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CBD Oil and Antibiotics

Does CBD Interact With Antibiotics?

Antibiotics are used to prevent or treat specific types of bacterial infections. In some cases, they are prescribed for an infection that keeps coming back or causes an increased risk of complications.

However, antibiotics are not effective against viral infections, such as the common cold or flu (1).

Can CBD Be Taken With Antibiotics?

There is no known interaction between CBD (cannabidiol) and antibiotics. However, there is a potential risk when combining CBD and antibiotics, as both are metabolized (broken down) through the cytochrome P450 enzyme system (2).

Due to how antibiotics are metabolized, the concentrations of these drugs could potentially increase when taken with CBD.

The CYP450 liver enzymes are responsible for breaking down toxic compounds, including over 60% of any over-the-counter or prescription drugs consumed.

Certain substances can affect processing times within this system, making drugs metabolize faster or slower than they would on their own.

Cannabidiol can inhibit the cytochrome P450 system’s ability to metabolize certain drugs, leading to an overall increase in processing times (3)

Antibiotics use the cytochrome P450 enzyme system and can interact with CBD, as reiterated by authors Eileen Konieczny, RN, and Lauren Wilson, in their book, Healing with CBD (4).

Until studies that specifically look at how CBD interacts with antibiotics are completed, talk with a doctor to make sure there are no CBD drug interactions with other medications currently taken.

CBD Oil As Antibiotic: What the Research Says

CBD oil has been shown to possess antimicrobial properties, making it another tool for fighting infection. 

Although it is not well-understood how CBD oil fights bacteria, studies have confirmed CBD’s antibiotic properties, which are particularly useful in attacking bacteria that have become resistant to traditional antibiotics.

One suchstudy investigated how various cannabinoids, including CBD and tetrahydrocannabinol (THC), affect pathogenic bacteria (5).

In the said study, each cannabinoid was tested against six strains of the antibiotic-resistant superbug, methicillin-resistant Staphylococcus aureus (MRSA). All cannabinoids showed potent activity against a variety of MRSA strains. 

Results of the study indicated that CBD has proven to be effective at fighting one of the most treatment-resistant strains of bacteria the field of medicine has ever seen.

Then, the researchers at the University of Queensland’s Institute for Molecular Bioscience discovered in 2019, through a series of test-tube experiments, that CBD could kill numerous strains of bacteria, including treatment-resistant strains like VRSA, VISA, and MRSA(6).

These strains have developed resistance to other existing Food and Drug Administration (FDA)-approved antibiotics over the years. However, they did not develop any resistance to CBD. 

In one of the experiments, the researchers found that despite exposing the strains to CBD for 20 days, this cannabis compound was able to outmanoeuvre the entire process of superbug development.

Moreover, CBD was found to be effective at disrupting biofilms, a physical form of bacteria growth that leads to difficult-to-treat infections. This breakthrough in microbiology could ultimately lead to the development of new treatments.

Lead author, Mark Blaskovich, stated there was no doubt CBD possessed a unique mechanism that worked against bacteria resistant to other antibiotics. He admitted, however, that he and his team still could not explain how this mechanism works. 

A laterstudy, conducted in August 2019 by scientists from the United Kingdom, has shed light on the workings of that unique mechanism (7).

In the said study, which was published in Frontiers in Cellular and Infection Microbiology, the authors examined the antibacterial effects of CBD and Escherichia Coli bacteria (E. coli)’s membrane vesicles, which the bacteria use to spread and communicate. 

The researchers discovered that the antibiotic's ability to prevent the release of those membrane vesicles is enhanced by CBD. 

The results suggested that CBD could help fight specific bacteria as a tailored co-application with selected antibiotics.

The researchers concluded that CBD might help increase antibiotic activity and reduce antibiotic resistance when used in tailored co-application.

Conclusion

The results of the studies demonstrating CBD’s antibiotic properties are especially exciting for the CBD community. 

However, it is essential to note that researchers still do not know what made CBD powerful at fighting the infections during the experiments. 

All the research was carried out in a lab, in test tubes and on bacteria cultures, not on humans.

To date, there has been no study that recommends taking CBD with antibiotics. Neither is there a study that suggests CBD can replace antibiotics in the treatment or prevention of some types of bacterial infections. 

Further research needs to be conducted to study the long-term side effects and resistance of CBD as an antibiotic. 

Before taking CBD or any CBD products to treat or prevent any infection, do research and consult with a doctor experienced in cannabis use for advice.



References

  1. NHS. (2019, May 23). Antibiotics Uses. Retrieved from https://www.nhs.uk/conditions/antibiotics/uses/.
  2. Pharmotech SA. CBD Drug Interactions. Retrieved from https://pharmotech.ch/cbd-drug-interactions/.
  3. Ibid. 
  4. Eileen Konieczny and Lauren Wilson. Healing with CBD: How Cannabidiol Can Transform Your Health without the High (California: Ulysses Press, 2018). P46-47.
  5. Giovanni Appendino, G et al. Antibacterial Cannabinoids from Cannabis sativa: A Structure−Activity Study. Journal of Natural Products 2008 71 (8), 1427-1430. DOI: 10.1021/np8002673.
  6. The University of Queensland. (2019, June 24). Cannabis compound could be powerful new antibiotic. Retrieved from https://imb.uq.edu.au/article/2019/06/cannabis-compound-could-be-powerful-new-antibiotic; CDC. (2010, Nov 24). General Information about VISA/VRSA. Retrieved from https://www.cdc.gov/hai/organisms/visa_vrsa/visa_vrsa.html; CDC. (2019, June 26). Methicillin-resistant Staphylococcus aureus (MRSA). Retrieved from https://www.cdc.gov/mrsa/community/index.html
  7. Kosgodage US, Matewele P, Awamaria B, et al. Cannabidiol Is a Novel Modulator of Bacterial Membrane Vesicles. Front Cell Infect Microbiol. 2019;9:324. Published 2019 Sep 10. DOI:10.3389/fcimb.2019.00324.

