
    
         Booker HE & Darcey B (1973) Serum concentrations of free
         diphenylhydantoin and their relationship to clinical intoxication.
         Epilepsia 14: 177
    
         Bramhall D, Levine M, (1988) Possible interaction of ranitidine
         with phenytoin Drug Intelligence and Clinical Pharmacy, 22: 
         979-980
    

         Brandt L & Nilson PG (1976) Lymphocytopenia in patients treated
         with phenytoin. Lancet, I: 308
    
         Bredfeldt GW (1992) Phenytoin-induced hyperplasia found in
         edentulous patients J Am Dental Assoc, 123: 61-64
    
         Britton HJ & Schwinghammer TL (1980) Phenytoin induced
         hyperglycaemia. Drug Intell Clin Pharm, 14: 544-547
    
         Browne TR, Szabo GK, Evans J, Evans BA, Greenblatt DJ (1988a)
         Phenobarbital does not alter phenytoin steady-state serum
         concentration of pharmacokinetics. Neurology, 38: 639-642
    
         Browne TR, Szabo GK, Evans JE, Evans BA, Greenblatt DJ (1988b)
         Carbamazepine increases phenytoin serum concentration and reduces
         phenytoin clearance. Neurology, 38: 1146-1130
    
         Bruni J, Gallo JM, Lee CS, Perchalski RJ, Wilder BJ (1980)
         Interaction of valproic acid with phenytoin Neurology, 30: 
         1233-1236
    
         Budavari S ed. (1996) The Merck Index: an encyclopedia of
         chemicals, drugs, and biologicals, 12th ed. Rahway, New Jersey,
         Merck and Co, Inc
    
         Buehler BA, Rao V, Finell RH (1994) Biochemical and molecular
         teratology of fetal hydantoin syndrome Neurologic Clinics, 12:
         741-748
    
         Cadle RM, Zenon GJ, Rodriguez-Barradas MC, Hamill RJ (1994)
         Fluconazole-induced symptomatic phenytoin toxicity. Ann
         Pharmacother, 28: 201-203
    
         Carter BL, Small RE, Mandel MD, Starkman MT (1981) Phenytoin-
         induced hyperglycaemia. Am J Hosp Pharm, 38: 1508-1512
    
         Chaiken BH, Goldberg BI  Segal JP (1950) Dilantin
         hypersensibility: report of a case of hepatitis with jaundice,
         pyrexia, and exfoliative dermatitis. N Eng J Med, 242: 897-898
    
         Choen BL & Bovasso GT (1973) Leucopenia as an unusual component of
         diphenylhydantoin hypersensibility: a case with pruritis, rash,
         fever, lymphoadenopathy, but low leucocyte count. Clin Pediatr
         (Phila) 12: 622-623
    
         Christensen LK & Skovsted L (1969) Inhibition of drug metabolism
         by chloramphenicol. Lancet, II: 1397-1399
    
         Cosh DG, Rowett DS, Lee PC, McCarthy PJ (1987) Case report-
         phenytoin therapy complicated by concurrent chloramphenicol and
         enteral nutrition. Austr.J Hosp Pharmacy, 17: 51-53
    

         Cucinell SA, Conney AH, Sansur M, Burns JJ (1965) Drug
         interactions in man. I. Lowering effect of Phenobarbital on plasma
         levels of bishydroxycoumarin (Dicoumarol) and diphenylhydantoin
         (Dilantin) Clin Pharmacol Ther, 6: 420-429
    
         Curtis DL, Piibe R, Ellenhorn MJ, Wasserberg J & Ordog G (1989)
         Phenytoin toxicity: predictors of clinical course. Vet Hum
         Toxicol, 31 (2): 162-163
    
         Dahlloef G, Axioe E, Modeer T (1991) Regression of phenytoin-
         induced gingival overgrowth after withdrawal of medication.
         Swedish Dental Journal, 15: 139-143
    
         Dahlqvist R, Borga O, Rane A, Walsh Z, Sjoqvist F (1979) Decreased
         plasma protein binding of phenytoin administration in patients on
         valproic acid. Br J Clin Pharmacy, 8: 547-552
    
         Dhar GJ, Ahamed PN, Pierach CA, Howard RB (1974)
         Diphenylhydantoin-induced hepatic necrosis. Post grad Med, 56:
         128-134
    
         Doecke CJ, Veronese ME, Pond SM, Miners JO, Birkett L, Sansom LN,
         McManus ME (1991) Relationship between phenytoin and tolbutamde
         hydroxylations on human liver microsomes. Br J Clin Pharmacol, 31:
         125-130
    
         Earnest MP, Marx JA, Drury LR (1983) Complications of intravenous
         phenytoin for acute treatment of seizures. JAMA, 249: 762-765
    
         Edeki TI & Brase DA (1995) Phenytoin disposition and toxicity:
         role of pharmacogenetic and interethnic factors. Drug metabolism
         reviews, 27: 449-469
    
         Ellenhorn MJ & Barceloux DG (1988) Medical Toxicology. Elsevier,
         New york, Amsterdam, London
    
         Francis J & Burnham M (1992) [3 H] Phenytoin identifies a novel
         anticonvulsive-binding domain on voltage-dependent sodium
         channels. Mol Pharmacol, 42: 1097-1103
    
         Fincham RW & Schottelius DD (1979) Decreased phenytoin levels in
         antineoplastic therapy. Ther Drug Monit, 1: 277-283
    
         Fraser DG, Ludden TM, Evens RP, Sutherland EW (1980) Displacement
         of phenytoin from plasma binding sites by salicylate. Clin
         Pharmacol Ther, 27: 165-169
    
         Furlanot M, Benetello P, Avogaro A, Dainese R (1978) Effects of
         folic acid on phenytoin kinetics in healthy subjects. Clin
         Pharmacol Ther, 24: 294-297
    
         Gately LE & Lam MA (1979) Phenytoin-induced toxic epidermal
         necrolysis. Ann Int Med, 91: 59
    

         Geaney DP, Carver JG, Davies CL, Aronson JK (1983) Pharmacokinetic
         investigation of the interaction of azopropazone with phenytoin.
         Br J Clin Pharmacol, 15: 727-734
    
         Gellerman GL & Martinez C (1967) Fatal ventricular fibrillation
         following intravenous sodium diphenylhydantoin therapy. JAMA,
         200:161-162
    
         Gill MA, Kern JW, Kaneko J, McKeon J, Davis C (1978) Phenytoin
         overdose. Kinetics. West J Med, 135: 418-422
    
         Goodman LS, Gilman A, Rall TW, Nies AS, Taylor P (1990) Goodman
         and Gilman's The Pharmacological Basis of Therapeutics, 8th Ed.,
         Pergamon Press New York
    
         Gore JM, Haffajee CI, Albert JS (1984) Interaction of amiodarone
         and diphenylhydantoin. Am J Cardiol, 54: 1145
    
         Gosselin RE, Hodge CH, Smith RP, Gleason MH (1976) Clinical
         Toxicology of Commercial Products IVth Ed. The Willims & Wilkins
         Co. Baltimore
    
         Gross DR, Kitzman JV, Adams HR (1979) Cardiovascular effects of
         intravenous administration of propylene glycol and oxytetracycline
         in propylene glycol in calves. Am J Vet Res, 40: 783-791
    
         Gugler R & Jensen JC (1985) Omeprazole inhibits oxidative drug
         metabolism. Gastroenterology, 89: 1235-1241
    
         Gugler R, Manion CV, Azarnoff D (1976) Phenytoin: Pharmacokinetics
         and bioavailability. Clin Pharmacol Ther, 19: 135-142
    
         Hansen JM, Kampmann JP, Siersback-Nielson K, Lumholtz IB, Arroe M
         (1979) The effect of different sulfonamides on phenytoin
         metabolism in man. Acta Med Scand (Suppl), 624: 106-110
    
         Hansen JM, Kristensen M, Skovsted L (1968) Sulthiame (Ospolot) as
         inhibitor of diphenylhydantoin metabolism. Lancet, 9: 17-22
    
         Hansen JM, Siersbaek-Nielsen K, Skovsted L (1971) Carbamazepine-
         induced accelaration of diphenylhydantoin and warfarin metabolism
         in man. Clin Pharmacol Therapeutics, 12: 539-543
    
         Harinasula U & Zimmerman HJ (1968) Diphenylhydantoin sodium
         hepatitis. JAMA, 203: 1015-1018
    
         Hassell TM & Hefti AF (1991) Drug-induced gingival overgrowth: old
         problem, new problem. Critical Reviews in Oral Biology and
         Medicine, 2: 103-137
    
         Heipertz R & Piltz H (1978) Interaction of nitrofurantoin with
         diphenylhydantoin. J Neurol. 218: 297-301
    

         Hendeles L, Wyatt R, Weinberger M, Schottelius D, Fincham R (1979)
         Decreased oral phenytoin absorption following concurrent
         theophylline administration. J.Allerg Clin Immunol.63: 156
    
         Holcomb R, Lynn R, Harvey B, Sweetman BJ, Gerber N (1972)
         Intoxication with 5,5-diphenyl-hydantoin (Dilantin): clinical
         features, blood levels, urinary metabolites, and metabolic changes
         in a child. J Pediatr 80:627-632
    