Rifampicin

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
   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
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of local available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
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 ENTRY
   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 Methods
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Therapeutic and toxic concentrations
      8.2.1 Test for active ingredients
      8.2.2 Test for biological sample
   8.3 Other laboratory analyses
      8.3.1 Biochemical analyses
      8.3.2 Arterial blood gases
      8.3.3 Haematological investigations
      8.3.4 Other relevant tests
   8.4 Interpretation
   8.5 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 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 Rifampicin (INN, 1992) 1.2 Group Antimycobacterials (JO4)/Drugs for the treatment of tuberculosis (J04A)/Antibiotics (J04AB). (ATC classification index [WHO] 1992]) 1.3 Synonyms Rifampin Rifaldazine Rifamycin (Merck Index, 1989) 1.4 Identification numbers 1.4.1 CAS number 13292-46-1 1.4.2 Other numbers RTECS VJ7000000 1.5 Brand names, Trade names Rimactan, Rifadin, Rifocine (Argentina) Rifadin, Rimycin (Australia) Rimactan, Rifadine (Belgium) Rofact (Canada) Rimactan (Denmark) Rimactan, Rifadine (France) Eremfat, Rifa, Rifoldine, Rimactan, Rimactane, Rifampin, Rifadin (Germany) Tibirim (India) Archidyn, Rimactan,Rifapiam (Italy) Apectin (Japan) Rimactan, Rifadin (Netherlands) Rimactan (Norway) Abrifam, Dipicin, Famidex, Lederrif, Medifam, Natricin, Ramicin, RAMP, Refam, Resimin, Rifadin, Rifamycin, Rifastat, Rifatrexin,Rimactane, Zyfam, Rimaped (Philippines) Fenampicin, Tregaldin, Rifaprodin, Seamicin, Rifonilo Riforal, Rimactan, Diabacil (Spain) Rifoldine, Rimactan, Chibro-Rifamycine (Switzerland) Rifadin, Rimactane (United Kingdom) Rifadin (USA) (Martindale, 1982, 1989; Phil. Index of Medical Specialties, 1990). (To be completed by each Centre using local data) 1.6 Manufacturers/Importers Merrell(UK) Rifadin Rifinah 150 and Rifinah 300 Ciba Rimactane Rimactazid 150 and Rimactazid 300 Lepetit (Argentina) Rifocina Rifadin Armstrong (Argentina) Rifampicina (To be completed by each Centre using local data) 1.7 Presentation, Formulation Monocomponent products Rifampicin capsules of 150 mg, 300 mg, 450 mg, 600 mg, Rifampicin syrup 100 mg/5 ml. Combination Products Dipicin Isoniazid 150 mg, Rifampicin 300 mg INH IsoRamp. Isoniazid 100 mg Rifampicin 150 mg Isoniazid 150 mg Rifampicin 300 mg Pyrina Isoniazid 150 mg, Rifampicin 150 mg, Pyrazinamide 500 mg Rambutol Isoniazid 200 mg, Ethambutol HCl 400 mg, Rifampicin 300 mg, Pyridoxine 25 mg Ramicin Isoniazid 150 mg, Rifampicin 300 mg Iso Resfaman Isoniazid 150 mg, Rifampicin 300 mg with INH Resimin Isoniazid 200 mg, Rifampicin 300 mg + H Rifater Isoniazid 80 mg, Rifampicin 120 mg, Pyrazinamide 250 mg Rifinah Isoniazid 100 mg, Rifampicin 150 mg Isoniazid 150 mg, Rifampicin 300 mg Isoniazid 300 mg, Rifampicin 450 mg Rifzin Isoniazid 100 mg, Rifampicin 120 mg, Pyrazinamide 250 mg, pyridoxine 7.5 mg Rimactazid Isoniazid 100 mg Rifampicin 150 Isoniazid 200 mg Rifampicin 225 Isoniazid 150 mg Rifampicin 300 Ophthalmic Rifampin 1% ophthalmic ointment. Intravenous infusion Powder for reconstitution, as rifampicin 300 mg, supplied with solvent. (To be completed by each Centre using local data) 2. SUMMARY 2.1 Main risks and target organs The main target organs are the liver and the gastrointestinal system. Risks of concern are toxic hepatitis with elevation of bile and bilirubin concentrations, anaemia, leucopenia, thrombocytopenia, bleeding. 2.2 Summary of clinical effects Some clinical manifestations of overdosage are extension of adverse effects. During therapy, rifampicin is usually well-tolerated, however, adverse side-effects are common in intermittent rifampicin intake. These include febrile reaction, eosinophilia, leucopenia, thrombocytopenia, purpura, haemolysis and shock, hepatotoxicity and nephrotoxicity. Gastrointestinal adverse reactions may be severe leading to pseudomembranous colitis. Neurotoxic effects include confusion, ataxia, blurring of vision, dizziness and peripheral neuritis. A common toxic effect is red skin with orange discolouration of body fluids. Fatalities from adverse reactions have been reported. Rifampicin has shown no significant effects on the human foetus. It diffuses into milk and other body fluids. 2.3 Diagnosis Presence of red skin or orange discolouration of body fluids (e.g. urine) are indicators of the diagnosis. Blood and urine may be used to determine qualitative analysis or quantitative levels. Spare tablets or capsules may be identified using colour reaction tests. 2.4 First aid measures and management principles For acute overdose Stabilize patient by providing basic life support (i.e. airway, breathing and circulation). In the fully conscious patient, consider emesis or gastric lavage if patient seen within 1 or 2 hours after ingestion. Activated charcoal should be given afterwards. The use of a cathartic is no longer recommended. There is no antidote for rifampicin overdosage. Provide adequate hydration to maintain circulation and urine output. For adverse reactions not related to overdosage Withdraw drug and provide symptomatic and supportive therapy promptly. Note the presence of bleeding, jaundice, and renal failure. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Rifampicin is a semisynthetic derivative of rifamycin antibiotics which are produced by the fermentation of a strain of Streptomyces mediterranei, a species which was first isolated in Italy in 1957 from a soil sample collected in France. The fermentation produces rifamycin B. Rifamycin B is transformed by a series of reactions into 3- formylrifamycin SV, which in turn is condensed with 1-amino- 4-methylpiperazine in peroxide-free tetrahydrofuran to give rifampicin. (IARC, 1980) 3.2 Chemical structure Structural formula Molecular formula C43H58N4O12 Molecular weight 822.96 Chemical names 3-[[(4-methyl-1-piperazinyl)imino]methyl)]rifamycin 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22- heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]2,7- (epoxypentadecal[1,11,13]trienimino)-naphtho[2,1-beta]furan- 1,11(2H)-dione 21-acetate (Merck Index, 1989) 3.3 Physical properties 3.3.1 Properties of the substance 3.3.1.1 Colour Red to orange 3.3.1.2 State/Form Powder 3.3.1.3 Description Odourless. Very slightly soluble in water (1 g in approximately about 762 mL water [pH < 6]), acetone, carbon tetrachloride, alcohol, ether. Freely soluble in chloroform, DMSO; soluble in ethyl acetate and methyl alcohol and tetrahydrofuran. Solubility in aqueous solutions is increased at acidic pH. Melting point 138 to 188 °C Rifampicin has 2 pKa since it is a Zwitterion, pKa 1.7 related to 4-hydroxy and pKa 7.9 related to 3-piperazine nitrogen (Merck Index, 1989). A 1% suspension in water has pH 4.5 to 6.5. 3.3.2 Properties of local available formulation To be completed by each Centre using local data. 3.4 Other characteristics 3.4.1 Shelf-life of the substance As a dry powder it is stable for more than five years at 25°C. As lyophilized preparations for intravenous use it is stable for at least two years before reconstitution (Martindale, 1989). 3.4.2 Shelf-life of the locally available formulation(s) To be completed by each Centre using local data. 3.4.3 Storage conditions Rifampicin should be protected from air, light and excessive heat and moisture. Store at temperature not exceeding 40 °C (preferably between 15 to 30 °C) in airtight containers in an atmosphere of nitrogen. Protect from light by amber coloured bottles. 3.4.4 Bioavailability To be completed by each Centre using local data. 3.4.5 Specific properties and composition Potency of not less than 900 mg of rifampicin/g (Merck Index, 1989). (To be completed by each Centre using local data) 4. USES 4.1 Indications 4.1.1 Indications The primary indications for rifampicin are for treatment of tuberculosis (pulmonary and extrapulmonary lesions) and for leprosy. It is also useful for elimination of Neisseria meningococci in carriers (but not recommended for active meningococcal infection) and for Gram positive (Staphylococcus aureus and epidermidis, Streptococcus pyogenes, viridans and pneumoniae) and gram negative bacteria (Haemophilus influenzae type B). It has some anti-chlamydial activity and in vitro activity against some viruses (poxvirus and adenovirus) at high doses. (Van Scoy et al, 1987). It has recently been used for brucellosis. 4.1.2 Description Not relevant. 4.2 Therapeutic dosage 4.2.1 Adults Oral Tuberculosis 10 mg/kg bodyweight single daily dose (maximum 600 mg) in combination with other antimycobacterial agents. 15 mg/kg bodyweight (maximum 900 mg) 2 or 3 times weekly in combination with other antimycobacterial agents. Leprosy 600 mg once monthly or once daily in combination with other anti-leprotic drugs. Haemophilus influenzae type B infection 20 mg/kg bodyweight once a day for 4 days. (maximum daily dose 600 mg) Meningococcal carriers 600 mg twice daily for two days. Eye Trachoma (i.e. hyperendemic trachoma or sexually transmitted trachoma-inclusion conjunctivitis) 1% ophthalmic ointment applied three times daily for six weeks. Parenteral Rifampicin has been administered intravenously at 20 mg/kg bodyweight (maximum daily dose 600 mg). (Martindale, 1993) 4.2.2 Children Oral Tuberculosis 10 mg/kg bodyweight single daily dose in combination with other antimycobacterial agents. 15 mg/kg bodyweight 2 or 3 times weekly in combination with other antimycobacterial agents. Generally, for children less than five years of age, the dosage has not been established yet. Clinicians, however, have recommended 10-20 mg/kg bodyweight daily in children and infants with a maximum of 10 mg/kg bodyweight in neonates less than one week of age for tuberculosis treatment. Meningococcal carriers 1 to 12 years 10 mg/kg bodyweight 3 to 12 months 5 mg/kg bodyweight Haemophilus influenzae type B infection Children over 3-months-old 20 mg/kg bodyweight once a day for 4 days. (Martindale, 1993) 4.3 Contraindications Rifampicin is contraindicated in known cases of hypersensitivity to the drug. It may be contraindicated in pregnancy (because of teratogenicity noted in animal studies and since the effects of drugs on fetus has not been established) except in the presence of a disease such as severe tuberculosis. It is contraindicated in alcoholics with severely impaired liver function and with jaundice. 5. ROUTES OF ENTRY 5.1 Oral This is the common route of entry. 5.2 Inhalation Not applicable. 5.3 Dermal Not applicable 5.4 Eye Use for ocular chlamydial infection treatment (Fraunfelder, 1982). 5.5 Parenteral Rifampicin may be given intravenously (Martindale,1989). 5.6 Other No data available. 6. KINETICS 6.1 Absorption by route of exposure Rifampicin is readily absorbed from the gastrointestinal tract (90%). Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose. After a 450 mg oral dose, plasma levels reach 6 to 9 µg/mL while a 600 mg dose on an empty stomach yields 4 to 32 µg/mL (mean 7 µg/mL). Food may reduce and delay absorption (Ellenhorn, 1988; Mandel, 1985). 6.2 Distribution by route of exposure Intravenous rifampicin has the same distribution as in oral route. Eighty nine (+/- 1) per cent of rifampicin in circulation is bound to plasma proteins.(Goodman & Gilman, 1990) It is lipid soluble. It is widely distributed in body tissues and fluids. When the meninges are inflamed, rifampicin enters the cerebrospinal fluid (4.0 µg/mL after a 600 mg oral dose). It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluid, liver, bile, and urine (Van Scoy, 1987). Rifampicin has a high degree of placental transfer with a foetal to maternal serum level ratio of 0.3. It is distributed into breastmilk (Chow & Jesesson, 1985). The apparent volume of distribution (VD) is 0.93 to 1.6 L/kg (Avery, 1976; Drug Information, 1984). 6.3 Biological half-life by route of exposure T1/2 = three hours range (2 to 5 hours). This half-life increases with single high doses or with liver disease. The half-life decreases by 40% during the first two weeks of therapy because of enhanced biliary excretion and induction of its own metabolism. Plasma half-life may decrease after repeated administration. The half-life of rifampicin decreased from 3.5 hours at start of therapy to 2 hours after daily administration for 1 to 2 weeks, and remained constant thereafter (Molavi, 1990). Plasma half- life shortens to 1.8 to 3.1 hours in the presence of anaemia (Avery, 1976). 6.4 Metabolism Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main and active metabolite - deacetylrifampicin. Rifampicin undergoes enterohepatic recirculation but not the deacetylated form. Rifampicin increases its own rate of metabolism. Rifampicin may also be inactivated in other parts of the body. Formylrifampicin is a urinary metabolite that spontaneously forms in the urine. 6.5 Elimination by route of exposure Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and 6 to 30% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Approximately 43 to 60% of oral dose is excreted in the faeces. (Van Scoy 1987; Drug Information, 1990). Intrinsic total body clearance is 3.5 (+/- 1.6) mL/min/kg, reduced in kidney failure (Goodman & Gilman, 1990) Renal clearance is 8.7 mL/min/kg. Rifampicin levels in the plasma are not significantly affected by haemodialysis or peritoneal dialysis. Rifampicin is excreted in breastmilk (1 to 3 µg/ml). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics Rifampicin causes cholestasis at both the sinusoids and canaliculi of the liver because of defect in uptake by hepatocytes and defect in excretion, respectively (Haddad, 1983). Rifampicin may produce liver dysfunction. Hepatitis occurs in 1% or less of patients, and usually in the patient with pre-existing liver disease. Hypersensitivity reactions may occur, usually characterized by a "flu" type syndrome. Nephrotoxicity appears to be related to a hypersensitivity reaction and usually occurs after intermittent or interrupted therapy. It has been suggested that some of the adverse effects associated with rifampicin may be attributed to its metabolite desacetylrifampicin. It is lipid soluble, and thus can reach and kill intracellular, as well as extracellular, Mycobacteria. Rifampicin does not bind to mammalian nuclear RNA polymerase and therefore does not affect the RNA synthesis in human beings. Rifampicin, however, may affect mammalian mitochondrial RNA synthesis at a concentration that is 100 times higher than that which affects bacterial RNA synthesis (Molavi, 1990). 7.1.2 Pharmacodynamics Rifampicin has high activity against mycobacterial organisms, including Mycobacterium tuberculosis and M.leprae. It is also active against Staphylococcus aureus, coagulase-negative staphylocci, Listeria monocytogenes, Neisseria meningitidis, Haemophilus influenzae, Legionella spp., Brucella, some strains of E. coli, Proteus mirabilis, anaerobic cocci, Clostridium spp., and Bacteroides (Molavi, 1990). Rifampicin is also reported to exhibit an immunosuppressive effect which has been seen in some animal experiments, but this may not be clinically significant in humans (Drug Information, 1990). Rifampicin may be bacteriostatic or bactericidal depending on the concentration of drug attained at site of infection. The bactericidal actions are secondary to interfering with the synthesis of nucleic acids by inhibiting bacterial DNA-dependent RNA polymers at the B-subunit thus preventing initiation of RNA transcription, but not chain elongation. (Fahr et al., 1985; Drug Information for Health Care Provider, 1984). 7.2 Toxicity 7.2.1 Human data Patients have survived overdoes of 12 grams (Ellenhorn, 1988; Fahr, 1985). For patients with previously normal liver function, derangements of liver enzymes secondary to rifampicin are mild and nonspecific. In patients with previously deranged liver condition, patients may develop clinical jaundice and a more severe liver damage may ensue. Hypersensitivity reactions which lead to acute renal failure are usually associated with intermittent intake of rifampicin developing antibodies. 7.2.1.1 Adults Eight case data studies of patients aged 14 to 55 who took doses ranging from 9 to 60 grams, developed clinical signs and symptoms of vomiting, lethargy, obtundation, seizures, pruritus, facial oedema, abdominal pain, pink to red discolouration of the skin, red coloured urine. Laboratory findings showed elevated liver transaminases, bilirubin and alkaline phosphatase which may be transient. Three patients out of these 8 cases died (Ellenhorn, 1988). 7.2.1.2 Children In a group of children aged 1 to 4 years given 100 mg/kg bodyweight inadvertently for chemoprophylaxis of H.influenzae type B infections resulted in skin discolouration, periorbital facial oedema, pruritus, vomiting, headaches and diarrhoea. Signs and symptoms developed 0.5 to 4 hours after administration and lasted approximately 28 hours ranging from 1 to 72 hours (Drug Information, 1990). 7.2.2 Relevant animal data LD50 (intraperitoneal) mice 640 mg/kg LD50 (intraperitoneal) rats 550 mg/kg LD50 (intravenous) mice 260 mg/kg LD50 (intravenous) rats 330 mg/kg (Merck Index, 1989) LD50 (acute oral) mouse 829.3 mg/kg LD50 (acute oral) rats 1303.3 mg/kg LD50 (acute oral) rabbits 2120.0 mg/kg (Arzneimittel-Forschung, 1971) 7.2.3 Relevant in vitro data No relevant data available. 7.3 Carcinogenicity One report showed that nasopharyngeal lymphoma may develop after therapy of two years for Pott's disease. This was probably secondary to the immunosuppressive effects of rifampicin (Rate et al., 1979). An increase of hepatomas in female mice has been reported in one strain of mice,following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Because of only limited evidence available for the carcinogenicity of rifampicin in mice and the absence of epidemiological studies, no evaluation of the carcinogenicity of rifampicin to humans could be made (IARC, 1980). 7.4 Teratogenicity Teratogenic effects noted in rodents treated with high doses 100 to 150 mg/kg bodyweight daily in rodents have been reported to cause cleft palate and spina bifida (Drug Information, 1984). Malformation and death have been reported in infants born to mothers exposed to rifampicin, although it was the same frequency as in the general population (Simpson, 1988). Rifampicin is teratogenic for rats and mice (IARC, 1980) 7.5 Mutagenicity The available studies on mutagenicity indicate an absence of mutagenic effect (IARC, 1980). 7.6 Interactions Food lowers peak blood levels because of interference with absorption of rifampicin. Antacids containing aluminium hydroxide reduced the bioavailability of rifampicin. Para-amino salicylic acid granules may delay rifampicin absorption (because of bentonite present as a granule excipient) which leads to an inadequate serum level of rifampicin. These two drugs should be given 8 to 12 hours apart (Van Scoy, 1987). Isoniazid and rifampicin interaction has led to hepatotoxicity. (Note: slow acetylators of isoniazid have accelerated rifampicin clearance). Alcohol intake with rifampicin increases the risk for hepatotoxicity. Rifampicin induces microsomal enzymes of the liver and therefore accelerates metabolism of some drugs, e.g. beta blockers, calciferol, coumadins, cyclosporin, dapsone, diazepam, digitalis, hexobarbitone, ketoconazole, methadone, oral contraceptive pills, oral hypoglycaemic agents, phenytoin, sulphasalazine, theophylline, some anti-arrhythmic drugs such as disopyramide, lorcainide, mexiletine, quinidine, and verapamil. Rifampicin induces liver steroid metabolising enzyme thus lowering the levels of glucocorticoids and mineralocorticoids . Rifampicin lowers chloramphenicol serum levels when the two drugs are used together. When rifampicin and oral contraceptives are used concomitantly, there is decreased effectiveness of oral contraceptives because of the rapid destruction of oestrogen by rifampicin and the latter being a potent inducer of hepatic metabolising enzymes. It was reported that rifampicin may be the cause of some menstrual disorders when used with oral contraceptive pills. When rifampicin and corticosteroids are used, there is a reduction of plasma cortisol half-life and increased urinary excretion of cortisol metabolite. It may be necessary to double or quadruple the dosage of the steroid. When rifampicin and cyclosporin are taken, the serum levels of cycloserine may be lowered. In the therapy of leprosy, rifampicin may induce dapsone metabolism, however, this is of minor significance in the clinical setting (Hastings & Franzblau, 1988). The clinical condition of patients, who are on rifampicin and also taking digoxin for heart failure, may deteriorate because of falling digoxin levels. Hence there may be a need to increase the dosage of digitalis. Another cardiac drug is disopyramide which is used for cardiac dysrhythmias, and when taken with rifampicin, there is a decrease in levels of the antiarrhythmic agent. The clinical importance of this effect has yet to be determined. Patients on methadone maintenance for narcotic detoxification may develop narcotic withdrawal when methadone plasma levels decreased as a consequence of taking rifampicin at the same time. It is also possible that rifampicin alters the distribution of methadone. Rifampicin induces hepatic enzyme metabolism which can decrease metoprolol blood levels, although this may be clinically insignificant. In patients who receive rifampicin and phenytoin together, there is an increase of clearance of phenytoin by twofold, significantly reducing the effects of the anticonvulsant drug. Modification of quinidine dose is necessary when this is used with rifampicin because of the risk of ventricular dysrhythmias. It is recommended that quinidine dosage be always readjusted when one adds or discontinues rifampicin therapy. When verapamil and rifampicin are taken together, rifampicin induces liver enzymes which increases the metabolism of the calcium channel blocker leading to undetectable verapamil levels. Rifampicin can lower the plasma calciferol (Vitamin D) level because of induction of enzyme activity (Griffin, 1988; Bacievicz, 1984). Barbiturates and salicylates decrease the activity of rifampicin (Fraunfelder, 1982). Effects with clofazimine range from no effect to decrease in the rate of absorption of rifampicin, delay in the time it reaches peak plasma concentrations, decrease in plasma rifampicin concentrations. Rifampicin can decrease the therapeutic levels of ketoconazole when given together (Drug Information, 1990). When rifampicin is taken with oral hypoglycaemic agents (e.g.tolbutamide and chlorpropamide), these latter medications had a decrease in elimination half-lives (Baciewicz, 1984). Rifampicin enhances antifungal actions of amphotericin B. Probenecid intake diminishes hepatic uptake of rifampicin (Van Scoy, 1987). 7.7 Main adverse effects Although rifampicin is usually well tolerated, the serious and life-threatening effects of rifampicin at therapeutic doses are severe gastrointestinal side-effects, necessitating withdrawal of drug (e.g. pseudomembranous colitis). Hypersensitivity, shock, shortness of breath, acute haemolytic anaemia and renal failure (nephrotoxicity) have been reported during intermittent therapy. This has been attributed to antibody-mediated immune reactions. The other adverse effects are staining of body fluids, rash, chills and fever, nausea and vomiting, arthralgia, diarrhoea, and peripheral neuritis. Ocular side effects as a consequent to rifampicin use occur in 5 to 15% of patients. Systemic rifampicin has been reported to cause decreased vision, affections of eyelids and conjunctiva, e.g. hyperaemia, erythema, blepharoconjunctivitis, oedema, yellow or red discolouration. Other effects are lacrimation, dyschromatopsia, orange staining of contact lenses, uveitis, subconjunctival/retinal hemorrhages, retrobulbar/optic neuritis. Angioneurotic oedema, urticaria, purpura, Stevens-Johnson syndrome, exfoliative dermatitis or pemphigoid lesions have been reported. Local ophthalmic use of rifampicin has caused irritation of the eyes which manifests transiently as lacrimation, hyperaemia, oedema and ocular pain (Fraunfelder, 1982). 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS 8.1 Methods 8.1.1 Collection No data available. 8.1.2 Storage The pharmaceutical sample should be stored below 40°C (104-F). Store in tight, lightproof container. 8.1.3 Transport No data available. 8.2 Therapeutic and toxic concentrations 8.2.1 Test for active ingredients Identity tests Description: a brick red to red-brown crystalline powder, odourless or almost odourless. Melting behaviour: 193-188°C with strong decomposition. Colour reaction tests for tables Dissolve about 1 mg in 3 ml of water, add 3 drops of copper (II) sulfate (160 mg/li) TS (test solution) and heat to boiling, a violet colour is produced. Dissolve about 1 mg in 2 mg of sulfuric acid (~ 1760 g/l) TS and heat on a water-bath for two minutes; an orange colour is produced which twins gradually to dark red. Dissolve 5 mg in 1.0 ml pyridine R (reagent), add 1.0 ml of sodium hydroxide (~ 80 g/l) TS and five drops of benzenesulfonyl chloride R and shake well; a dark red- violet colour is observed. (Basic Test for Pharmaceutical Substances, WHO Expert Advisory Panel on International Pharmacopoeia, 1988). 8.2.2 Test for biological sample Chemical colour reaction test for urine The basis of this test of antibiotic in the urine is upon the chemical property of rifampicin and its desacetylated metabolite. One test consists of mixing 10 ml of urine with 2 ml chloroform-PR. THe chloroform layer changes colour from yellow to orange according to the quantity of rifampicin in the urine. Another test calls for adding 0.5 ml of a reagent containing 5 mg of phenic nitrate and 10 ml of concentrated nitric acid in 100 ml of distilled water, to 10 ml of urine. If rifampicin is present, a chromogen is released varying from pink to red in colour relative to the concentration of the drug. The presence of other anti- tuberculosis drugs will not interfere with these tests (Arzneimittel-Forschung, 1971). Chemical test for serum A centifuge tube containing 5 ml of liquid to be assayed and 5 ml of butanolbenzene (4:1) solvent and M/15 phosphate buffer pH 7.4 are added. The tube is centrifuged at 2500 r.p.m. for 10 minutes. Extinction of the supernatant liquid is then determined at 340 and 480 mu., using solvent as blank. Standard dilutions of rifampicin are prepared in the same buffer as for the body fluid. The extinctions of these dilutions at 340 and 480 mu are plotted on a graph to give the titration curve, from which the concentrationof the drug in the sample under the curve can be calculated. This method is reliable for antibiotic concentration in the regiona of 0.5 µg/ml (Arzneimittel-Forschung, 1971). 8.3 Other laboratory analyses 8.3.1 Biochemical analyses While patients are on rifampicin therapy, SGOT and SGPT determinations may be indicated monthly, or more frequently. 8.3.2 Arterial blood gases Not necessary. 8.3.3 Haematological investigations Baseline complete blood count (platelets included) and prothrombin time determinations: 8.3.4 Other relevant tests Hepatic biopsy for histologic confirmation of hepatic necrosis (Scheuer, 1974). 8.4 Interpretation Rifampicin can affect normal human physiology such that the following laboratory parameters may be deranged or elevated. Blood urea nitrogen serum creatinine, serum alanine aminotransferase (SGPT), serum aspartate aminotransferase (SGOT), serum alkaline phosphatase, serum bilirubin, and serum uric acid concentrations. Although liver enzyme values may be elevated, they are not always predictive of clinical hepatitis and may return to normal or continued therapy with rifampicin. Rifampicin may interfere with results of certain diagnostic tests such as a positive Coomb's test may be produced; serum B12; sulphobromophthlein (BSP) hepatic uptake and excretion in liver function tests (may be delayed by rifampicin, resulting in BSP retention); urine analysis using colour reaction because of the reddish brown discolouration of urine (Drug Information, 1984). Through the inhibitory of rifampicin on cellular immunity, rifampicin may interfere with cutaneous reactivity to intradermal tuberculosis (Alford, 1990). Rifampicin therapeutic and toxic concentration Therapeutic concentrations The bactericidal concentration for rifampicin against S. Aureus is 3-12 ng/ml while the minimal inhibitory concentration of N. Meningitides is 0.1-0-8 µg/ml (Farr, 1985). Blood levels of 6µg/ml considered therapeutic (Ellenhorn, 1988). Toxic concentrations Blood levels of 55 µg/ml have been reported in an alcoholic patient who took 14-15 grams who subsequently died. A level of 182 µg/ml resulted in death. A level of 204 µg/ml done 5 hours after ingestion of 12 grams did not result in death. A level of 400 µg/ml after 12 hours from ingestion of 12 grams did not result in death. 8.5 References See section 13. 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Acute overdosage by ingestion will give the following clinical effects: Firstly, rifampicin may affect the gastrointestinal system causing nausea, vomiting and abdominal pain. There may be hepatomegaly with impairment of liver function. Secondly, the haemopoietic system may be affected leading to anaemia, and bleeding. The nervous system may be affected by rifampicin overdose manifesting as confusion, lethargy, ataxia, dizziness, blurring of vision, peripheral neuritis. Lastly, rifampicin may cause a red discolouration of the mucous membranes, the skin and all body fluids. Discolouration has been reported to occur within 0.5 to 4 hours post-ingestion. 9.1.2 Inhalation Not known. 9.1.3 Skin exposure Not known. 9.1.4 Eye contact Irritation effects. 9.1.5 Parenteral exposure Not known. 9.1.6 Other No data available. 9.2 Chronic poisoning 9.2.1 Ingestion Chronic poisonings in humans have been associated with intermittent intake of rifampicin. The reactions are gastrointestinal disturbance and include nausea, vomiting, anorexia, constipation, abdominal pain and diarrhoea. Hepatotoxicity and nephrotoxicity may occur. Flu-like symptoms, thrombocytopenia, haemolytic anaemia, leukopenia, eosinophilia and bleeding have been reported. Chronic administration of rifampicin has resulted in hepatic changes particularly in patients with pre-existing liver disease or a history of alcoholism. Animal data with chronic ingestion at dose of 200 mg/kg/day for 6 months in rats, there was slight increase of liver weight, with slight cloudy swelling and/or hydropic degeneration in the liver. No adverse effects noted at 50 to 100 mg/kg/day for 6 months in rats, while in a six months chronic toxicity study in monkeys, there were no adverse effects at 15 to 75 mg/kg/day but at 105 mg/kg/day, emesis, depression, weight loss and elevated alkaline phosphatase were noted (Arzneimittel-Forschung, 1971). 9.2.2 Inhalation Not known. 9.2.3 Skin exposure Not known. 9.2.4 Eye contact Not known. 9.2.5 Parenteral exposure Not known. 9.2.6 Other 9.3 Course, prognosis, cause of death Overdosage of rifampicin produces signs and symptoms which are extensions of adverse reactions, with reddish orange discolouration of skin and body fluids. These appeared within 0.5 to 4 hours after oral administration and lasted for an average of 28 hours (range 1 to 72 hours). Hepatotoxicity may be marked, while effects on the haematopoietic system, acid-base and electrolyte balance are unlikely. Reversal of hepatomegaly and biochemical and transaminase elevation will occur within 72 hours in patients with adequate hepatic function (Drug Information, 1990). 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension and shock. 9.4.2 Respiratory Shortness of breath. 9.4.3 Neurological 9.4.3.1 Central Nervous System (CNS) Rare cases of organic brain syndrome have been reported (i.e. confusion, lethargy, ataxia, dizziness and blurring of vision). 9.4.3.2 Peripheral Nervous System Peripheral neuropathy affecting the limbs, muscle, joints in the form of numbness and pain has been reported 9.4.3.3 Autonomic Nervous System No relevant data available. 9.4.3.4 Skeletal and smooth muscle No relevant data available. 9.4.4 Gastrointestinal Nausea, vomiting, diarrhoea. Pseudomembranous colitis is possibly associated with resistant strains of Clostridium difficile. Pancreatitis is possible, but rare in occurrence. 9.4.5 Hepatic Hepatotoxicity and overt clinical hepatitis (e.g. jaundice). In decompensated liver cirrhosis, rifampicin hepatotoxicity may develop over a period of 4 to 150 days and may lead to death (Di Piazza, 1978). Asymptomatic elevations of serum transaminase enzymes, increase in serum bile acids and bilirubin concentrations can occur. Marked elevation of serum alkaline, phosphatase and bilirubin suggests rifampicin toxicity. Doses of rifampicin below 100 mg/kg show a mild choleretic action in bile secretion, while at high doses (above 100 mg/kg) there is marked cholestatic effect (Haddad, 1983; Scheuer, 1974). 