         Horwitz SL, Klipstein FA, Lovelace RE (1968) Relation of abnormal
         folate metabolism to neuropathy developing during anticonvulsive
         drug therapy. Lancet I: 536
    
         Houghton GW & Richens A (1974) Inhibition of phenytoin metabolism
         by sulthiame in epileptic patients Br J Clin Pharmacol, 1: 59-66
    
         Howard PA, Engen PL, Dunn MI (1991) Phenytoin hypersensitivity
         syndrome: a case report. Ann Pharmacother, 25: 929-932
    
         Howard CE, Robert S, Ely DS, Moyee RA (1994) Use of multiple-dose
         activated charcoal in phenytoin toxicity. Ann Pharmacother 28:
         201-203
    
         Hunt SJ (1995) Cutaneous necrosis and multinucleate epidermal
         cells associated with intravenous phenytoin. Am J Dermatopath.
         17:399-402
    
         Hvidberg EF & Dam M (1976) Clinical pharmacokinetics of
         anticonvulsants. Clin Pharmacokinet, 1: 161-188
    
         Ishizaka A, Nakanishi M, Kasahara E, Mizutani K, Sakiyama Y,
         Matsumoto S (1992) Phenytoin-induced IgG2 and IgG4 deficiencies in
         a patient with epilepsy. Acta Pediatrica, 81: 646-648
    
         Informatorium Medicamentorum (1995) Koniklijke Nederlanse
         Maatschappij ter bevordering van de Pharmacie (Ed). The Hague
    
         Jacobsen D, Alvik A, Bresesen JE (1986) Pharmacokinetics of
         phenytoin. Acute intoxication in an adult and in two children.
         (Abst) Vet Hum Toxicol 28: 473
    
         Jalil P (1992) Toxic reaction following the combined
         administration of fluoxetine and phenytoin: two case reports. J
         Neurol Neurosurg Psychiat, 55: 412-413
    
         Jamerson BD, Dukes GE, Brouwer KL, Donn KH, Messenheimer JA,
         Powell JR (1994) Venous irritation related to intravenous
         administration of phenytoin versus fosphentoin. Pharmacotherapy,
         14: 47-52
    

         Janinis J, Panagos G, Panousaki A, Sklorlos D, Athanasiou E,
         Karpasatis N, Pirounaki M (1993) Stevens-Johnson syndrome and
         epidermal necrolysis after administration of sodium phenytoin with
         cranial irradiation. European Journal of Cancer, 29A: 478-479
    
         Jensen JC & Gugler R (1985) Interaction between metronidazole and
         drugs eliminated by oxidative metabolism. Clin Pharmacol
         Therapeutics, 37:407-410
    
         Kaminsky LS, de Morais SMF, Faletto DA, Dunbar DA, Goldstein JA
         (1993) Correlation of human P4502C substrate specificities with
         primary structure: warfarin as a probe. Mol Pharmacol, 43: 
         234-239
    
         Kay L, Kampmann JP, Svendsen TL, Vergman B, Hansen JEM (1985)
         Influence of rifampicin and isoniazid on the kinetics of
         phenytoin. Br J Clin Pharmacol, 20: 323-326
    
         Kizer JS, Vargas-Gordon M, Brendel K, Bressler R (1970) The in
         vitro inhibition of insulin secretion by diphenylhydantoin. J Clin
         Invest, 49: 1942-1948
    
         Kondo N, Takao A, Tomatsu S, Shimozawa N, Suzuki Y, Ogawa T, Iwata
         H, Orii T (1994) Suppression of IgA production by lymphocytes
         induced by diphenylhydantoin. J Invest Allerg and Clin Immun, 4:
         255-257
    
         Kutt H, Brennan R, Dehejia H, Verebely K (1970) Dipkenylhydantoin
         intoxication-a complication of isoniazid therapy. Am Rev Resp
         Disease, 101: 377-384
    
         Kutt H, Haynes J, Verebely K, McDowell F (1969) The effect of
         phenobarbital on plasma diphenyl-hydantoin level and metabolism in
         man and in rat liver microsomes. Neurology, 19: 611-616
    
         Kutt H, Wolk M, Scherman R, McDowell F (1964) Insufficient
         parahydroxylation as a cause of diphenylhydantoin toxicity.
         Neurology (NY) 14: 542-548
    
         Laubscher FA (1966) Fatal diphenylhydantoin poisoning. JAMA, 198:
         1120-1121
    
         Laurenson IF, Buckoke C, Davidson C, Gutteridge C (1994) Delayed
         fatal agranulocytosis in an epileptic taking primidone and
         phenytoin. The Lancet, 344: 332-333
    
         Leonard RF, Knott PJ, Rankin GO, Robinson DS, Melnick DE (1981)
         Phenytoin-salicylate interaction. Clin Pharmacol Therapeutics, 29:
         56-60
    
         Levin SR, Booker J, Smith DF, Grodsky GM (1970) Inhibition of
         insulin secretion by diphenylhydantoin in the isolated perfused
         pancreas. J Clin Endocrinol Metab, 30: 400-401
    

         Levine M & Chang Y (1990) Therapeutic drug monitoring of phenytoin
         rationale and current status. Clin Pharmacokinet, 19: 341-358
    
         Levine M, Jones MW, Sheppard (1985) Differential effect of
         cimetidine on serum concentrations of carbamazepine and phenytoin.
         Neurology, 35: 562-565
    
         Liu E & Rubinstein M (1982) Phenytoin removal by plasmapheresis in
         thrombotic thrombocytopenic purpura. Clin Pharmacol Ther, 31: 
         762-765
    
         Louis S, Kurt H, McDowell F (1967) The cardiocirculatory changes
         caused by intravenous dilantin and its solvent. Am Heart J, 74:
         523-529
    
         Lumholz B, Siersbaek-Nielsen K, SkovstedL, Kampmann J, Hansen JM
         (1975) Sulfamethizole-induced inhibition of diphenylhydantoin,
         tolbutamide, and warfarin metabolism. Clin Pharmacol Therapeutics,
         11: 731-734
    
         Lunde PKM, Rane A, Yaffe SJ, Lund L, Sjokvist F, (1970) Plasma
         protein binding of diphenylhydantoin in man interaction with other
         drugs and the effect of temperature and plasma dilution. Clin
         Pharmacol Theapeutics, 11: 846-855
    
         Manto M, Preiser J-C, Vincent J-L (1996) Hypoglycaemia associated
         with phenytoin intoxication. Clin Toxicol, 34: 205-208
    
         Maxwell JD, Hunter J, Stewart BA, Ardemans S, Williams R (1972)
         Folate deficiency after anticonvulsant drugs: an effect of hepatic
         enzyme induction ? Br Med J, 1: 279
    
         McEvoy GK ed. (1995) American hospital formulary service, drug
         information, Bethesda, American Society of Hospital Pharmacists,
         pp 1441-1444
    
         McLoughlin P, Newman L, Brown A (1995) Oral squamous cell
         carcinoma arising in phenytoin-induced hyperplasia. British Dental
         Journal, 178: 183-184
    
         Mellick LB, Morgan JA, Mellick GA (1989) Presentations of acute
         phenytoin overdose. Am J Emerg Med, 7, 1: 61-67
    
         Monks A, Boobis S, Wadsworth J, Richens A (1978) Plasma protein
         binding interaction between phenytoin and valproic acid in vitro.
         Br J.Clin Pharmacol, 6: 487-492
    
         Monks A & Richens A (1980) Effect of single doses of sodium
         valproate on serum phenytoin levels in epileptic patients. Clin
         Pharmacol Therapeutics 27: 89-95
    
         Natelli AA Jr. (1992) Phenytoin-induced gingival overgrowth: a
         case report. Compendium 13: 786
    

         Neuvonen PJ, Elfving SM, Elonen E (1978) Reduction of absorption
         of digoxin, phenytoin and aspirin by activated charcoal in man.
         Eur J Clin Pharmacol, 13: 213-218
    
         Neuvonen PJ, Lehtovaara R, Bardy A, Elomaa E (1979) Antipyretic
         analgesics in patients on antiepileptic drug therapy. Eur J Clin
         Pharmacol, 15: 263-268
    
         Neuvonen PK, Tokola RA, Kaste M (1981) Cimetidine-phenytoin
         interaction: effect on serum phenytoin concentration.and
         antipyrine test. Eur J Clin Pharmacol, 21: 215-220
    
         Panegyres PK & Rischbieth RH (1991) Fatal phenytoin warfarin
         interaction. Postgrad Med J, 67: 98
    
         Parker KD, Eliott HW, Wright JA (1970) Blood and urine
         concentrations of subjects receiving barbiturates, meprobamate,
         glutethimide and diphantoin. Clin Toxicol, 2: 131-145
    
         Parker WA & Shearer CA (1979) Phenytoin hepatotoxicity: a case
         report and review. Neurology, 29: 175-178
    
         Patsalos PN & Lascelles PT (1977) Valproic may lower serum-
         phenytoin. Lancet, I: 50-51
    