9.4.6 Urinary 9.4.6.1 Renal Intermittent or interrupted therapy with rifampicin is a common denominator for inducing renal failure (i.e. acute haemolysis and shock) as in acute interstitial nephritis and usually preceded by fever and flu-like symptoms. Glycosuria and proteinuria with associated acidifying defects have been noted. This renal failure may be aggravated in the presence of dehydration (Ellenhorn, 1988; Warrington, 1977; Fahr, 1985). 9.4.6.2 Other No data available. 9.4.7 Endocrine and reproductive systems Prolonged use of rifampicin causes a reduction of 25- hydroxycholecalciferol levels without changing 1,25 dihydroxycholecalciferol or parathyroid hormone. Complications of osteomalacia may develop. It also causes increased deiodination and biliary clearance of thyroxine, thus lowering thyroxine serum concentration (Fahr, 1985; Martindale, 1989). 9.4.8 Dermatological Discolouration of skin to glowing red-orange; pruritus at doses five times the therapeutic dose - called "red man syndrome". Chronic daily therapy led to self-limiting rash in up to 5% of cases. Eczematous patches, flaccid bullae and crusted plaques on the skin which are reversible when rifampicin was discontinued (Bolan, 1986). Rarely, exfoliative dermatitis and toxic epidermal necrolysis (Fahr, 1990). 9.4.9 Eye, ear, nose, throat: local effects Ocular effects are primarily adverse side effects such as vision disturbance, eyelid and conjunctival inflammation, angioneurotic oedema, staining of lacrimal fluid, uveitis and subconjunctival/retinal bleeding and pain. No acute or chronic otovestibular toxicity was noted with rifampicin. 9.4.10 Haematological Haemolytic anaemia. Agranulocytosis, haemorrhage, leucopenia, thrombocytopenia. Higher frequency of folic acid deficiency leading to megaloblastic anaemia (because of induction of hepatic microsomal enzymes). (Fahr, 1985; Haddad, 1983). 9.4.11 Immunological Some of the adverse reactions are secondary to immunological mechanisms because of sensitization to intermittent rifampicin intake (e.g. nephritis, anaemia). Other immunological disturbances such as rheumatoid or lupoid syndromes may occur (Remington, 1985). Rifampicin with possible immunosuppressive effects has led to a report of nasopharyngeal carcinoma developing in one case (Rate, 1979). Rifampicin depresses polymorphonuclear cells function leading to immunosuppression and immunologically- mediated thrombocytopenia. Note: The immunosuppressive effects of rifampicin are reversible. 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances No data available. 9.4.12.2 Fluid and electrolyte disturbances Potassium wasting may occur with associated interstitial nephritis and high fractional uric acid excretion and glycosuria (Cheng & Kahn, 1984). 9.4.12.3 Others No data available. 9.4.13 Allergic reactions No relevant data available. 9.4.14 Other clinical effects No relevant data available. 9.4.15 Special risks Pregnancy Malformation, death and haemorrhage (hypoprothrombinemia) have been documented in infants whose mothers were exposed to rifampicin. Rifampicin may be used with caution in pregnant patients with severe tuberculosis, however, the safety has not been well established. Breast feeding Rifampicin is found in breast milk. As only about 0.57% of the usual therapeutic dose for an infant is found there is no need to stop breast feeding, unless the infant is receiving antituberculosis agents. 9.5 Other Rifampicin causes orange-red staining of all body fluids. It has no potential as a substance of abuse. 9.6 Summary Not relevant. 10. MANAGEMENT 10.1 General Principles Symptomatic and supportive care is the basis for treatment of rifampicin overdosage. 10.2 Relevant laboratory analyses 10.2.1 Sample collection See Section 8. 10.2.2 Biomedical analysis Direct and total bilirubin levels, hepatic enzymes, renal function tests. 10.2.3 Toxicological analysis It is possible to measure levels of rifampicin in blood, but this is of no value in the management of poisoning. 10.2.4 Other investigations Not relevant 10.3 Life supportive procedures and symptomatic/specific treatment If the patient is assessed to be in a critical condition (i.e. cardiorespiratory distress) maintain a clear airway, aspirate secretions if these are present in the airway, administer oxygen, perform endotracheal intubation if indicated, provide artificial ventilation if indicated, maintain an intravenous line to support circulation. Monitor vital signs (sensorium, blood pressure, heart and respiration rate) regularly and correct hypotension with isotonic fluids or inotropic agents. Monitor fluid and electrolyte balance (i.e. input and urine output). If there are cardiac dysrhytmias, provide appropriate antiarrhythmic agents. If there is an interaction problem between rifampicin and antiarrhythmic drugs, one may have to increase the dose of cardiac medications. If bleeding ensues, correct by doing appropriate component transfusion only if indicated. Re-evaluate other drugs which patient may be taking and which may have been affected with rifampicin interactions. Symptomatic treatment for severe nausea and vomiting caused by rifampicin may be in the form of anti-emetic. Withdraw drug use in all adverse events except for asymptomatic mild liver enzyme elevation which is only transient. 10.4 Decontamination In the fully conscious patient, consider emesis or gastric lavage if patient seen within 1 or 2 hours after ingestion. Activated charcoal should be given afterwards. The use of a cathartic is not generally recommended. Gastric lavage to be performed after proper insertion of orogastric or nasogastric tube and appropriate protection for the airway (i.e. endotracheal intubation). Administration of activated charcoal is by multiple dosing every 2 to 6 hours to block enterohepatic recirculation. If the adverse event involved ocular contact, flush or irrigate eyes with copious amount of water. 10.5 Elimination Due to its high protein binding, forced diuresis or dialysis will not be effective in removal of rifampicin. Due to its relatively low volume of distribution and low intrinsic clearance, haemoperfusion may theoretically remove rifampicin, but this is not documented (Goodman & Gilman, 1990). 10.6 Antidote treatment 10.6.1 Adults There is no antidote. 10.6.2 Children There is no antidote. 10.7 Management discussion There are conflicting suggestions as regards the use of dialysis. It appears that peritoneal dialysis and haemodialysis do not appreciably promote rifampicin elimination (Van Scoy, 1987; Drug Information, 1990). 11. ILLUSTRATIVE CASES 11.1 Case reports from literature Case 1 A 40-year-old man who took 9 g of rifampicin (with 6 g isoniazid and 20 g ethambutol) and presented with orange urine. Discharged after 10 days, following haemodialysis (Ducobu et al., 1982). Case 2 A 14-year-old female overdosed on 12 g of rifampicin. After one hour she experienced pruritus and after 5 hours the skin became orange. She was treated with gastric lavage, activated charcoal, catharsis and forced diuresis, and was discharged after 3 days. (Wong et al., 1984) Case 3 A 28 year-old-male alcoholic died after intentionally overdosing on 14 to 15 g of rifampicin. Skin had orange- yellow discolouration (Plomp et al., 1981) Case 4 A report of lethargy, obtundation, pruritus, facial oedema and orange discolouration of the skin, mucous membranes, sclerae, and urine, following overdose of unknown quantity of rifampicin in a 15-year-old female (Meisel & Brower, 1980). Case 5 Nausea, vomiting, diffuse abdominal pain, intense pruritus and orange discolouration of the skin were seen in a 26- year-old male (with a history of alcohol abuse) who died after ingestion of 60 g of rifampicin (Broadwell et al., 1978). Case 6 A 28-year-old male died after ingesting an unknown quantity of rifampicin and ethambutol. He was found lying in the street and was dead on admission to hospital. At necropsy, bright red urine, a pink discolouration of the skin and internal organs (particularly the oesophagus) were noted. No injury to the mouth or throat was found. The lining of the aorta was also pink. The following concentrations of rifampicin, ethambutol and ethanol were found in blood and urine: Blood Rifampicin 182 mcg/mL (Therapeutic 6 mcg/mL) Ethambutol 84 mcg/mL (Therapeutic 2 to 4 mcg/mL) Ethanol 20 mg/dL Urine Rifampicin 3.3 mg/mL Ethambutol 6.8 mg/mL Ethanol 24 mg/dL (Jack et al., 1978). Case 7 A 55-year-old male with a prior history of overdosage and alcohol abuse recovered after 2 days of treatment following ingestion of 12 g of rifampicin. Toxicity signs were flushing, profuse sweating, bright red skin and hypertension (160/110). Elevated levels of plasma bilirubin, alkaline phosphatase and aspartate aminotransferase were noted (Newton & Forrest, 1975). Case 8 A report of nasopharyngeal lymphoma developed in a 41-year- old man following treatment with isoniazid, ethambutol and rifampicin for two years. It was suggested that this was due to the immunosuppressive effects of rifampicin following long-term therapy (Rate et al., 1979). Case 9 Report of an unsuccessful suicide in a 20-year-old male who recovered after 3 days, following ingestion of 9 g of rifampicin. Prominent symptoms were a transient skin rash, red urine, faeces and saliva. Transient cholestasis and hepatomegaly were noted (Konietsko & Burkhardt, 1971). Case 10 A case of fatal aplastic anaemia or agranulocytosis, probably due to rifampicin, has been reported (Inman, 1977). Case 11 A 75-year-old man treated with isoniazid, ethambutol and rifampicin developed neutropenia which was re-induced, on challenge, by each of the three agents (Jenkins et al., 1980). Case 12 Hepatitis occurred in a child treated with rifampicin and ethambutol. Additional symptoms included polyarthritis and the presence of anti-native DNA antibodies (Grennan & Sutrrock, 1976). Case 13 Rifampicin administered daily to a 60-year-old man was associated with the development of an acute organic brain syndrome in which he became confused, disorientated, agitated, and incoherent and suffered hallucinations and delusions (Pratt, 1979). Case 14 Myopathy in one patient induced by rifampicin was reported (Jenkins & Emerson, 1981). Case 15 Pehphigus foliaceous which developed in a patient receiving isoniazid and rifampicin cleared completely within five weeks on withdrawal of rifampicin, without need for systemic therapy (Lee et al., 1984). 11.2 Internally extracted data on cases No data available. 11.3 Internal cases To be completed by each Centre using local data. 12. ADDITIONAL INFORMATION 12.1 Availability of antidotes No known antidote. 12.2 Specific preventive measures Since an increased risk may exist for individuals with liver disease, benefits must be weighed carefully against the risk of further liver damage; periodic liver function monitoring is advised. The possible teratogenic potential in women of child- bearing age should be carefully weighed against the benefits of therapy. Since rifampicin has been reported to cross the placental barrier and appear in cord blood, neonates of rifampicin- treated mothers should be carefully observed for any evidence of adverse effects. Rifampicin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases. In patients receiving anticoagulants and rifampicin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant. Soft contact lenses may be permanently stained, and individuals to be treated should be made aware of these possibilities. In the presence of diminishing creatinine clearance, there is no need to change maintenance dose intervals. When the renal failure is a consequence of rifampicin overdose or its adverse reactions, it should be discontinued (Avery, 1976). For patients with liver dysfunction, use a dose not exceeding 8 mg/kg bodyweight. 12.3 Other No relevant data available. 13. REFERENCES Alford R. (1990) Chapter 32 Antimycobacterial Agents. Principles and Practice of Infectious Diseases, 3rd ed. John Wiley and Sons. American Hospital Formulary Service Drug Information 1989 & 1990. Published by American Society of Hospital Pharmacists. Avery G ed. (1976) Drug Treatment: Principles and Practice of Clinical Pharm & Therap. Adis Press. Baciewicz A & Self T (August 1984) Rifampin Drug Interactions. Arch Intern Med, 144. Barbarash RA (August 1986) Verapamil-Rifampicin Interaction. Drug Intell Clin Pharm, 19(7-8): 559-560. Binda et al. (1971) Arzneimittel-Forschung (Drug Res.) 21. Bolan G et al. (May 1986) Red man syndrome: Inadvertent Administration of an Excessive Dose of Rifampicin to Children in a Day-care Center. Pediatrics, 77: 633-635. Broadwell RO 111, Broadwell SD, Comer PB et al (1978) Suicide by rifampin overdose. JAMA, 240: 2283-2284. Cheng JT & Kahn T (1984) Potassium wasting and other renal tubular defects with Rifampicin Nephrotoxicity. Am J Nephrol, 4: 379-382. Chow AW & Jewesson PJ (1985) Pharmacokinetics & Safety of Antimicrobial Agents during Pregnancy. Rev of Infectious Diseases, 7: 287-313. Di Piazza S et al. (1978) Severe rifampicin-associated liver failure in patients with compensated cirrhosis. The Lancet [letter]: 774. Drug Information for Health Care Providers (1984) USPDI, Vol I. The United States Pharmacopoeia Convention Inc. Ducobu J, Dupont P, Laurent M, et al. (1982) Acute isoniazid/ethambutol/ rifampicin overdosage. Lancet, 1: 632. Ellenhorn MJ & Barceloux DG (1988) Anti-infective Drugs. Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Amsterdam, Elsevier. Fahr B & Mandell G. (1985) Chapter 22, Rifampicin: Principles and Practice of Infectious Diseases. 2nd ed., Vol.1: 216-220, and Chapter 24, Rifampicins. Principles and Practice of Infectious Diseases, 3rd ed. Vol.1, John Wiley & Sons, 1990. Fraunfelder FT & Meyer SM (1982) Drug-induced ocular side- effects and drug interactions. 2nd ed. Lea and Febiger. Goldberger M (1988) Antituberculosis Agents. Update on Antibiotic II, The Medical Clinics of North America, 72: No.3: 661-668. WB Saunders Co. Griffin JP et al. (1988) A Manual of Adverse Drug Interactions, 4th ed. Butterworth & Co. Haddad L & Winchester J (1983) Clinical Management of Poisoning and Drug Overdose. WB Saunders Co. Hastings RC & Franzblau SG (1988) Chemotherapy of Leprosy. Annual Rev Pharmacol Toxicol, 28: 231-245. Jack DB, Knepil J, & McLary WDS. (1978) Fatal rifampicin- ethambutol overdosage. Lancet, 2: 1107-1108. Konietsko N & Burkhardt H (1971) Unsuccessful suicide attempt with rifampicin. Pneumonologia, 144: 82-84. Kyriazopoulou V. et al (?) Rifampicin-induced adrenal crisis in Addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 59: 1204-1206. Lee CW et al (1984) Pemphigus Foliaceus induced by Rifampicin. Br J Dermatol, 5: 619-622. Mandel GL & Sande MA (1985) Antimicrobial Agents. Goodman & Gilman's the Pharmacologic Basis of Therapeutics, 7th ed. MacMillan Publish Co. Meisel S & Brower R (1980) Rifampin: a suicidal dose. Ann intern med, 92: 263-263. Newton RW & Forrest ARW (1975) Rifampicin overdosage - The red man syndrome. Scot Med Journ, 20: 55-56. Goodman & Gilman (1990) p1706 Martindale's The Extra Pharmacopoeia, 28th ed. (1982) & 29th ed. (1989). JEF Reynolds ed. London, The Pharmaceutical Press. Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals (1989) 11th ed. Merck & Col. Molavi A (1990) Antimicrobials III: Sulfonamides, Trimethoprim and Anti-Mycobacterial Agents, in Joseph di Palma & John Di Gregorio's Basic Pharmacology in Medicine, 3rd ed. McGraw-Hill Book. Philippine Index of Medical Specialties Coccabo SC (ed.) (1990) 19, No.1, IMS Pacific Ltd. April 1990. Plomp TA, Battista HJ & Unterdorfer H. A case of fatal poisoning by rifampicin. Arch Toxicol 1981, 48: 245-252. Rate R et al. (1979) Annals of Internal Medicine [letter], 90: 276. Remington's Pharmaceutical Sciences (1985) Gennaro A ed, 17th ed, Mack Publishing Co. Scheuer PJ et al (1974) Rifampicin Hepatitis. The Lancet: 421- 425. Simpson M et al (1988) Chapter 15. Bacterial Infections during Pregnancy. Medical Complications during Pregnancy, 3rd ed. WB Saunders Co. Van Scoy R & Wilkowske C (1987) Antituberculosis agents. Mayo Clinic Proceedings. 62: 1129-1136. Warrington R et al. (1977) Insidious Rifampicin-associated renal failure with light-chain proteinuria. Arch Intern Med, 137. Wong P, Bottorff MB, Heritage RW & et al. (1984) Acute rifampin overdose: A pharmacokinetic study and review of the literature. J pediat, 104: 781-783. 14. AUTHOR(S), REVIEWER(S), DATE(S)(INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author Kenneth Hartigan-Go, M.D. Department of Pharmacology UP College of Medicine Manila Philippines Tel 63-2-5218251 Fax 63-2-407168 Date January 1990 Reviewers M. Balali-Mood Poisons Centre Imam Reza Hospital Mashad 91735 Iran Tel 051-93043 Fax 051-92083 J. Magarey Poisons Information Centre Royal Childrens Hospital Melbourne 3052 Australia Tel 03-345 56 78 Peer review Adelaide, Australia, April 1991

See Also:
        Rifampicin (IARC Summary & Evaluation, Volume 24, 1980)

The following information has been extracted from our CHEMINFO database, which also contains hazard control and regulatory information. [More about...] [Sample Record]

 

Access the complete CHEMINFO database by contacting CCOHS Client Services.

 

SECTION 1. CHEMICAL IDENTIFICATION

 

CHEMINFO Record Number: 181

CCOHS Chemical Name: Acetic acid (solutions greater than 10%)

Synonyms:

Ethanoic acid

Ethylic acid

Glacial acetic acid

Methanecarboxylic acid

Acetic acid (non-specific name)

Acide acetique glacial

Chemical Name French: Acide acétique

Chemical Name Spanish: Acido acético

Acido acetico

Acido etanoico

CAS Registry Number: 64-19-7

UN/NA Number(s): 2789 2790

RTECS Number(s): AF1225000

EU EINECS/ELINCS Number: 200-580-7

Chemical Family: Saturated aliphatic carboxylic acid / saturated aliphatic monocarboxylic acid / alkanoic acid / acetic acid

Molecular Formula: C2-H4-O2

Structural Formula: CH3-C(=O)-OH

 

SECTION 2. DESCRIPTION

 

Appearance and Odour:

Pure acetic acid is a clear, colourless liquid above 16 deg C and colourless, icelike crystals below 16 deg C; strong, pungent odour of vinegar. Hygroscopic (absorbs moisture from the air).(17,28,29)

Odour Threshold:

0.037-0.15 ppm (detection) (geometric mean odour threshold: 0.074 ppm).(35)

Warning Properties:

GOOD - The TLV is more than 10 times the odour threshold.

Composition/Purity:

Acetic acid is available as the pure liquid or as solutions in water (6-90%). Virtually pure acetic acid (99.5% or higher) is called glacial acetic acid. Refer to CHEMINFO record 752 for information on acetic acid solutions of 10% and less. Water is the chief impurity in glacial acetic acid. Other impurities include acetaldehyde, acetic anhydride, formic acid, biacetyl, methyl acetate, ethyl acetoacetate, iron and mercury. Acetic acid forms a monohydrate containing about 23% water.(28)

Uses and Occurrences:

Chemical intermediate (e.g. vinyl acetate monomer, cellulose acetate, acetic anhydride, chloroacetic acid, terephthalic acid), used in manufacture of latex emulsion resins, paints, coatings, adhesives, rubber, nylon, fibres, dyes, aspirin and other pharmaceuticals and medicinals, plastics, lacquers, herbicides, solvents, and other chemicals and products; textile dyeing and finishing; laboratory reagent; etching compound; deliming agent, acidifying and neutralizing agent (e.g. oil well acidizer); food additive or flavorant; constituent of photographic fixing baths, bacteriocide, fungicide.(17,28,29)

Occurs widely in the environment. Occurs naturally in plant and animal tissues and is a normal metabolite in both plants and animals. Occurs naturally in many fruit juices and in the stems and woody parts of plants.(17)

 

SECTION 3. HAZARDS IDENTIFICATION



EMERGENCY OVERVIEW:

Pure acetic acid is a clear, colourless liquid above 16 deg C and colourless, icelike crystals below 16 deg C. Has a strong, pungent odour of vinegar. Hygroscopic. COMBUSTIBLE LIQUID AND VAPOUR. Vapour is heavier than air and may spread long distances. Distant ignition and flashback are possible. Harmful if inhaled or swallowed. Vapour is irritating to the respiratory tract. May cause lung injury--effects may be delayed. Concentrated solutions are CORROSIVE to eyes and skin. Causes permanent eye damage, including blindness, and skin burns, including tissue death and permanent scarring. May be an aspiration hazard. Swallowing or vomiting of the liquid may result in aspiration into the lungs.





POTENTIAL HEALTH EFFECTS

 

Effects of Short-Term (Acute) Exposure

 

Inhalation:

Accidental inhalation of high concentrations has produced nose and throat irritation, shortness of breath, cough, wheezing, and reversible lung injury in people exposed occupationally. In one case, symptoms of airways hyperresponsiveness (chest tightness, coughing and shortness of breath) were still present 3 years later.

A maintenance worker inhaled a large cloud of hot glacial acetic acid (99.8%) as it vapourized. Seven days after the incident, he developed progressive exertional shortness of breath. Follow-up showed reversible airways obstruction and interstitial pneumonitis. He had no history of respiratory illness and was a not a smoker.(2) A hospital worker was exposed to an unspecified amount of glacial acetic acid during a spill. Within 15 to 30 minutes, she experienced nose and throat irritation, followed by chest tightness, mild shortness of breath and a slight cough. Over the next several days, she experienced frequent wheezing, worse at night and upon exertion. Chest x-rays and spirometry tests were normal. Despite treatment, mild episodes of airways hyperresponsiveness (chest tightness, coughing and shortness of breath) were still present 3 years later.(5)

Follow-up of 51 employees also exposed in the above incident (5), showed an increased incidence of reactive airways dysfunction in the "high" exposure group (3/14). No conclusions can be drawn from this aspect of the study due to limitations such as potential recall biases, lack of exposure information, and the small number of individuals followed up.

Skin Contact:

The degree of irritation depends on the concentration of acetic acid and the length of exposure. Based on animal evidence, highly concentrated solutions or pure acetic acid can cause corrosive tissue injury with deep burns, tissue death and permanent scarring. Less concentrated solutions can cause mild to severe irritation. Application of 10% acetic acid to the intact or abraded skin of human volunteers in a 4-hour patch test showed slight irritation.(9)

Eye Contact:

Even very dilute solutions of acetic acid have cause severe irritation in animal studies. Concentrated solutions are corrosive and can cause permanent eye damage, including blindness. There are 2 case reports where glacial acetic acid (99.8%) was accidentally used instead of eye drops. In one case, clouding of the cornea, fluid accumulation and inflammation of the iris were observed shortly after the incident. Clouding and loss of sensation of the cornea were observed 2.5 months later. In the second case, fluid accumulation was observed shortly after the incident. Follow-up 2 weeks later showed loss of sensation and permanent clouding of the cornea.(6)

Ingestion:

Intentional ingestion of 100-200 mL of 80-100% acetic acid has caused severe corrosive injury to the gastrointestinal tract and stomach.(15,16) Another report describing kidney injury in 2 people who ingested 80% acetic acid, cannot be evaluated due to the lack of information.(17)

Based on physical properties (viscosity and surface tension), acetic acid may be aspirated (inhaled into the lungs) during ingestion or vomiting. Aspiration of even a small amount of liquid could result in a life-threatening accumulation of fluid in the lungs. Severe lung damage (edema), respiratory failure, cardiac arrest and death may result.

Ingestion is not a typical route of occupational exposure.

Effects of Long-Term (Chronic) Exposure

 

There are 2 case reports involving workers exposed to acetic acid during the production of cellulose acetate. One report describes workers exposed to 60 ppm acetic acid daily, with a one-hour exposure to 100-260 ppm. No evidence of injury was reported, other than slight irritation of the air passages, stomach and skin.(7) Another report describes 5 workers who were exposed to 82 and 265 ppm acetic acid during particular work phases for 7-12 years. Chronic bronchitis (asthmatic-like in 3 cases and emphysema in one) was observed.(18) These brief reports involved a very small number of workers and do not indicate if there were any other potential exposures or if there were any personal pre-disposing factors. Therefore, no conclusions can be drawn.

Another report describes a photographer who developed reversible airways obstruction after long-term exposure to acetic and sulfuric acids in a dark room.(3) No conclusions can be drawn due to the concurrent exposure and lack of exposure information.

 

SKIN SENSITIZATION: There is one case report of occupational skin sensitization. A worker occupationally exposed to soldering flux which contained acetic acid, among other ingredients, developed contact dermatitis. No history of allergy was recorded. Patch testing showed a positive result for 2% acetic acid.(19) This single case report does not prove that acetic acid is a skin sensitizer. Two other reports of skin sensitization due to acetic acid cannot be evaluated due to lack of information.(20,21)

 

RESPIRATORY SENSITIZATION: There is one case report of a 58-year old man developing an asthmatic response following occupational exposure to glacial acetic acid (99.8%). The man had a history of childhood asthma, but remained symptom free from age 11-56 until the current exposure commenced. The asthmatic response was confirmed by pulmonary function testing.(4) This single report does not prove that acetic acid is a respiratory sensitizer.

Carcinogenicity:

There is no animal or human information available.

The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.

The American Conference of Governmental Industrial Hygienists (ACGIH) has not assigned a carcinogenicity designation to this chemical.

The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.

Teratogenicity and Embryotoxicity:

There is no animal or human information available.

Reproductive Toxicity:

There is no animal or human information available.

Mutagenicity:

There is no human information available. The mutagenicity of acetic acid appears to be an effect of pH on the culture media, rather than mutagenic activity of acetic acid itself. There have been no positive reports of mutagenicity, once the effect of pH on the culture media has been controlled.

Toxicologically Synergistic Materials:

Oral administration of 3% acetic acid to male rats for 8 months has increased the incidence of esophageal cancer caused by N-nitrososarcosin ethyl ester (NSEE).(13) Dermal application of acetic acid to female mice has increased the incidence and rate of development of skin carcinomas caused by 7,12-dimethylbenz[a] anthracene.(14)

Potential for Accumulation:

Acetic acid is absorbed from the gastrointestinal tract and through the lungs. Acetic acid is a normal body component and does not accumulate in the body. It is rapidly metabolized by most tissues and excreted, or used in the production of chemicals required for bodily functions.(17)

 

SECTION 4. FIRST AID MEASURES



Inhalation:

Take proper precautions to ensure your own safety before attempting rescue (e.g. wear appropriate protective equipment, use the buddy system). Remove source of contamination or move victim to fresh air. If breathing is difficult, oxygen may be beneficial if administered by trained personnel, preferably on a doctor's advice. DO NOT allow victim to move about unnecessarily. Symptoms of pulmonary edema can be delayed up to 48 hours after exposure. Immediately transport victim to an emergency care facility.

Skin Contact:

Avoid direct contact. Wear chemical protective clothing, if necessary. As quickly as possible flush contaminated area with lukewarm, gently flowing water for at least 20-30 minutes, by the clock. If irritation persists, repeat flushing. DO NOT INTERRUPT FLUSHING. If necessary, keep emergency vehicle waiting. Under running water, remove contaminated clothing, shoes and leather goods (e.g. watchbands, belts). Discard contaminated clothing, shoes and leather goods.

Eye Contact:

Avoid direct contact. Wear chemical protective clothing, if necessary. Immediately flush the contaminated eye(s) with lukewarm, gently flowing water for at least 20-30 minutes, by the clock, while holding the eyelid(s) open. Neutral saline solution may be used as soon as it is available. DO NOT INTERRUPT FLUSHING. If necessary, keep emergency vehicle waiting. Take care not to rinse contaminated water into the unaffected eye or onto the face. If irritation persists, repeat flushing. Quickly transport victim to an emergency care facility.

Ingestion:

NEVER give anything by mouth if victim is rapidly losing consciousness, is unconscious or is convulsing. Have victim rinse mouth thoroughly with water. DO NOT INDUCE VOMITING. Have victim drink 240 to 300 mL (8 to 10 oz.) of water to dilute material in the stomach. If milk is available, it may be administered AFTER the water has been given. If vomiting occurs naturally, have victim lean forward to reduce the risk of aspiration. Have victim rinse mouth and repeat administration of water. Quickly transport victim to an emergency care facility.

First Aid Comments:

Consult a doctor and/or the nearest Poison Control Centre for all exposures except minor instances of inhalation or skin contact.

Some recommendations in the above sections may be considered medical acts in some jurisdictions. These recommendations should be reviewed with a doctor and appropriate delegation of authority obtained, as required.

All first aid procedures should be periodically reviewed by a doctor familiar with the material and its conditions of use in the workplace.





SECTION 5. FIRE FIGHTING MEASURES

 

Flash Point:

39 deg C (103 deg F) (glacial) (31); 43 deg C (109 deg F) (glacial) (28); 50 deg C (122 deg F) (85%) (33) (closed cup values)

Lower Flammable (Explosive) Limit (LFL/LEL):

4% (28); 5.3-5.4% (32) (glacial)

Upper Flammable (Explosive) Limit (UFL/UEL):

16% (28,32); 19.9% (30) (glacial)

Autoignition (Ignition) Temperature:

463-465 deg C (867-869 deg F) (28,30); 516 deg C (961 deg F) (30) (glacial)

Sensitivity to Mechanical Impact:

Probably not sensitive. Stable material.