         Paxton JW (1980) Effects of aspirin on salivary and serum
         phenytoin kinetics in healthy subjects. Clin Pharmacol
         Therapeutics, 27: 170-178
    
         Perlik F, Kolinova M, Zvarova M, Patzelova V (1995) Phenytoin as a
         risk factor in gingival hyperplasia Therapeutic Drug Monitoring,
         17: 445-448
    
         Peruccca E, Hebdige S, Frigo GM, Gatti G, Lecchini S (1980)
         Interaction between phenytoin and valproic acid: plasma protein
         and metabolic effects. Clin Pharmacol Ther, 28: 779-789
    
         Perucca E, Hedges A, Makki K, Ruprah M, Wilson JF (1984) A
         comparative study of the relative enzyme inducing properties of
         anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol,
         18: 401-410
    
         Pezzimenti JF & Hahn AL (1970) Anicteric hepatitis induced by
         diphenylhydantoin. Arch Intern Med, 125: 118-120
    
         Physician's Desk Reference (1995) 49th ed, R Arky & C Davidson, D
         Sifton editor, Medical Economics
    
         Picard EH (1983) Side effects of metronidazole. Mayo Clinic
         Proceedings, 5: 401
    

         Pond SM, Olson KR, Osterloh JD, Tong TG (1984) Randomized study in
         the treatment of phenobarbital overdose with repeated doses of
         activated charcoal. JAMA, 251: 3104-3108
    
         Randazzo DN, Ciccone A, Schweizer P, Winters SL (1995) Complete
         atrioventricular block with ventricular asystole following
         infusion of intravenous phenytoin. J Electrocardiol, 28:
         157-159
    
         Rawanduzy A, Sarkis A, Rovit RL (1993) Severe phenytoin-induced
         bone marrow depression and agranulocytosis treated with human
         recombinant granulocyt-macrophage colony-stimulating factor Case
         report. J Neurosurg, 79: 121-124
    
         Ray-Chaudhuri K, Pye IF, Boggild M (1989) Hypersensitivity to
         carbamazepine presenting with a leukemoid reaction, eosinophilia,
         erythroderma and renal failure. Neurology, 39: 436-438
    
         Rettie AE, Korzekwa KL, Kunze KL, Lawrence RF, Eddy AC, Aoyama H,
         Gelboin HV, Gonzalez FJ, Trager WF (1992) Hydroxylation of
         warfarin by human cDNA expressed cytochrome P-450. A role for
         P4502C9 in the etiology of (S)-warfarin drug intoxications. Chem
         Res Toxicol, 5: 54-59
    
         Reynolds (1982) The extra Pharmacopoeia 28th Ed. E.F.Reynolds
         (editor) The Pharmaceutical Press, London
    
         Reynolds (1996) The extra Pharmacopoeia 31st Ed. E.F.Reynolds
         (editor) The Pharmaceutical Press, London
    
         Richens A & Houghton GW (1975) Effect of drug therapy on the
         metabolism of phenytoin. In Schneider (Ed) Clinical Pharmacololgy
         of Antiepileptic Drugs, pp 87-95, Springer Verlag, Berlin
    
         Riker WK, Downes H, Olsen GD (1978) Conjugate lateral gaze
         nystagmus and free phenytoin concentrations in plasma. Lack of
         correlation. Epilepsia, 19: 93-98
    
         Rindone JP & Bryan G (1996) Phenytoin toxicity associated with
         ticlopidine administration Arch Int.Med, 156: 1113
    
         Roberts CJC, Daneshmend TK, Macfarlane D, Dieppe PA (1981)
         Anticonvulsant intoxication precipitated by azopropazone.
         Postgaduate Medical Journal, 57: 191-192
    
         Robinson JD, Morris BA, Aherne GW (1975) Pharmacokinetics of a
         single dose of phenytoin in man measured by radioimmunoassay. Br
         J.Clin Pharmacol, 2: 345-349
    
         Rodriguez-Garcia JL, Sanchez-Corral J, Martinez J, Bellas C, Guado
         M, Serrano M (1991) Phenytoin-induced benign lymphadenopathy with
         solid spleen lesions mimicking a malignant lymphoma. Ann of
         Oncology, 2: 443-445
    

         Roe TF, Podosin, Blaskovics ME (1975) Drug interaction: diazoxide
         and diphenylhydantoin. J Pediatr, 87: 480-484
    
         Rolan PE, Somogyi AA, Drew MJR (1983) Phenytoin intoxication
         during treatment with parenteral miconazole. Br Med J, 287:
         1760
    
         Roy AK, Mahoney HC, Levine RA (1993) Phenytoin-induced chronic
         hepatitis. Digestive Diseases and Sciences, 38: 740-743
    
         Sambol NC, Upton RA, Chremos AN, Lin ET, Williams RL (1989) A
         comparison of the influence of famotidine and cimetidine on
         phenytoin elimination and hepatic blood flow. Br J Clin Pharmacol,
         27: 83-87.
    
         Sanderson DR (1996) Drug interaction between risperidone and
         phenytoin resulting in extrapyramidal symptoms. J.Clin Psychiat,
         57: 177
    
         Sandyk R (1982) Phenytoin toxicity induced by interaction with
         ibuprofen. South Afr Med J, 62: 592
    
         Sanson LN, Beran RC, Schapel GJ (1980) Interaction between
         phenytoin and valproate. Med J Austr, 2: 212
    
         Schackleford EJ & Watson FT (1987) Amiodarone-phenytoin
         interaction. Drug Intelligence Clin Pharmacy, 21: 921.
    
         Scharf J, Ruder M, Harms D (1990) Plasmaseparation bei akuter
         intravenoeser Phenytoin Intoxication Monatschrift Kinderheilkunde,
         138: 227-230
    
         Schulz P, Giacomini KM, Luttrell S, Turner-Tamiyasu K, Blaschke TF
         (1983) Effect of low doses of heparin on the plasma binding of
         phenytoin and prazosin in normal man. Eur J Clin Pharmacol, 25:
         211-214.
    
         Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner A,
         Gladstone R, Asby P, Weksberg R Einarson T, Koren G (1994)
         Neurodevelopment of children exposed in utero to phenytoin and
         carbamazepine monotherapy. JAMA, 271: 767-770
    
         Seymour RA (1993) Drug-induced gingival overgrowth. Adverse Drug
         Reactions and Toxicological Reviews, 12: 215-232
    
         Skovsted L, Kristensen M, Hansen JM, Siersbaaek-Nielsen K (1976)
         The effect of different oral anticoagulants on phenytoin (DPH) and
         tolbutamide metabolism. Acta Medica Scandinavica, 199: 513-515
    
         Smyth MA & Umstead GS (1989) Phenytoin hepatotoxicity: a review of
         the litterature. Ann Pharmacother, 23: 13-17
    

         Stilman N & Masdeu SC (1985) Incidence of seizures with phenytoin
         toxicity. Neurology, 35: 1769-1772
    
         Subik M & Robinson DS (1982) Phenytoin overdose with high plasma
         levels (case report) West Va Med J, 78: 781-782
    
         Thomason JM, Seymour RA, Rawlins MD (1992) Incidence and severity
         of Phenytoin-induced gingival overgrowth in epileptic patients in
         general medical practice. Community Dentistry and Oral
         Epidemiology, 20: 288-291
    
         Tigaran S (1994) A 15-year follow-up of phenytoin-induced
         unilateral gingival hyperplasia; a case report Acta Neurologica
         Scandinavica, 90: 367-370
    
         Ting S, Maj MC, Dunsky EH (1982) Diphenylhydantoin-induced
         hepatitis. Ann Allergy, 48: 331-332
    
         Tong TG, Pond SM, Kreek MJ et al. (1981) Phenytoin-induced
         methadone withdrawal. Ann Intern Med, 94: 349-351
    
         Troupin AS (1984a) The measurement of anticonvulsant agent levels.
         Ann Intern Med, 100: 854-858
    
         Toupin AS (1984b) Phenytoin therapy and toxicities. Ann Intern
         Med, 101: 568
    
         Tsan MF, Mehlman DJ, Green S (1976) Dilantin, agranulocytosis and
         phagocytic marrow histocytes. Ann Intern Med, 84, 710
    
         Unger AH & Sklaroff HJ (1967) Fatalities following intravenous use
         of sodium diphenylhydantoin for cardiac arrhythmias. JAMA, 200:
         159-160
    
         Vajda FJE, Prineas RJ, Lovell RRH (1971) Interaction between
         phenytoin and the benzodiazepines. Br Med J, 1: 346
    
         Vasko MR, Bell RD, Daly DD, Pippenger CE (1980) Inheritance of
         phenytoin hypometabolism: a kinetic study of one family. Clin
         Pharmacol Ther, 27: 96-103
    
         Veronese ME, Doecke CJ, Mackenzie PI, McManus ME, Miners JO, Rees
         DLP, Gasser R, Meyer UA, Birkett DJ (1993) Site-directed mutation
         studies of human liver cytochrome P-450 isoenzymes in the CYP2C
         subfamily. Biochem J, 289: 533-538
    
         Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO,
         Birkett DJ (1991) Tolbutamide and phenytoin hydroxylations by
         cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res
         Commun, 175: 1112-1118
    
         Vittirio CC & Muglia JJ (1995) Anticonvulsant hypersensitivity
         syndrome. Arch Int Med, 155: 2285-2290.
    