Sensitivity to Static Charge:

Information not available. Will not accumulate static discharge. The electrical conductivity of acetic acid (6 x 10(5) pS/m) is high.(33)

Combustion and Thermal Decomposition Products:

Irritant gases, which may include unburned acid and toxic constituents.(30,32)

Fire Hazard Summary:

Combustible liquid. Can form explosive mixtures with air at, or above, 39 deg C. Vapour is heavier than air and may travel a considerable distance to a source of ignition and flash back to a leak or open container. Vapours from warm liquid can accumulate in confined spaces, resulting in a flammability and toxicity hazard. Closed containers may rupture violently when heated. NOTE: The fire properties of acetic acid depend upon the strength of the solution. In concentrated form, its properties approach those of glacial acetic acid.(30)

Extinguishing Media:

Carbon dioxide, dry chemical powder, "alcohol resistant" foam, polymer foam, water spray or fog.(32,34)

 

Fire Fighting Instructions:

Evacuate area and fight fire from a safe distance or protected location. Approach fire from upwind to avoid hazardous vapours and toxic decomposition products.

If possible, isolate materials not yet involved in the fire, and move containers from fire area if this can be done without risk, and protect personnel. Otherwise, fire-exposed containers or tanks should be cooled by application of hose streams. Application should begin as soon as possible and should concentrate on any unwetted portions of the container. If this is not possible, use unmanned monitor nozzles and immediately evacuate the area.

If a leak or spill has not ignited, use water spray in large quantities to disperse the vapours, protect personnel attempting to stop a leak and dilute the spill to a nonflammable mixture. Water spray may be used to flush spills away from ignition sources. Solid streams of water may be ineffective and spread material.

For a massive fire in a large area, use unmanned hose holder or monitor nozzles. If this is not possible, withdraw from fire area and allow fire to burn. Stay away from ends of tanks. Withdraw immediately in case of rising sound from venting safety device or any discolouration of tank due to fire.

Acetic acid and its decomposition products are hazardous to health. Do not enter without wearing specialized protective equipment suitable for the situation. Firefighter's normal protective clothing (Bunker Gear) will not provide adequate protection. Chemical resistant clothing (e.g. chemical splash suit) and positive pressure self-contained breathing apparatus (MSHA/NIOSH approved or equivalent) may be necessary.





NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION

 

NFPA - Health: 3 - Short exposure could cause serious temporary or residual injury. (Glacial acetic acid)

NFPA - Flammability: 2 - Must be moderately heated or exposed to relatively high ambient temperatures before ignition can occur. (Glacial acetic acid)

NFPA - Instability: 0 - Normally stable, even under fire conditions, and not reactive with water. (Glacial acetic acid)

 

SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES

 

Molecular Weight: 60.05

Conversion Factor:

1 ppm = 2.45 mg/m3; 1 mg/m3 = 0.408 ppm at 25 deg C (calculated)

Physical State: Liquid

Melting Point: FREEZING POINT: 16.6 deg C (61.9 deg F) (100%) (29,32); -7.4 deg C (80.6%); -19.8 deg C (50.6%); -6.3 deg C (18.11%) (29)

Boiling Point: 117.9 deg C (244.2 deg F) (glacial) (28,29,32)

Relative Density (Specific Gravity): 1.05 at 20 deg C (100%) (28,29); 1.08 (80%); 1.06 (50%); 1.03 (20%) at 15 deg C (28,29) (water = 1)

Solubility in Water: Soluble in all proportions.(32)

Solubility in Other Liquids: Soluble in all proportions in ethanol, acetone, diethyl ether, glycerol and benzene.(17)

Coefficient of Oil/Water Distribution (Partition Coefficient): Log P(oct) = -0.31 (17)

pH Value: 2.4 (1M solution in water (approx. 6%)) (17,36)

Acidity: pKa = 4.76 at 25 deg C (17,29)

Viscosity-Dynamic: 1.22 mPa.s (1.22 centipoises) (100%) at 20 deg C (17,36). 2.39 mPa.s (90 wt.%); 2.72 mPa.s (80%); 2.16 mPa.s (50%); 1.43 mPa.s (20%) at 20 deg C (36)

Surface Tension: 27.57 mN/m (27.57 dynes/cm) (100%) at 20.1 deg C (28,29); 34.3 mN/m (69.9 wt.%); 38.4 mN/m (49.96%); 43.6 mN/m (30.09%) at 30 deg C (36)

Vapour Density: 2.07 (air = 1) (34)

Vapour Pressure: 1.52 kPa (11.4 mm Hg) at 20 deg C (17,34)

Saturation Vapour Concentration: 1.5% (15000 ppm) at 20 deg C (calculated)

Evaporation Rate: 0.97 (n-butyl acetate = 1) (17)

 

SECTION 10. STABILITY AND REACTIVITY

 

Stability:

Normally stable.

Hazardous Polymerization:

Does not occur.

Incompatibility - Materials to Avoid:

NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.



STRONG OXIDIZING AGENTS (e.g. chromic acid, hydrogen peroxide, nitric acid, perchloric acid, potassium permanganate, sodium peroxide) - react violently, with risk of fire and explosion.(30,31,33,37)

STRONG ALKALIS or CAUSTICS (e.g. sodium or potassium hydroxide), or BASES - may react violently.(30,31)

MOST COMMON METALS (except aluminum) - may give off flammable hydrogen gas.(31,33)

ACETALDEHYDE - polymerization occurs, with evolution of heat.(30,37)

2-AMINOETHANOL, CHLOROSULFONIC ACID, ETHYLENE DIAMINE, ETHYLENEIMINE, OLEUM - mixing in a closed container caused the temperature and pressure to rise.(30)

AMMONIUM NITRATE - may ignite when warmed.(30)

BROMINE PENTAFLUORIDE, CHLORINE TRIFLUORIDE - may react violently, with fire and explosion likely.(30,37)

PHOSPHORUS ISOCYANATE - react violently.(30)

PHOSPHORUS TRICHLORIDE - explosion may occur due to the possible formation of spontaneously flammable phosphine.(30,37)

POTASSIUM tert-BUTOXIDE - ignition occurs after 3 minutes.(30,37)

n-XYLENE - during production of terephthalic acid in which n-xylene is oxidized in the presence of acetic acid, detonating mixtures may be produced.(30)

Hazardous Decomposition Products:

None reported.

Conditions to Avoid:

Temperatures above 39 deg C, open flames, static charge, sparks and other ignition sources.

Corrosivity to Metals:

Acetic acid attacks most common metals, including steel, iron, most stainless steels, copper, bronze and brass, particularly when diluted with water. Depending on conditions, acetic acid (greater than 99%) may be used with or stored and shipped in stainless steel grades 316, 318 and 321, and aluminum. Aluminum slowly corrodes, forming a layer of aluminum acetate that prevents further corrosion. Water increases the corrosion rate, while mercury, present as an impurity, catalyzes the corrosion of aluminum.(28,29,32,38)

Stability and Reactivity Comments:

Attacks many forms of plastics, rubber and coatings. It dissolves synthetic resins and rubber.(32)

 

SECTION 11. TOXICOLOGICAL INFORMATION

 

LC50 (mouse): 2810 ppm (4-hour exposure); cited as 5620 ppm (1-hour exposure) (22)

LD50 (oral, rat): 3530 mg/kg (concentration not specified) (23)

LD50 (dermal, guinea pig): 3300 mg/kg (cited as 3.2 mL/kg) (28% solution) (24, unconfirmed)

Eye Irritation:

There is no specific information on acetic acid solutions greater than 10%. Solutions of 10% and less have produced moderate to very severe eye irritation in rabbits, including corrosive injury.(23,24,25)

Skin Irritation:

Application of 0.01 mL of 100% acetic acid produced strong redness, swelling or slight tissue death in rabbits (graded 5/10).(23) Application of 0.1 mL of glacial acetic acid (99.8%), under cover, produced severe irritation in rabbits (scores of 2.6/4 (intact skin) or 3.2/4 (abraded skin); where 4 is corrosive tissue injury).(8)

Effects of Short-Term (Acute) Exposure:

Inhalation:

Reversible upper respiratory tract irritation and reversible effects on respiratory function have been observed in mice and guinea pigs following inhalation of the vapour. Guinea pigs were exposed for 1 hour to 5, 40, 120 or 570 ppm. Dose-dependent reversible effects on respiratory function (e.g. increased pulmonary flow resistance and decreased compliance) were observed. Concentrations of 120 and 570 ppm also caused a decrease in respiration rate and minute volume and increased resistance to airflow.(1) Mice exposed to concentrations greater than 1000 ppm experienced reversible irritation of the upper respiratory tract.(22)

Ingestion:

Ingestion of 40 or 50% solutions by rabbits has been reported cause slightly caustic or caustic injury to the esophagus, respectively.(26, unconfirmed)

Effects of Long-Term (Chronic) Exposure:

Inhalation:

Continuous exposure to a low concentration (2 ppm) has produced slight changes in the blood and slight changes in liver function in male rats.(27)

Mutagenicity:

The mutagenicity of acetic acid appears to be an effect of pH on the culture media, rather than mutagenic activity of acetic acid itself. There have been no positive reports of mutagenicity, once the effect of pH on the culture media has been controlled.(10,11) One study showed positive results in Eschericheri coli, but the effects of pH were not considered in the evaluation.(12)

 

SECTION 16. OTHER INFORMATION

 

Selected Bibliography:

(1) Amdur, M.O. The respiratory response of guinea pigs to the inhalation of acetic acid vapor. Industrial Hygiene Journal. Vol. 22, no. 1 (February, 1961). p. 1-5

(2) Rajan, K.G., et al. Reversible airways obstruction and interstitial pneumonitis due to acetic acid. British Journal of Industrial Medicine. Vol. 46, no. 1 (January, 1989). p. 67-68

(3) Hodgson, M.J., et al. Respiratory disease in a photographer. American Journal of Industrial Medicine. Vol. 9, no. 4 (April, 1986). p. 349-354

(4) Kivity, S., et al. Late asthmatic response to inhaled glacial acetic acid. Thorax. Vol. 49, no. 7 (July, 1994). p. 727-728

(5) Kern, D.G. Outbreak of the reactive airways dysfunction syndrome after a spill of glacial acetic acid. American Review of Respiratory Disease. Vol. 144, no. 5 (November, 1991). p. 1058-1064

(6) Shafto, C.M. Two cases of acetic acid burns of the cornea. British Journal of Ophthalmology. Vol. 34 (1950). p. 559-562

(7) Vigliani, E.C., et al. Experiences of the Clinica del Lavoro with maximum allowable concentrations of industrial poisons. Archiv fuer Gewerbepathologie und Gewerbehygiene. Vol. 13 (1955). p. 528-535. (English translation: Archives of Industrial Health. Vol. 13 (1956). p. 403)

(8) Campbell, K.I., et al. Dermal irritancy of metal compounds: studies with palladium, platinum, lead and manganese compounds. Archives of Environmental Health. Vol. 30 (April, 1975). p. 168-170

(9) Nixon, G.A., et al. Interspecies comparisons of skin irritancy. Toxicology and Applied Pharmacology. Vol. 31 (1975). p. 481-490

(10) Sipi, P., et al. Sister-chromatid exchanges induced by vinyl esters and respective carboxylic acids in cultured human lymphocytes. Mutation Research. Vol. 279, no. 2 (16 May, 1992). p. 75-82

(11) Morita, T., et al. Evaluation of clastogenicity of formic acid, acetic acid and lactic acid on cultured mammalian cells. Mutation Research. Vol. 240, no. 3 (March, 1990). p. 195-202

(12) Demerec, M., et al. A survey of chemicals for mutagenic action in E. Coli. The American Naturalist. Vol. LXXXV, no. 821 (March-April, 1951). p. 119-136

(13) Alexandrov, V.A., et al. The stimulating effect of acetic acid, alcohol and thermal burn injury on esophagus and forestomach carcinogenesis induced by N-nitrososarcosin ethyl ester in rats. Cancer Letters. Vol. 47 (1989). p. 179-185

(14) Rostein, J.B. et al. Acetic acid, a potent agent of tumor progression in the multistage mouse skin model for chemical carcinogenesis. Cancer Letters. Vol. 42, nos. 1,2 (September/October, 1988). p. 87-90

(15) Jurim, O., et al. Disseminated intravascular coagulopathy caused by acetic acid ingestion. Acta Haematologica. Vol. 89 (1993). p. 204- 205

(16) Hakenbeck, Von H., et al. Vergiftung mit 80%iger Essigsaure. [English summary]. Zeitschrift fur Urologie und Nephrologie. Vol. 77 (1984). p. 311-314

(17) HSDB record for acetic acid. Last revision date: 96/01/18

(18) Parmeggiani, L., et al. On the injuries to health caused by acetic acid in the production of cellulose acetate. [English summary]. Medicina del Lavoro. Vol. 45 no. 5 (1954). p. 319-323

(19) Goh, C.L. Occupational dermatitis from soldering flux among workers in the electronics industry. Contact Dermatitis. Vol. 13. no. 1 (1985). p. 85-90

(20) Weil, A.J., et al. Allergic reactivity to simple aliphatic acids in man. Journal of Investigative Dermatology. Vol. 17 (October, 1951). p. 227-231

(21) Vaneckova, J., et al. Hypersensitivity to rubber surgical gloves in healthcare personnel. Contact Dermatitis. Vol. 31, no. 4 (October, 1994). p. 266-268

(22) Ghiringhelli, L., et al. Pathology due to acetic acid: observations on experimental animals and on men. [English summary]. Medicina del Lavoro. Vol. 48, no. 10 (1957). p. 559-565

(23) Smyth, Jr., H.F., et al. Range-finding toxicity data: list IV. Archives of Industrial Hygiene and Occupational Medicine. Vol. 4 (1951). p. 119-122

(24) Acetic acid. Hygienic Guide Series. American Industrial Hygiene Association, June 1978.

(25) Murphy, J.C., et al. Ocular irritancy responses to various pHs of acids and bases with and without irrigation. Toxicology. Vol. 23 (1982). p. 281-291

(26) v. Muhlendahl, K.E., et al. Local injuries by accidental ingestion of corrosive substances by children. Archives of Toxicology. Vol. 39 (1978). p. 299-314

(27) Takhirov, M.T. Hygienic standards for acetic acid and acetic anhydride in air. Hygiene and Sanitation. Vol. 34, no. 4 (June, 1969). p. 122-125

(28) Wagner, Jr., F.S. Acetic acid. In: Kirk-Othmer encyclopedia of chemical technology. 4th edition. Volume 1. John Wiley and Sons, 1991. p. 121-139

(29) Aguilo, A, et al. Acetic acid. In: Ullmann's encyclopedia of industrial chemistry. 5th completely revised edition. Volume A 1. VCH Verlagsgesellschaft, 1985. p. 45-64

(30) Fire protection guide to hazardous materials. 13th ed. Edited by A.B. Spencer, et al. National Fire Protection Association, 2002. NFPA 325; NFPA 49; NFPA 491

(31) NIOSH pocket guide to chemical hazards. National Institute of Occupational Safety and Health, June 1994. p. 2-3

(32) Emergency action guide for acetic acid. Association of American Railroads, January, 1988

(33) Chemical safety sheets: working safely with hazardous chemicals. Kluwer Academic Publishers, 1991. p. 3,4

(34) The Sigma-Aldrich library of chemical safety data. Edition II. Volume 1. Sigma-Aldrich Corporation, 1988. p. 13A

(35) Odor thresholds for chemicals with established occupational health standards. American Industrial Hygiene Association, 1989. p. 12, 42

(36) Weast, R.C., ed. Handbook of chemistry and physics. 66th edition. CRC Press, 1985-1986. p. C-47, D-146, D-161, D-221, F-31, F- 63

(37) Urben, P.G., ed. Bretherick's handbook of reactive chemical hazards. 5th edition. Volume 1. Butterworth-Heinemann Ltd., 1995. p. 319-320

(38) Corrosion data survey: metals section. 6th edition. National Association of Corrosion Engineers, 1985. p. 2-4,5,6 to 3-4,5,6

(39) European Economic Community. Commission Directive 93/72/EEC. September 1, 1993

(40) Forsberg, K., et al. Quick selection guide to chemical protective clothing. 4th ed. Van Nostrand Reinhold, 2002

(41) Occupational Safety and Health Administration (OSHA). Acetic and Formic Acids in Workplace Atmospheres. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc.html>

(42) Occupational Safety and Health Administration (OSHA). Acetic Acid. In: OSHA Analytical Methods Manual. Revision Date: Oct. 31, 2001. Available at: <www.osha-slc.gov/dts/sltc/methods/toc.html>

(43) National Institute for Occupational Safety and Health (NIOSH). Acetic Acid. In: NIOSH Manual of Analytical Methods (NMAM(R)). 4th ed. Edited by M.E. Cassinelli, et al. DHHS (NIOSH) Publication 94-113. Aug. 1994. Available at: <www.cdc.gov/niosh/nmam/nmammenu.html>

Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.

 

Review/Preparation Date: 1996-11-28

 

Revision Indicators:

Ingestion (Health) 1997-05-01

Ingestion (First Aid) 1997-05-01

Emergency Overview 1997-05-01

US transport 2002-12-10

TDG 2003-08-14

Resistance of materials for PPE 2004-04-05

ERPG-1 2004-06-30

ERPG-2 2004-06-30

ERPG-3 2004-06-30

Bibliography 2005-03-10

Passive Sampling Devices 2005-03-10

Sampling/analysis 2005-03-10

Toxicological info 2007-07-09

Relative density 2007-07-09













Clofazimine

  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

   1.7 Presentation, Formulation

  1. 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

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Properties of the substance

         3.3.1.1 Colour

         3.3.1.2 State/Form

         3.3.1.3 Description

      3.3.2 Properties of the locally available formulation(s)

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Shelf-life of the locally available formulation(s)

      3.4.3 Storage conditions

      3.4.4 Bioavailability

      3.4.5 Specific properties and composition

  1. 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

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Others

  1. 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

  1. 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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Material sampling plan

      8.1.1 Sampling and specimen collection

      8.1.2 Storage of laboratory samples and specimens

      8.1.3 Transport of laboratory samples and specimens

   8.2 Toxicological analyses and their interpretation

      8.2.1 Tests on active 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 qualitative method(s)

   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

      8.3.2 Arterial blood gas analyses

      8.3.3 Haematologic 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

  1. 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. ADDITIONAL INFORMATION

   12.1 Availability of antidotes

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




  1. NAME

 

       1.1 Substance

 

           Clofazimine (INN)

 

           (WHO, 1992)

 

       1.2 Group

 

           ATC classification index

 

           Antimycobacterials (JO4)/Drugs for treatment of lepra (JO4B)

           

           (WHO, 1992)

 

       1.3 Synonyms

 

           Riminophenazine

           B-663

           G-30320

 

           (Budavari, 1989; Reynolds, 1989).

 

           (To be completed by each Centre using local data)

 

       1.4 Identification numbers

 

           1.4.1 CAS number

 

                 2030-63-9

 

           1.4.2 Other numbers

 

                 RTECS

 

                 SG1578000

 

       1.5 Brand names, Trade names

 

           Lamprene

           

           (To be completed by each Centre using local data)

 

       1.6 Manufacturers, Importers

 

           Ciba-Geigy

           

           (To be completed by each Centre using local data)

 

       1.7 Presentation, Formulation

 

           Capsule containing 50 mg

           Capsule containing 100 mg

 

           (To be completed by each Centre using local data)

 

  1. SUMMARY

 

       2.1 Main risks and target organs

 

           Acute poisoning

           

           No reports are available on acute toxicity.

           

           Chronic poisoning

           

           One report mentioned abdominal disposition of clofazamine

           crystals and one report of splenic infarction.

           

           Target organs

           

           CNS; gastrointestinal; ocular effects.

           

       2.2 Summary of clinical effects

 

           Dermal

           

           Pink to brownish-black discolouration of the skin; dryness;

           ichthyosis; pruritus; acneform eruptions, skin rashes; and

           photosensitivity reactions.

           

           Eye

           

           Reddish-brown discolouration of the cornea, conjunctiva and 

           lacrimal fluid.  Occasionally there could be dryness, 

           itchiness, irritation, burning and watering of the eyes.

           

           Gastrointestinal tract

 

           Nausea, vomiting, abdominal pain and diarrhoea, 

           discolouration of faeces.  There was even note of splenic 

           infarction seen in a patient receiving clofazimine for the 

           treatment of pyoderma gangrenosum.

           

           Nervous system

 

           Headache, dizziness, drowsiness, fatigue, and taste disorder. 

           Some patients became depressed because of skin discolouration.

           

           Haematopoietic system

           

           Eosinophilia; elevated ESR.

           

           Liver

           

           Elevated albumin, bilirubin and SGOT.

 

           Others

           

           Discolouration of the sweat, sputum and urine.

           

                        (McEvoy, 1990; Reynolds, 1989; PDR, 1990)

 

       2.3 Diagnosis

 

           By exclusion: If the patient taking clofazimine presents with 

           symptoms and signs as above in 2.2., it may be caused by 

           chronic clofazimine poisoning. Other causes that have these 

           symptoms and signs such as rifampicin toxicity may have to be 

           excluded.

           

           Clofazimine may be measured in biological fluids by Thin-

           Layer Chromatographic method (Hauffe et al., 1986), or High 

           Pressure Liquid Chromatography can also be used (Moffat, 

           1986). However, these methods are usually of no value in the 

           diagnosis in the acute stage. 

 

       2.4 First aid measures and management principles

 

           Control for hypokalaemia and its effects on ECG.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

       3.1 Origin of the substance

 

           Substituted iminophenazine derivative (synthetic)

 

       3.2 Chemical structure

 

           Structural formula

           

           Molecular formula

           

           C27H22C12N4

           

           Molecular weight

           

           473.41

           

           Chemical names

           

           3-(4-Chloroanilino)-10-(4-chlorophenyl)-2,10-dihydro-2-

           phenazin-2-ylideneisopropylamine

           

           N,5-Bis(4-Chlorophenyl)-3,5-dihydro-3-[(1-methylethyl)imino]-

           2-phenazinamine

           

           3-(p-Chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-

           (isopropylimino)-phenazine

           

           2-(4-Chloroanilino)-3-isopropylimino-5-(4-chlorophenyl)-3,5-

           dihydrophenazine

           

           2-p-Chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-

           isopropyliminophenazine

           

           (Budavari, 1989; Reynolds, 1993)

           

       3.3 Physical properties

 

           3.3.1 Properties of the substance

 

                 3.3.1.1 Colour

 

                         Reddish-brown

 

                 3.3.1.2 State/Form

 

                         Fine powder

 

                 3.3.1.3 Description

 

                         Melting point about 215 °C

                         Odourless

                         Readily soluble in benzene, soluble in 

                         chloroform, slightly soluble in methanol and 

                         ethanol, very slightly soluble in ether, poorly 

                         soluble in acetone and ethyl acetate, 

                         practically insoluble in water (Reynolds, 1989; 

                         PDR, 1990).

    

           3.3.2 Properties of the locally available formulation(s) 

 

                 To be completed by each Centre using local data.

 

       3.4 Other characteristics

 

           3.4.1 Shelf-life of the substance

 

                 Five years (Weber & Kop, 1987).

             

           3.4.2 Shelf-life of the locally available formulation(s) 

 

                 To be completed by each Centre using local data.

 

           3.4.3 Storage conditions

 

                 With the storage condition at 23°C, the physical 

                 properties and rate of disintegration of the capsules 

                 remained the same.  If stored at higher temperature, 

                 they became useless and would stick together.  The 

                 capsules should be protected from heat and moisture 

                 (Weber & Kop, 1987). 

 

           3.4.4 Bioavailability

 

                 Clofazimine has a variable absorption rate ranging from 

                 45% to 62% after oral administration. Absorption is 

 

                 influenced by particle size. Food increases its 

                 bioavailability.  Its half-life is approximately 70 

                 days.

                 

                 (To be completed by each Centre using local data)

 

           3.4.5 Specific properties and composition

 

                 To be completed by the local centre.

 

  1. USES

 

       4.1 Indications

 

           4.1.1 Indications

 

                 As an antileprotic in association with other agents.

                 

                 Has anti-inflammatory properties in erythema nodosum 

                 leprosum reactions. 

                 

                 For use in the treatment of Lobo's disease (a chronic 

                 topical mycosis), Crohn's disease, Leishmaniasis.

                 

                 It has been used in the treatment of cutaneous 

                 elastolytic lymphoma (von den Driesch P et al., 

                 1994).

                 

                 Chronic skin ulcers (Buruli ulcer) (Gilman et al., 

                 1990) 

 

           4.1.2 Description

 

                 Not relevant

 

       4.2 Therapeutic dosage

 

           4.2.1 Adults

 

                 Clofazimine, 50 to 100 mg daily. WHO recommends a 

                 regimen in which rifampicin 600mg and clofazimine 300 

                 mg are given once monthly, together with Dapsone 100 mg 

                 daily, self-administered (for at least 2 years) 

                 (Reynolds, 1993).

                 

                 The treatment of erythema nodosum leprosum reactions 

                 depends on the severity of symptoms. In general, the 

                 basic antileprosy treatment should be continued. Dosage 

                 of clofazimine above 200 mg daily is not recommended, 

                 and the dosage should be tapered to 100 mg daily as 

                 quickly as possible after the reactive episode is 

                 controlled (PDR, 1990).

                 

                 (Note: Antileprotic regimen is in accordance with the 

                 recommendation of the World Health Organization (WHO). 

                 Depending on the indication, dosage regimen varies. 

 

                 Because adverse effects on the gastrointestinal tract 

                 are dose related, it has been recommended that daily 

                 doses of 300 mg or more should not be administered for 

                 more than three months). 

 

           4.2.2 Children

                         

                 10-14 years old

                 

                 Clofazimine 200 mg once monthly, supervised; and 50 mg 

                 on alternate days, self-administered (Reynolds, 1993).

                 

                 Note: The dose should be adjusted for children with low 

                 bodyweight as follows:

                 

                 over 35 kg    50 mg daily and 300 mg monthly

                 20 to 35 kg   50 mg every 2nd day and 200 mg monthly

                 12 to 20 kg   50 mg every 2nd day and 100 mg monthly

                 12 kg or less 50 mg twice weekly and 100 mg monthly 

                 

                 (Dollery, 1991)

                 

                 (Note: The optimum effective dose has not yet been 

                 established.  The dose recommended above for children 

                 is half the adult dose, adjusted for operational 

                 suitability, since clofazimine is marketed in capsules 

                 of 100 mg and 50 mg). 

 

       4.3 Contraindications

 

           Use of clofazimine should be avoided during pregnancy or 

           lactation unless absolutely necessary.

           

           Administration of the drug should be modified or discontinued 

           in the presence of liver and kidney function disorder.

           

           It should be used with caution together with diuretics to 

           avoid hypokalaemia. 