         Viukari NMA (1968) Folic acid and anticonvulsants. Lancet, I:
         980
    
         Walubo A & Aboo A (1995) Phenytoin toxicity due to concomitant
         antituberculosis therapy. South Afr Med J, 85: 1175-1176
    
         Weichbrodt GD & Elliot SP (1987) Treatment of phenytoin toxicity
         with repeated does of activated charcoal. Ann Emerg Med, 16: 
         1387-1389
    
         Weidle PJ, Skiest DJ, Forrest A (1991) Multiple-dose activated
         charcoal as adjunct therapy after chronic phenytoin intoxication.
         Clin Pharm, 10: 711-714
    
         Wesseling H & Mols-Thurkow I (1975) Interaction of
         diphenylhydantoin (DPH) and tolbutamide in man. Eur J Pharmacol,
         8: 75-78
    
         Wilder BJ, Duchanan RA, Serrano EE (1973) Correlation of acute
         diphenylhydantoin intoxication with plasma levels and metabolic
         excretion. Neurology, 23: 1329-1332
    
         Wilder BJ, Willmore LJ, Bruni J, Villareal HJ (1978) Valproic acid
         interaction with other anticonvulsant drugs. Neurology, 28: 
         892-896
    
         Wilson JT, Huff JG, Kilroy AW (1979) Prolonged toxicity following
         acute phenytoin overdose in a child. J Pediatr, 95: 135-138
    
         Wolff de FA, Vermey P, Ferrari MD, Buruma OJS, Breimer DD (1983)
         Impairment of phenytoin parahydroxylation as a cause of severe
         intoxication. Ther Drug Monitoring, 5: 213-215
    
         Wong DD, Longenecker RG, Liepman M, Baker S, LaVergne M (1985)
         Phenytoin-dexamethasone: A possible drug-drug interaction. JAMA,
         254: 2062-2063
    
         Yokochi K, Yokochi A, Chiba K, Ishizaki T (1982) Phenytoin-
         allopurinol interaction: Michaelis Menten kinetic parameters of
         phenytoin with and without allopurinol in a child with Lesch-Nyhan
         syndrome. Ther Drug Monitoring, 4: 353-357
    
         Zielinski JJ, Haidukewych D, Leheta BJ (1985) Carbamazepine-
         phenytoin interaction: Elevation of plasma phenytoin
         concentrations due to carbamazepine comedication. Ther Drug Monit,
         7:51-53
    
         Zifkin B, Sgerwin A, Andermann F (1991) Phenytoin toxicity due to
         interaction with clobazam. Neurology 41: 313-314
    
         Zoneraich S, Zoneraich O, Siegel J (1976) Sudden death following
         intravenous sodium diphenylhydantoin. Am Heart J, 91: 375-377

    12. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADRRESS(ES)

        Author:                 Prof.Dr.A.N.P.van Heijst
                                Baarnseweg 42 A
                                3735 MJ Bosch en Duin
                                The Netherlands
                                Tel. (31) 30 228 7178
                                Fax  (31) 30 225 1368
                                E-mail: 106072.2411@compuserve.com
                                December 1996.
    
        Reviewer:               MO Rambourg Schepens
                                Centre Anti-Poisons de Champagne Ardenne
                                Centre Hospitalier Universitaire
                                F-51092 Reims Cedex
                                France
                                E-mail: marie-odile.rambourg@wanadoo.fr
                                August 1997
    
        Peer review:            N Ben Salah, A Borges, J Gregan, M Mathieu
                                Nolf, L Murray (coordinator), MO Rambourg
                                Schepens
                                Rio, September 1997
    
        Finalization/Edition:   L Murray, MO Rambourg Schepens
                                November 1997
    

See Also:
        Phenytoin (IARC Summary & Evaluation, Volume 66, 1996)




Valproic acid
1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.2.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Others
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)

VALPROIC ACID

    International Programme on Chemical Safety
    Poisons Information Monograph 551
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Valproic acid

        1.2  Group

             Antiepileptic (N03)/Fatty acid derivatives (N03AG)

        1.3  Synonyms

             Abbott-44089;
             2-Propylpentanoic acid;
             2-Propylvaleric acid;
             Di-n-dipropylacetic acid

        1.4  Identification numbers

             1.4.1  CAS number

                    99-66-1

             1.4.2  Other numbers

                    CAS number:
                    Sodium Valproate      1069-66-5
                    Semisodium Valproate  76584-70-8
                    Valproate Pivoxil     77372-61-3
                    Valpromide            2430-27-5

                    RTECS Valproic acid  YV7875000

        1.5  Brand names, Trade names

             Convulex, Convulexette (Belgium)
    
             Promonta, Mylproin, Valcote (Germany)
    
             Byk, Propymal (Netherlands)
    
             Gerot (Switzerland)
    
             Depakene (Canada, Japan, USA, Philippines)
    
             Depakin (Italy)
    

             Depakine (Belgium, France, Netherlands, Spain, Switzerland)
    
             Depamide (France, Italy, Netherlands, Spain)
    
             Deparkine (Denmark, Norway)
    
             Epilim (Australia, South Africa, UK)
    
             Epival (Canada)
    
             Leptilan (Denmark, Germany)
    
             Ergenyl, Leptilen, Orfilept (Sweden)
    
             Logical (Argentina)
    
             Orfiril (Denmark, Germany, Norway, Switzerland)
    
             Vistora (Spain)

        1.6  Manufacturers, Importers

             Promonta (Germany)
             Sigmatau (Italy)
             Labanz (France, Spain, Switzerland, Germany, South Africa)
             Labanz Sanofi (Netherlands, UK)
             Reckitt and Colman (Australia)
             Geigy (Denmark, Germany)
             Leo Rhodia (Sweden)
             Rhône Poulenc (Switzerland, Denmark)
             Vita (Spain)

    2.  SUMMARY

        2.1  Main risks and target organs

             After oral administration, the drug is rapidly absorbed
             from the gastrointestinal tract and metabolized in the
             liver.
    
             Fatal hepatic failure has been reported in patients on
             valproic acid therapy, especially those on chronic use.
    
             Central nervous system depression and convulsions may
             occur.
    
             The drug crosses the placental barrier and has been found in
             breastmilk.
    
             Pancreatitis has also been reported, usually seen in patients
             receiving normal therapeutic dosage.

        2.2  Summary of clinical effects

             Reports showed that acute toxicity is rare, and usually
             follows a benign course (Ellenhorn, 1988).
    
             Fatal hepatic failure is usually seen following chronic use
             of valproic acid. 
    
             The most commonly reported adverse effects are anorexia,
             nausea and vomiting.
    
             Gastrointestinal:
    
             Nausea, vomiting, diarrhoea, pancreatitis (usually receiving
             normal therapeutic doses).
    
             Central nervous system:
    
             Drowsiness, possibly apathy and withdrawal, confusion,
             restlessness, hyperactivity. Less frequently, seizures and
             coma may occur.  Asterixis of both hands and feet.  Delayed
             cerebral oedema.
    
             Sedative effects are more pronounced when drug is used
             together with other anti-epileptic agents.
    
             Liver:
    
             Hepatic failure (centrilobular necrosis).
    
             Haematopoietic system:
    
             Thrombocytopenia, abnormal bleeding time and partial
             thromboplastin time with decreased fibrinogen levels and
             prolonged prothrombin time leading to bruising, petechiae,
             haematoma, and epistaxis.
    
             Skin:
    
             Pruritic macular rashes.
    
             Hair:
    
             Transient alopecia.
    
             Metabolic:
    
             Hyperammonaemia, hypocalcaemia, metabolic acidosis.
    
             Endocrine system:
    
             Altered thyroid functions (clinical significance is unknown).

        2.3  Diagnosis

             Clinical diagnosis is difficult because of multiorgan
             toxicity.
    
             Serum, urine, plasma and breastmilk can be used as samples
             for determining valproic acid and its metabolites using
             either gas chromatography, gas chromatography-mass
             spectrophotometry and high pressure liquid chromatography.

        2.4  First aid measures and management principles

             Assess airway, breathing, circulation and neurological
             status of the patient.  Maintain a clear airway, aspirate
             secretions.  If respiratory depression is present, intubate
             and ventilate.
    
             Emesis with syrup of ipecac is not advisable since, although
             the patient may be conscious on admission, he/she may rapidly
             deteriorate and become somnolent and stuporous.  Gastric
             lavage should be considered, if the patient is seen within 1
             to 2 hours after ingestion. However, if the patient is
             comatose, convulsing or has lost the gag reflex, endotracheal
             intubation is needed.  This procedure, however, is of limited
             value when the drug was taken in syrup form due to rapid
             absorption of the drug.  The use of activated charcoal may be
             considered after oral overdosage.
    
             Enhancement of elimination either by forced alkaline
             diuresis, haemodialysis or haemoperfusion may be of little
             value, because of its high protein binding.
    
             Supportive therapy is the mainstay in the management of
             valproic acid overdose.
    
             If the patient is stuporous, drowsy or somnolent, but
             otherwise with normal vital signs and baseline liver function
             tests are within normal, then simple observation with
             supportive therapy and good nursing care for 24 to 72 hours
             may be sufficient (Ellenhorn & Barceloux, 1988).

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Valproic acid may be synthesized from 4-heptanol by
             successive conversions to 4-bromoheptane with HBr, to
             4-cyanoheptane with HCN and to 2-propyl pentanoic (valproic)
             acid by alkaline hydrolysis of the 4-cyanoheptane (Gennaro,
             1985).

        3.2  Chemical structure

             Molecular formula:
    
             Valproic acid          C8H16O2
             Sodium Valproate       C8H15NaO2
             Semisodium Valproate   C16H31NaO4
             Valproate Pivoxil      C14H26O4
             Valpromide             C8H17NO
    
             Molecular weight:
    
             Valproic acid           144.2
             Sodium Valproate        166.2
             Semisodium Valproate     310.4
             Valproate Pivoxil        258.4
             Valpromide               143.2
    
             Chemical names:
    
             Valproic acid
             2-Propylpentanoic acid
             2-Propylvaleric acid
             Di-n-dipropylacetic acid
    
             Sodium Valproate
             Sodium 2-propylvalerate
             Sodium 2-propylpentanoate
    
             Semisodium Valproate
             2-Propylvaleric acid-sodium 2-propylvalerate
             Sodium hydrogen bis(2-propylvalerate)
    
             Valproate Pivoxil 
             Hydroxymethyl 2-propylvalerate pivalate
    
             Valpromide
             Dipropylacetamide
             2-propylvaleramide
    
             (Reynolds, 1989; USP, 1990)

        3.3  Physical properties

             3.3.1  Colour

                    Colourless to pale yellow

             3.3.2  State/Form

                    Liquid-viscous liquid

             3.3.3  Description

                    It is slightly soluble in water (1.2 mg/mL);
                    fully soluble in acetone, chloroform, ether and methyl
                    alcohol.
    
                    (Ellenhorn & Barceloux, 1988; Reynolds, 1989)

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No data available.

             3.4.2  Storage conditions

                    Store in airtight containers and protect from
                    light.  Valproic acid capsules should be stored at 15
                    to 30°C and freezing should be avoided. (Reynolds,
                    1989; McEvoy, 1991).

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Antiepileptic preparation
                    Antiepileptic drug
                    Fatty acid derivative; antiepileptic

             4.2.2  Description

                    Valproic acid is used solely or in combination
                    with other anticonvulsants in the treatment of simple
                    (petit mal) and complex absence seizures.
    
                    Valproate may be effective against myoclonic and
                    atonic seizures in young children and considered by
                    some experts as the agent of choice.
                    (Gilman et al., 1990).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Oral
    
                    Initial dose of sodium valproate in the UK is 600 mg
                    daily in divided doses, increased every other 3 days
                    by 200 mg daily to a usual range of 1 to 2 g daily (20

                    to 30 mg/kg/day); further increase to a maximum of
                    2.5 g daily may be necessary if adequate control has
                    not been achieved.
    
                    In the USA, doses are expressed in terms of valproic
                    acid with an initial dose of 15 mg/kg/day increased at
                    one-week intervals by 5 to 10 mg/kg/day to a maximum
                    of 60 mg/kg/day.
    
                    The dose for valpromide is from 600 mg to 1800 mg
                    daily in divided doses.
    
                    Parenteral
    
                    Sodium valproate may be administered by slow
                    intravenous infusion or injection.  The suggested
                    initial dose is up to 10 mg/kg followed by further
                    doses as necessary, up to a total of 2.5 g/day.
                    (Reynolds, 1993).

             4.2.2  Children

                    Oral
    
                    A suggested initial dose for children weighing more
                    than 20 kg is 400 mg daily (irrespective of weight) in
                    divided dose, gradually increased until control is
                    achieved, with the usual range of 20 to 30 mg/kg/day;
                    children weighing less than 20 kg may be given a dose
                    of 20 mg/kg/day which may be increased to 40 mg/kg/day
                    in severe cases.  It has been recommended that the
                    dose of 40 mg/kg/day should only be exceeded in
                    patients where plasma concentration, clinical
                    chemistry and haematological parameters are being
                    monitored (Reynolds, 1993).

        4.3  Contraindications

             Valproic acid should not be used in patients with
             hepatic disease and substantial hepatic dysfunction.
    
             Children younger than 2 years and patients receiving multiple
             anticonvulsant therapy or those with congenital metabolic
             disorder or organic brain disease may be at particular risk
             of hepatotoxicity, thus valproic acid should be used with
             extreme caution; the benefits of seizure control must be
             weighed against the risks.
    
             Hypersensitivity to the drug is also a contraindication.
    

             Since the drug crosses the placental barrier and is also
             found in breastmilk, its use in pregnant women is
             contraindicated, however, there is no known effect on nursing
             infants.
    
             (Physician's Desk Reference, 1990)

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Valproic acid is administered orally either as a tablet,
             a syrup or a capsule.

        5.2  Inhalation

             No data available.

        5.3  Dermal

             No data available.

        5.4  Eye

             No data available.

        5.5  Parenteral

             May be given as slow intravenous injection or infusion
             in the form of sodium valproate powder 400 mg (provided with
             diluent).

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             The drug is well absorbed after oral ingestion. 
    
             The extent of availability (i.e. the percentage of an oral
             dose that reaches the arterial blood in an active form to
             produce pharmacological actions) is estimated at 100% (Gilman
             et al., 1990; Moffat, 1986).
    
             Tablets and syrup are rapidly absorbed from the
             gastrointestinal tract.  Blood concentrations of 50 to 100
             mg/mL may be reached at therapeutic dose levels.  Peak plasma
             levels occur from 15 to 60 minutes after ingestion of the
             syrup, and 1 to 4 hours after a single oral tablet dose. 

             After a meal, enteric-coated capsules are absorbed within 1
             to 4.5 hours with peak plasma levels reached at 3 to 7.5
             hours post-ingestion (McEvoy, 1991; Ellenhorn & Barceloux,
             1988).

        6.2  Distribution by route of exposure

             The apparent volume of distribution is about 0.2 L/kg. 
             The bound drug is restricted to the circulation and rapidly
             exchangeable extracelluar water.  The apparent volume of
             distribution of the free drug in the plasma is 1 L/kg which
             indicates some penetration and binding.
    
             Protein binding at therapeutic concentration is about 90%. 
             At higher blood concentration, protein binding decreases,
             thereby causing changes in the clearance and elimination.
    
             Valproic acid appears to localize in structures with the
             highest levels of gamma-aminobutyric acid degradative
             enzymes.  It is distributed mainly to the serum, liver,
             lungs, spleen, skeletal muscles, kidney and the gut.  The
             concentration of valproic acid detected in the CSF is
             approximately 10% that of the plasma.  Its concentration in
             the saliva is 0.5 to 4%.  It crosses the placental barrier
             and appears in breastmilk (1 to 10%).
    
             (Gilman et al., 1990; Ellenhorn & Barceloux, 1988; McEvoy,
             1991).

        6.3  Biological half-life by route of exposure

             A half-life of 7 to 15 hours (Gilman et al.,1990,
             estimate 14 hours) is observed in healthy normal individuals.
             It may be longer in elderly patients, patients with cirrhosis
             and neonates, and in epileptics on valproic acid alone.  The
             half-life is the same after a single or multiple doses. When
             other anticonvulsants are used with valproic acid, the mean
             half-life may be reduced.
    
             In children the half-life of valproic acid alone is 10  to 11
             hours; when other medications are added, half-life may be
             reduced to 8 to 9 hours.  Half-lives of up to 30 hours have
             been reported in overdosage.
    
             (Ellenhorn & Barceloux, 1988; McEvoy, 1991)

        6.4  Metabolism

             Valproic acid is metabolized principally in the liver by
             the beta and omega oxidation.  There is no evidence that it
             can enhance its own metabolism, but metabolism may be
             enhanced by other drugs which induce hepatic microsomal
             enzymes.
    

             More than 10 metabolites have been identified in human blood
             and urine, but only 2-propyl 2-pentanoic acid (2-en-VPA) has
             been shown to accumulate in the brain and is 1.3 times more
             potent than its parent compound and it contributes
             significantly to the anti-convulsant effect of chronically
             administered valproic acid.

        6.5  Elimination and excretion

             The total systemic clearance of the drug from plasma is
             0.11 mL/min/kg. About 1.8% per cent of the administered dose
             is excreted unchanged in the urine of a healthy young adult
             (Gilman et al., 1990).
    
             Valproic acid is eliminated by first order kinetics. Plasma
             clearance after a therapeutic dose is 5 to 10 mL/min and is
             independent of liver blood flow. The free drug is cleared
             much more rapidly about 77 mL/min.  Excretion occurs
             partially in the form of ketone bodies (Ellenhorn &
             Barceloux, 1988).
    
             Metabolites are excreted in the urine as unchanged valproic
             acid 1 to 3%; valproic acid glucuronide 20%; 3-oxovalproic
             acid 3 to 60% and omega oxidation products 2 to 30%. 
             Elimination also occurs by faecal excretion 2 to 3% and in
             expired air.  About 7% of the dose undergoes enterohepatic
             recirculation - results of studies in rats (Ellenhorn &
             Barceloux, 1988; Reynolds, 1989; McEvoy, 1991).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    No data available.

             7.1.2  Pharmacodynamics

                    The mechanism of action of valproic acid is
                    unknown.  Effects of the drug may be related, at least
                    in part, to increased brain concentrations of the
                    inhibitory neurotransmitter GABA.  Animal studies have
                    shown that valproic acid inhibits GABA transferase and
                    succinic aldehyde dehydrogenase, enzymes which are
                    important for GABA catabolism.  Results of one study
                    indicate the drug inhibits neuronal activity by
                    increasing potassium conductance.  In animals,
                    valproic acid protects against seizure induced by
                    electrical stimulation, as well as those induced by
                    pentylenetetrazol (McEvoy, 1991).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Toxic effects are frequently
                             associated with daily doses of over 1,800 mg
                             per day and blood levels of over 100 mg/mL.
                             Unconsciousness occurs when more than 200
                             mg/kg has been ingested.  Death has been
                             associated with blood levels of 1970 mg/mL
                             and recovery at blood levels at 218 mg/mL. 
                             However, plasma concentration and clinical
                             effects are not correlated sufficiently
                             closely to be of value clinically (Ellenhorn
                             & Barceloux, 1988).

                    7.2.1.2  Children

                             In a study of 88 paediatric patients
                             receiving sodium valproate monotherapy, side
                             effects were noted in 71 patients and
                             although average doses in these patients were
                             significantly higher than in the 17 patients
                             with no side effects, no difference in plasma
                             concentration was noted.  Behavioural
                             alterations, digestive disorders, and
                             neurological changes were the common side
                             effects observed.  None of the children
                             showed hepatic or pancreatic dysfunction
                             except for 2 cases who had transient increase
                             in their transaminases (Reynolds, 1989).

             7.2.2  Relevant animal data

                    LD50 oral (rats) (valproic acid) 670
                    mg/kg
    
                    LD50 oral (mice) (sod. valproate) 1700 mg/kg
    
                    (Budavari, 1989)
    
                    In 2-year rat and chronic mouse studies using dosages
                    of 80 to 170 mg/kg/day, an increased incidence of
                    subcutaneous fibrosarcoma occurred in male rats at the
                    higher dosage level and a dose-related trend for an
                    increased incidence of benign pulmonary adenomas was
                    observed in male mice.  The importance of these
                    findings to humans is not known (McEvoy, 1991).

             7.2.3  Relevant in vitro data

                    No relevant data available.

        7.4  Teratogenicity

             Safe use of valproic acid during pregnancy has not been
             established.  Adverse foetal effects have been observed in
             reproduction studies in rats and mice.  Although several
             reports suggest an association between the use of valproic
             acid in pregnant epileptic women and an increased incidence
             of birth defects (particularly neural tube defects) in
             children born to these women, a causal relationship remains
             to be established (McEvoy, 1991).

        7.5  Mutagenicity

             Studies to date have not shown any evidence of mutagenic
             potential for the drug (McEvoy, 1991).

        7.6  Interactions

             Phenobarbital levels increase when valproic acid is
             given concomitantly, enhancing sedative effects.  Mechanism
             is unknown.  Phenobarbital dose should be reduced.
    
             Carbamazepine serum concentration is increased when valproic
             acid is added to the treatment regimen.  This is largely due
             to an increase in the carbamazepine epoxide level.
    
             Phenobarbital, primidone, phenytoin and carbamazepine may
             produce enzyme inducing effects that can lower the half life
             of valproic acid.
    
             Valproic acid increases the half life of levodopa.
    
             Valproic acid potentiates the CNS depressant effects of
             alcohol.
    
             Administration of clonazepam and valproic acid has been
             reported to produce absence status epilepticus.
    
             Valproic acid inhibits the secondary phase of platelet
             aggregation reflected in an altered bleeding time.  Caution
             is recommended when it is administered with acetylsalicylic
             acid or warfarin.
    
             Cimetidine and ranitidine slightly increase the half life of
             valproic acid when they are added in the treatment regimen. 
             They do not affect volume of distribution or clearance of
             valproic acid.
    

             Valproic acid may potentiate the effects of MAO inhibitors
             and other anti-depressant drugs.  Dosage reduction of these
             drugs may be necessary when given with valproic acid.
    
             Serum protein binding of diazepam is competitively inhibited
             by valproic acid.
    
             (Ellenhorn & Barceloux, 1988; Reynolds, 1989; Griffin, 1988).

        7.7  Main adverse effects

             Gastrointestinal
    
             The most frequent effects of valproic acid are nausea, and
             vomiting.  These adverse effects are usually transient,
             rarely require discontinuation of the drug, and can be
             minimized by administering the drug with meals or by
             gradually increasing the dose. Hypersalivation, anorexia with
             weight loss, increased appetite with weight gain, abdominal
             cramps, diarrhoea and constipation have been reported in
             patients receiving valproic acid.  Acute pancreatitis has
             also been reported (McEvoy, 1991).
    
             These transitory gastrointestinal disturbances are dose-
             related and occurs approximately in 16% of patients treated
             with the drug.
    
             Nervous system
    
             Sedation and drowsiness may occur with valproic acid therapy,
             especially in patients receiving other anticonvulsants.  Some
             patients have reported increased alertness during valproic
             acid therapy.  Rarely paraesthesia, ataxia, headache,
             nystagmus, diplopia spots before the eyes, tremors,
             asterixis, dysarthria, dizziness and incoordination have been
             reported.  Anxiety, confusion, emotional upset, mental
             depression, hallucinations and other behavioural disturbances
             have been reported in a few children receiving valproic acid
             (McEvoy, 1991).
    
             Hepatic
    
             Minor elevation in serum transaminases and lactate
             dehydrogenase occur frequently in patients receiving valproic
             acid.  Occasionally, increases in serum bilirubin
             concentrations and abnormal changes in other hepatic
             functions may reflect potentially serious hepatoxicity
             (McEvoy, 1991).
    
             Prodromal symptoms include anorexia, vomiting followed by
             jaundice, ascites then hepatic encephalopathy eventually by
             death after a few weeks.
    

             Metabolic
    
             Hyperammonaemia with or without lethargy or coma may occur in
             patients receiving valproic acid and may occur in the absence
             of abnormal liver function.  Hyperglycaemia has also been
             reported in valproic acid therapy (McEvoy, 1991).
    
             Haematological
    
             Valproic acid inhibits the secondary phase of platelet
             aggregation and may prolong bleeding time.  Thrombocytopenia,
             petechiae, bruising, haematoma, epistaxis, otorrhagia,
             lymphocytosis, leucopenia, eosinophilia, decreased fibrinogen
             levels, anaemia and bone marrow depression have been reported
             (McEvoy, 1991).
    
             Dermatological
    
             Transient alopecia, curliness of the hair, generalized
             pruritus, photosensitivity and erythema multiforme have been
             reported in valproic acid therapy (McEvoy, 1991).
    
             Others
    
             Rare adverse effects include muscular weakness, enuresis and
             fatigue, irregular menses and secondary amenorrhoea.  Altered
             thyroid function has been reported but the clinical
             significance is not known (McEvoy, 1991; Physician's Desk
             Reference, 1990).

    8.  TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
    
             Blood collected on EDTA for plasma sample.  Other samples
             used are serum, urine and breastmilk.  Blood samples should
             be collected 1 to 4 hours post-ingestion.
    
             Biomedical analysis
    
             Gas chromatography mass spectrophotometry is a useful and
             accurate method of measuring valproic acid and its
             metabolites.
    
             Toxicological analysis
    
             Measuring blood levels of valproic acid and its metabolites
             is not considered to be of practical assistance in the
             clinical management of valproic acid poisoning since plasma
             concentrations and clinical effects do not correlate closely.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Toxic effects are frequently associated with
                    dose levels over 1,800 mg per day and blood levels of
                    >100 mg/mL.  Unconsciousness occurs when 200 mg/kg
                    has been ingested (Ellenhorn & Barceloux, 1988).

             9.1.2  Inhalation

                     No data available.

             9.1.3  Skin exposure

                    No data available.

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Hepatoxicity associated with valproic acid use
                    manifests itself in 3 ways:
    
                    Asymptomatic elevation in serum concentration of liver
                    enzymes (fairly common).
    
                    Hyperammonaemia associated with lethargy, vomiting,
                    stupor or coma but generally not accompanied with
                    hepatocellular damage.
    
                    Acute hepatoxicity that may terminate fatally, usually
                    seen in children and adolescents during the first six
                    months of therapy.  Its frequency is 1 in 5,000
                    children.  Hepatic failure has been observed
                    displaying a Reye's syndrome like illness (Ellenhorn &
                    Barceloux, 1988).

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Acute valproic acid poisoning is observed relatively
             infrequently compared to other anticonvulsants.  Reports have
             shown that in most patients the poisoning follows a benign
             course.  Death is rare but if it occurs it results from
             cardio-pulmonary arrest secondary to hepatic failure.
    
             Hepatoxicity following chronic use may be asymptomatic or may
             have a fulminant course (Ellenhorn & Barceloux, 1988).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension

             9.4.2  Respiratory

                    Depression; arrest in fulminant course.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Patient is usually drowsy, may be
                             apathetic and withdrawn, stuporous, confused,
                             restless, hyperactive.  Rarely seizures,
                             myoclonic movements, unconsciousness, coma. 
                             No dysarthria, nystagmus or ataxia. 
                             Asterixis.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Muscle weakness.

             9.4.4  Gastrointestinal

                    Nausea, vomiting, diarrhoea and pancreatitis.

             9.4.5  Hepatic

                    Centrilobular necrosis, hepatic failure.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Nocturnal enuresis.

                    9.4.6.2  Others

             9.4.7  Endocrine and reproductive systems

                    Irregular menses and secondary amenorrhoea.
    
                    Altered thyroid function test (clinical significance
                    is not known).

             9.4.8  Dermatological

                    Macular pruritic rashes.

             9.4.9  Eye, ear, nose, throat

                    Pupils may pinpoint and sluggishly reactive to
                    light. 

                    Tablets may cause irritating sensation in the throat
                    if accidentally chewed.

             9.4.10 Haematological

                    Petechiae, bruising, haematoma, epistaxis.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Metabolic acidosis has been
                             reported (Dupuis et al., 1990).

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hypocalcaemia (Dupuis et al.,
                             1990).

                    9.4.12.3 Others

                             Hyperammonaemia with or without
                             lethargy, or coma with or without deranged
                             liver function.

             9.4.13 Allergic reactions

                    Pruritic rash

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy
    
                    Increased risk of neural tube defects (spina bifida)
                    if used during first trimester.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Establish the airway and breathing and evaluate
             circulatory status.  If respiration is depressed on
             admission, then perform endotracheal intubation and support
             ventilation using appropriate mechanical device.  Supportive
             treatment is the mainstay in the management of valproic acid
             overdose.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Supportive treatment is the mainstay of valproate
             overdose.  Maintenance of adequate urine output and
             discontinuation of all anticonvulsive drugs and all hepatic
             enzyme inducers will be sufficient for rapid recovery within
             24 to 72 hours.  Hepatic and pancreatic function should be
             monitored by appropriate biochemical investigations.
    

             The drug should be discontinued and seizures should be
             managed by the use of intravenous diazepam (0.1 to 0.3 mg/kg)
             to a maximum of 20 mg in an adult.  This may be repeated in
             10 to 20 minutes if required.
    
             If patients are stuporous, somnolent, or drowsy, but
             otherwise have normal vital signs and liver function tests,
             then simple observation with good nursing care and supportive
             therapy for 24 to 72 hours in a hospital intensive care unit
             may be sufficient.

        10.3 Decontamination

             Emesis with syrup of ipecac is not ordinarily advisable
             since although the patient may be awake on admission, he/she
             may deteriorate rapidly and become somnolent or stuporous and
             aspiration is possible.
    
             Gastric lavage may be considered.  However, if the patient is
             comatose, convulsing, or has lost the gag reflex,
             endotracheal intubation is needed.  This procedure  may be of
             limited value if the drug was taken in syrup form because of
             the very rapid absorption of the drug.
    
             Activated charcoal (adults, 50 to 100 g; children, 15 to 30
             g) may adsorb valproate still in the gut after the overdose. 
             Cathartics are no longer recommended.

        10.4 Enhanced elimination

             No systematic studies are available to support the
             usefulness of forced alkaline diuresis, haemodialysis,
             peritoneal dialysis, exchange transfusion, or haemoperfusion. 
             The high degree of protein binding, minimal amount of
             unchanged drug excreted through the kidneys, and short
             spontaneous course to recovery with supportive treatment
             alone would tend to preclude the need for such
             measures.

        10.5 Antidote treatment

             10.5.1 Adults

                    No data available.

             10.5.2 Children

                    No data available.

        10.6 Management discussion

             The use of naloxone at a dose of 0.01 mg/kg
             intravenously given in patients who are unconscious following
             ingestion of large amount of valproic acid has been reported
             to cause improvement in a 19-month-old male who ingested 2.25
             g of valproic acid (serum level of 185 mg/ml) and presented
             as unconsciousness with poorly reactive pupils three hours
             post-ingestion.  This treatment, however, has yet to be
             confirmed.  Naloxone has been reported to reverse the CNS
             depressant effects of valproic acid overdosage and
             theoretically it could also reverse the anti-epileptic
             effects of valproic acid, therefore naloxone should be used
             with caution (Ellenhorn & Barceloux, 1988; Physician's Desk
             Reference, 1990).

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1
    
             A 16-year-old epileptic female ingested 30 g of enteric
             coated sodium valproate tablets and 5 hours later appeared
             somnolent, though other physical examination findings appear
             to be within normal.  The serum valproate levels was 689.5
             mg/mL 6 hours after ingestion.  She was treated with gastric
             lavage and activated charcoal and awoke 12 hours post-
             ingestion (Ellenhorn & Barceloux, 1988).
    
             Case 2
    
             A 24-year-old female on 2.2 g/day of sodium valproate was
             stuporous, withdrawn and confused and suffered from visual
             hallucinations with a serum valproic acid level of 113 mg/mL.
             Dose was adjusted to 1.8 g/day and symptoms were resolved
             (Ellenhorn & Barceloux, 1988).
    
             Case 3
    
             A 15-year-old girl ingested an unknown amount of sodium
             valproate, became comatose and died of cardio-respiratory
             arrest at the 20th hour with a plasma level of 1,914 mg/L
             (Ellenhorn & Barceloux, 1988).
    
             Case 4
    
             One adult who ingested 36 g of valproic acid in addition to
             1 g of phenobarbital and 300 mg of phenytoin became deeply
             comatose 4 hours post-ingestion of the drugs.  The patient
             recovered following supporting therapy (McEvoy, 1991).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Drugs should not be used in patients with hepatic
             disease or significant hepatic dysfunction.  It should not be
             used in pregnant women.  It should be used with caution in
             children below 2 years old, patients with multiple anti-
             epileptic therapy, congenital metabolic disorders, and those
             with organic brain disease.

        12.2 Others

             No data available.

    13. REFERENCES

        Budavari S ed. (1989) The Merck index, an encyclopedia of
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,
        Merck and Co., Inc.
    
        Dupuis RL, Lichtman SIV, & Pollack GM (1990) Acute valproic
        overdose: Clinical course and pharmacokinetic disposition of
        valproic acid and metabolites. Drug Safety, 5(1) 65: 71.
    
        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis
        and treatment of human poisoning. New York, Elsevier Science
        Publishing Co, Inc, p 261-265.
    
        Gennaro AR ed. (1985) Remington's pharmaceutical sciences 17th ed.
        Easton, Pennsylvania, Mack Publishing Company, p 1082.
    
        Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New
        York, Pergamon Press, pp 450-453, 1714.
    
        Griffin JP ed.(1988) A Manual of Adverse Drug Interactions, 4th
        ed. (1988) Butterworth and Co (Publishers) Ltd, p 173.
    
        McEvoy GK ed. (1991)  American hospital formulary service, drug
        information. Bethesda, MD, American Society of Hospital
        Pharmacists, p 1147.
    
        Moffat AC ed.  (1986) Clarke's isolation and identification of
        drugs in pharmaceuticals, body fluids, and post-mortem material.
        2nd ed. London, The Pharmaceutical Press, p 1059.
    
        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 29th
        ed. London, The Pharmaceutical Press, p 413.
    
        Physician's Desk Reference (1990) 44th ed. Ordell NJ, Medical
        Economics.
    

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th
        ed. London, The Pharmaceutical Press. pp 311-313.
    
        United States Pharmacopeia, 22nd rev. The National formulary 17th
        ed. (1990)  Rockville MD, United States Pharmacopeial Convention, 
        p 1400.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author: Dr M Mercedes Maat
        National Poisons Control and Information Service
        University of the Philippines
        College of Medicine
        Philippine General Hospital
        Ermita
        Manila 1000
        Philippines
    
        Fax 63-2-50 10 78
    
        Date: December 1991
    
        Reviewer: Dr Tempowski, London Centre
    
        Date: February 1995
    
        Peer review:  Cardiff, United Kingdom, March 1995 (Drs Pronczuk,
        Hartigan-Go, Tempowski, & Ten Ham).
    
        Editor: Dr M. Ruse (October, 1997)
    


PHENYTOIN
(Group 2B)
For definition of Groups, see Preamble Evaluation.

VOL.: 66 (1996) (p. 175)

CAS No.: 57-41-0
Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione

CAS No: 630-93-3
Chem. Abstr. Name: 5,5-Diphenyl-2,4-imidazolidinedione, monosodium salt

5. Summary of Data Reported and Evaluation
5.1 Exposure data

Phenytoin, often administered as its sodium salt, has been widely used since the 1930s as an anticonvulsant in the treatment of epilepsy and, to a lesser extent and more recently, in the treatment of certain cardiac arrhythmias.

5.2 Human carcinogenicity data

Many case reports have suggested that there may be a relationship between lymphomas and anticonvulsants, especially phenytoin. In a cohort study in Denmark of epileptic patients exposed to anticonvulsants, including phenytoin, there was an increase in overall cancer risk, attributable to an excess of brain and lung cancer. Nevertheless, brain tumours probably caused the seizure disorder; an evaluation of brain tumour risk over time showed that these tumours were unlikely to be drug-related.

Nested case-control studies based on the Danish cohort investigated in detail the influence of several treatments with anticonvulsants on the risk of cancers of the lung, bladder and liver and non-Hodgkin lymphoma. Anticonvulsant treatment with phenytoin was not associated with lung, bladder or liver cancer. There was an elevated risk for non-Hodgkin lymphoma associated with phenytoin use, but this was not significant.

Two case-control studies investigated the relationship between multiple myeloma and the use of phenytoin, among many other factors. One found no association between phenytoin use and a risk for multiple myeloma. The other study found a nonsignificantly elevated risk associated with the use of phenytoin. The power of both studies to assess an effect of phenytoin was low.

5.3 Animal carcinogenicity data

Phenytoin was tested for carcinogenicity by oral administration in three experiments in mice and in two experiments in rats. It was also tested by perinatal/adult exposure in one study in mice and rats and by intraperitoneal administration in one study in mice.

In one experiment in three strains of female mice, oral administration of the sodium salt of phenytoin was reported to increase the incidence of lymphomas. Oral administration to female mice in another study decreased the incidence of mammary gland adenocarcinomas, leukaemias and polyps of the endometrium; in a further study, the incidence of hepatocellular tumours was reduced in males. Oral administration to rats did not increase the incidence of tumours in two studies.

In the experiment using combinations of adult and perinatal exposure, adult exposure resulted in a dose-dependent increase in the incidence of hepatocellular tumours in female mice. Perinatal treatment followed by adult exposure increased the incidence of hepatocellular tumours in both male and female mice and slightly in male rats. Following intraperitoneal injection of phenytoin into mice, leukaemias and lymphomas were observed.

In one experiment in mice, phenytoin increased the incidence of hepatocellular tumours induced by N-nitrosodiethylamine. In a mouse lung adenoma assay, phenytoin decreased the multiplicity of lung adenomas induced by urethane.

5.4 Other relevant data

Phenytoin is well absorbed in humans. It is eliminated mainly as the glucuronide of the major metabolite, 5-(4'-hydroxyphenyl)-5-phenylhydantoin, which typically accounts for 67-88% of the dose in urine. Several other metabolites are known. The elimination kinetics are non-linear, but an apparent mean half-life of 22 h is a useful guide.

5-(4'-Hydroxyphenyl)-5-phenylhydantoin is the main metabolite in all animal species except dogs (5-(3'-hydroxyphenyl)-5-phenylhydantoin) and cats (the N-glucuronide).

Acute phenytoin intoxication in humans presents usually with cerebellar-vestibular effects such as nystagmus, ataxia, diplopia, vertigo and dysarthria. Chronic administration of phenytoin at therapeutic doses may rarely induce various adverse health effects such as symptoms associated with impairment of the nervous system described above. Gingival overgrowth, sometimes together with increased thickness of the craniofacial bones as well as folic acid deficiency and development of megaloblastic anaemia, are well established adverse effects of the drug. Phenytoin has also been associated with various forms of cutaneous hypersensitivity reactions, sometimes accompanied by lymphadenopathy and benign lymphoid hyperplasia. In rare cases, the histological architecture of the lymph nodes is lost (pseudolymphoma). Phenytoin may also induce a variety of endocrine effects such as reduction of thyroxine concentrations, hypocalcaemia, osteomalacia and hyperglycaemia.

The nervous system appears to be the major target of acute and chronic phenytoin toxicity in experimental animals. In addition, repeated administration of phenytoin induces increased liver and kidney weights, centrilobular hepatic hypertrophy and diverse immunosuppressive effects. Phenytoin may reduce thyroxine concentrations and increase bone thickness in rodents, but gingival hyperplasia has been observed only in cats and monkeys and not in rodents. Phenytoin is an inducer of certain hepatic cytochrome P450 activities in humans and mice. There is evidence for the teratogenicity of phenytoin in humans ingesting 100-800mg per day during the first trimester of gestation. Phenytoin is teratogenic in mice and rats. Animal and a few human studies suggest that neurobehavioural deficits occur at doses which produce no dysmorphic effect.

Phenytoin induced mutations in Salmonella typhimurium in the presence of a metabolic activation system in one study. No mutagenic effect was observed in Drosophila or in mammalian cells in vitro in the absence of an exogenous metabolic system. Aneuploidy was induced in one study in primary mouse embryonic fibroblasts in vitro. Cell transformation was induced in Syrian hamster embryo. A single study showed increased clone sizes of murine macrophages in a host-mediated assay. Phenytoin inhibited gap-junctional intercellular communication. In human lymphocytes in vitro, sister chromatid exchanges were induced in one study and chromosomal aberrations were induced in two of five studies. Aneuploidy was observed in human amnion cells but not in lymphocytes. Phenytoin induced micronuclei in three of five studies in rodents in vivo. Aneuploidy, in one of two studies, aberrant sperm morphology and dominant lethal mutations were induced, but not sister chromatid exchange or chromosomal aberrations.

In general, studies of human lymphocytes in vivo showed no induction of micronuclei, chromosomal aberrations or aneuploidy but an increase of polyploidy was found in one study and of sister chromatid exchange frequencies in three of seven studies. Neither chromosomal aberrations nor aneuploidy were induced in human bone marrow.

The metabolite 5-(4'-hydroxyphenyl)-5-phenylhydantoin was mutagenic in Salmonella typhimurium in the presence of a metabolic activation system; it did not induce micronuclei in mouse bone marrow in vivo.

Mechanistic considerations

Evidence is available to support the conclusion that phenytoin induces liver tumours in mice by a promoting mechanism. The increase in liver weight, centrilobular hypertrophy and pattern of cytochrome P450 induction are similar to those observed with other non-genotoxic mouse liver tumour promoters such as phenobarbital. In addition, the inhibition of cell-cell communication by phenytoin in vitro supports the role of promotion in mouse carcinogenesis.

The metabolic activation of phenytoin to a reactive intermediate has been proposed to account for the teratogenicity and possible genotoxicity of phenytoin. One possible intermediate is an arene oxide, that is hypothesized to result in binding to cellular macromolecules. However, this possibility has not been evaluated definitively, and studies of potential DNA damage in mouse liver or hepatocytes have not been reported. The mechanism of induction of aneuploidy by phenytoin in vitro is unclear, as is its relationship to carcinogenicity in mouse liver.

5.5 Evaluation

There is inadequate evidence in humans for the carcinogenicity of phenytoin.

There is sufficient evidence in experimental animals for the carcinogenicity of phenytoin.

Overall evaluation

Phenytoin is possibly carcinogenic to humans (Group 2B).

For definition of the italicized terms, see Preamble Evaluation

Previous evaluation: Suppl. 7 (1987) (p. 319)

Synonyms for Phenytoin

Aleviatin
Denyl
Difhydan
Dihycon
Di-Hydan
Dihydantoin
Dilabid
Di-Lan
Dilantin
Dilantin-125
Dilantin Infatabs
Dilantin-30 Pediatric
Dintoina
Diphantoin
Diphedan
Diphenylhydantoin
DPH
Diphentyn
Ekko
Enkefal
Epanutin
Epdantoin Simple
Epelin
Epiland
Epinat
Eptoin
Fenantoin
Hidantal
Hydantin
Hydantol
Lehydan
Lepitoin
Novophenytoin
Phenhydan
Phenhydantin
Sodanton
Tacosal
Zentropil
Synonyms for Phenytoin Sodium

Soluble phenytoin
Alepsin
Aleviatin
Aleviatin sodium
Antisacer
Citrullamon
Danten
Dantoin
Denyl
Difenin
Difetoin
Difhydan
Dilantin
Di-Len
Dintoina
Diphantoine
Di-Phen
Diphenin
Diphenine
Diphenylan
Diphenylhydantoin sodium
5,5-Diphenylhydantoin sodium
Ditoin
Enkefal
Epanutin
Epdantoin Simple
Epelin
Epilan D
Epilantin
Epsolin
Eptoin
Hidantal
Hydantin
Hydantoinal
Idantoin
Minetoin
Muldis
Neosidantoina
Novodiphenyl
Om-Hydantoïne;
Phenhydan
Pyorédol
SDPH
Sodium diphenylhydantoin
Sodium 5,5-diphenylhydantoin
Sodium diphenylhydantoinate
Sodium 5,5-diphenyl-2,4-imidazolidinedione
Sodium phenytoin
Solantyl
Tacosal
Thilophenyt
Zentropil
Last Updated 05/22/97
See Also:
        Phenytoin (PIM 416)