 

  1. ROUTES OF ENTRY

 

       5.1 Oral

 

           This is the usual route of administration for therapeutic 

           use. 

 

       5.2 Inhalation

 

           Not relevant.

 

       5.3 Dermal

 

           Not relevant.

 

       5.4 Eye

 

           Not relevant.

 

       5.5 Parenteral

 

           Not relevant.

 

       5.6 Others

 

           Not relevant.

 

  1. KINETICS

 

       6.1 Absorption by route of exposure

 

           Clofazimine has a variable absorption rate ranging from 45 to 

           62% after oral administration. About 20% of a dose is 

           absorbed from the gastrointestinal tract when clofazimine is 

           administered as coarse crystals, but 45 to 70% of a dose may 

           be absorbed when the drug is administered as capsules 

           containing a microcrystalline (micronized) suspension of the 

           drug in an oil-wax base.  Presence of food in the GIT may 

           increase the rate and extent of absorption of Clofazimine 

           (McEvoy, 1990).  According to Alford (1989) absorption is 

           variable with 9 to 74% of an administered dose appearing in 

           faeces. 

 

       6.2 Distribution by route of exposure

 

           Clofazimine is highly lipophilic and is distributed 

           principally to fatty tissue and cells of the 

           reticuloendothelial system; the drug is taken up by 

           macrophages throughout the body.  It accumulates in high 

           concentrations in the mesenteric lymph nodes, adipose tissue, 

           adrenals, liver, lungs, gallbladder, bile, and spleen and in 

           lower concentrations in the skin, small intestine, lungs, 

           heart, kidneys, pancreas, muscle, omentum, and bone. 

           Clofazimine crystals have also been found in bone marrow, 

           sputum, sebum, and sweat, and in the iris, conjunctiva, 

           macula, sclera, and cornea.  The drug does not appear to 

           distribute into the brain or CSF (McEvoy, 1990).  It crosses 

           the placental barrier and is distributed into breast milk. 

 

       6.3 Biological half-life by route of exposure

 

           At least 70 days after repeated therapeutic dose (AHFS, 1990; 

           Alford, 1989).

           

           Repeated therapeutic doses result with a biological half life 

           of approximately 70 days with a plasma concentration of 

           0.4-3_µg/ml (McEvoy, 1990; Alford R, 1989). 

 

       6.4 Metabolism

 

           The metabolic fate of clofazimine has not been fully 

           elucidated, but the drug appears to accumulate in the body 

           and to be excreted principally unchanged.  Clofazimine 

           appears to be partially metabolized and at least 3 

           metabolites have been found in urine of patients receiving 

           the drug.  Metabolite I is formed by hydrolytic 

           dehalogenation of clofazimine, metabolite II presumably is 

           formed by a hydrolytic deamination reaction followed by 

           glucuronidation, and metabolite III appears to be a hydrated 

           clofazimine glucuronide (McEvoy, 1990). 

 

       6.5 Elimination  by route of exposure

 

           Clofazimine is excreted principally in faeces, both as 

           unabsorbed drug and via biliary elimination. Faecal 

           elimination of clofazimine exhibits considerable 

           interindividual variation, and 35% to 74% of a single oral 

           dose may be excreted unchanged in faeces over the first 72 

           hours after the dose. Following oral administration of a 

           single 200 mg or 300 mg dose, elimination of unchanged 

           clofazimine and its metabolites in urine is negligible during 

           the first 24 hours. Following multiple doses of the drug, 

           less than 1% of the daily dose is excreted in urine over a 

           24-hour period. Small amounts of the drug also are excreted 

           via sebaceous and sweat glands. (McEvoy, 1990)

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

       7.1 Mode of action

                         

           7.1.1 Toxicodynamics

 

                 No data available.

 

           7.1.2 Pharmacodynamics

 

                 The precise mechanism of the drug's antimycobacterial 

                 effect has not been fully elucidated just like its 

                 anti-inflammatory and immunosuppressive effects. The 

                 drug binds preferentially to mycobacterial DNA at base 

                 sequences containing guanine resulting to inhibition of 

                 mycobacterial replication and growth.  The inhibitory 

                 concentration of clofazimine in tissue is between 0.1 

                 and 1_µg/kg (Alford R, 1989).

                 

                 Studies in vivo and in vitro showed that clofazimine 

                 causes a progressive, dose-dependent inhibition of 

                 neutrophil motility and mitogen-induced lymphocyte 

                 transformation.  Clofazimine also increases synthesis 

                 of prostaglandin E2 by the polymorphonuclear leucocytes 

                 in vitro.  However, most of the studies done showed 

                 that clofazimine increases the phagocytic activity and 

                 oxidative metabolism of the polymorphonuclear cells and 

 

                 macrophages in vitro and in vivo (McEvoy, 1990; 

                 Reynolds, 1989,  Alford, 1989). 

 

       7.2 Toxicity

 

           7.2.1 Human data

 

                 7.2.1.1 Adults

 

                         Severe abdominal symptoms have necessitated 

                         exploratory laparotomies in some patients on 

                         clofazimine therapy. Rare reports have included 

                         splenic infarction, bowel obstruction, and 

                         gastrointestinal bleeding. Deaths have been 

                         reported, following severe abdominal symptoms. 

                         Autopsies revealed crystalline deposits of 

                         clofazimine in various tissues including the 

                         intestinal mucosa, liver, spleen and mesenteric 

                         lymph nodes (PDR, 1992).

                         

                         To minimise toxicity it is recommended that 

                         daily doses of 300 mg or more should not be 

                         administered for more than three months and 

                         patients on doses greater than 100 mg daily 

                         should be under medical supervision (Reynolds, 

                         1993).  

     

                 7.2.1.2 Children

 

                         No data available.

 

           7.2.2 Relevant animal data

 

                 Oral LD 50 (rabbits)  3.3 g/kg

                 

                 Oral LD 50 (mice, rats and guinea pigs) >4 g/kg.

                 

                 (McEvoy, 1990; Budavari, 1989).

 

           7.2.3 Relevant in vitro data

 

                 No data available.

 

       7.3 Carcinogenicity

 

           No data available.

 

       7.4 Teratogenicity

 

           There is no evidence of teratogenicity.  However, clofazimine 

           crosses the human placenta.  The skin of infants born to 

           women who had received the drug during pregnancy was deeply 

           pigmented at birth. However, no evidence of teratogenicity 

           was noted.  There are no adequate and well-controlled studies 

           in pregnant women, but 3 neonatal deaths had been reported in 

 

           15 pregnancies in patients given clofazimine.  (McEvoy, 1990; 

           Reynolds, 1989; Farb et al., l982; PDR, 1990).

 

       7.5 Mutagenicity

 

           The drug was not mutagenic in the Ames microbial mutagen test 

           with or without metabolic activation (McEvoy, 1990).  

           However, genotoxic micronuclear testing studies in mice bone 

           marrow and spermatocytes revealed increase of chromosomal 

           aberrations.  The mechanism is not well understood but has 

           been suggested to be secondary to generation of hydroxyl 

           radicals and their effects on chromosomes (Das & Roy, 1990). 

           However, there is a significant higher incidence of 

           micronucleus in bone marrow erythrocytes and regenerated 

           hepatocytes indicating that clofazamine has a clastogenic 

           effect.  Clofazamine has been noted to have antimitotic 

           effects and the proposed mechanism is impairment of DNA 

           template or antimitochondrial activity (Roy & Das, 1990).

 

       7.6 Interactions

 

           Several studies done showed that concomitant clofazimine 

           administration does not affect the pharmacokinetics of 

           dapsone, but a few patients showed transient increase in the 

           urinary excretion of dapsone. However, there is some evidence 

           that the anti-inflammatory effects of clofazimine may be 

           decreased or nullified by dapsone; since, in vitro studies 

           showed that there is an opposite effect of both drugs on the 

           neutrophil motility and lymphocyte transformation.  But there 

           is no evidence of interference between the two drugs with 

           regard to their antimycobacterial activity.

           

           Clofazimine with rifampicin alone, or in conjunction with 

           dapsone, results in a delay in time to reach peak serum 

           rifampicin concentration, decrease in the rate of absorption 

           of rifampicin, and slight decrease in the area under the 

           plasma concentration curve (AUC) of the drug.  But, in a 

           study of lepromatous leprosy patients receiving dapsone 100 

           mg daily and rifampicin 600 mg daily, concomitant 

           administration of clofazimine 100 mg daily did not affect 

           plasma rifampicin concentrations of the AUC, plasma half-life 

           or urinary elimination of rifampicin.

           

           In a study of lepromatous leprosy patients receiving 

           clofazimine 300 mg daily, concomitant administration of 

           isoniazid 300 mg daily resulted in increased urinary and 

           plasma concentrations of clofazimine and decreased 

           concentration of the drug in the skin (McEvoy, 1990). 

 

       7.7 Main adverse effects

 

           Potentially life-threatening

           

           When clofazimine is given in high dosage for months or years, 

           crystals of the drug are deposited in the lamina propria and 

 

           submucosa of the small intestine, and in the mesenteric lymph 

           nodes (Dollery, 1991). The ileal wall may become thickened 

           with nodular or polypoid changes, and the mucosal pattern 

           coarsen and eosinophilic enteritis may also occur (Mason et 

           al., 1977; de Bergeyck, 1980).

           

           One patient, who received clofazimine in dosage varying 

           between 100 mg and 600 mg daily for 6 years for severe ENL, 

           after 3 years developed severe, progressive loss of weight, 

           recurring anorexia, nausea, diarrhoea and abdominal pain. She 

           died 4 months after stopping clofazimine from presumed 

           electrolyte imbalance (Jopling, 1976; Harvey et al., 1977).

           

           Other patients, whose clofazimine dosage was stopped at an 

           earlier stage, have usually gradually become symptom free, 

           although clofazimine crystals have been detected in a 

           mesenteric lymph node 46 months later (Jopling, 1976).  One 

           patient, who received 300 to 400 mg clofazimine daily for 

           only 11 months, developed a splenic infarct with evidence of 

           considerable accumulation of crystals in the spleen with 

           massive accumulation in a mesenteric lymph node (McDougal et 

           al., 1980).

           

           Dermal

           

           Adverse effects are usually dose-related, they include:

           

           Pink to brownish-black discolouration of the skin: dryness, 

           ichthyosis, pruritus, acneform eruptions, skin rashes and 

           photosensitivity reactions.

           

           Ocular

           

           Reddish-brown discolouration of the cornea, conjunctiva, and 

           lacrimal fluid.  Occasionally there could be dryness 

           itchiness, irritation, burning and watering of the eyes.

           

           Gastrointestinal

           

           Nausea, vomiting, abdominal pain and diarrhoea, 

           discolouration of faeces.  There was even note of splenic 

           infarction in a patient receiving clofazimine for the 

           treatment of pyoderma gangrenosum. Bowel obstruction and 

           G.I.S. bleeding in less than 1% of patients.

           

           Nervous system

           

           Headache, dizziness, drowsiness, fatigue and taste disorder. 

           Some patients developed depression because of the skin 

           discolouration.

           

           Haematopoietic effects

           

           Elevated ESR, eosinophilia.

 

           Liver

           

           Elevated albumin, bilirubin and SGOT.

           

           Other

           

           Discolouration of sweat, sputum, urine and breast milk, 

           hypokalaemia.

           

           (McEvoy, 1990; Reynolds, 1989; PDR, 1990). 

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

       8.1 Material sampling plan

 

           8.1.1 Sampling and specimen collection

 

                 Blood samples are collected in heparinized tubes and 

                 these would be centrifuged.  The plasma must be 

                 separated and transferred into a plastic tube (Hauffe 

                 et al, 1986; Weber and Kop, 1987). 

 

           8.1.2 Storage of laboratory samples and specimens

 

                 The samples are to be kept frozen at -20°C until 

                 required for analysis (Hauffe et al, 1986, Weber and 

                 Kop, 1987). 

 

           8.1.3 Transport of laboratory samples and specimens

 

                 Samples can be transferred in containers which could 

                 provide a temperature of -20 °C (Hauffe et al., 1986; 

                 Weber and Kop, 1987). 

 

       8.2 Toxicological analyses and their interpretation

 

           8.2.1 Tests on active 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)

 

                         Photometric determination alone.

                         

                         Photometric determination after TALC-separation

                         (Weber & Kop, 1987).

 

                 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)

 

                         Thin-layer chromatographic method.

                         

                         High pressure liquid chromatography (Moffat, 

                         1986). 

 

                 8.2.2.4 Advanced qualitative method(s)

 

       8.3 Biomedical investigations and their interpretation

 

           8.3.1 Biochemical analysis

 

                 8.3.1.1 Blood, plasma or serum

 

                         Use function test as ALT, AST, albumin, 

                         bilirubin, SGOT. 

 

                 8.3.1.2 Urine

 

           8.3.2 Arterial blood gas analyses

 

           8.3.3 Haematologic analyses

 

                 ESR, total eosinophile count, prothrombin time.

 

           8.3.4 Interpretation of biomedical investigations

 

       8.4 Other biomedical (diagnostic) investigations and their 

           interpretation 

 

           ECG.

 

       8.5 Overall interpretation of all toxicological analyses and

           toxicological investigations

 

           In view of the distribution and the lack of information on 

           therapeutic and/or toxic blood levels, measuring has no 

           practical relevance in the management of intoxication. 

 

       8.6 References

 

           See Section 13.

 

  1. CLINICAL EFFECTS

 

       9.1 Acute poisoning 

 

           9.1.1 Ingestion

 

                 No data available.

 

           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

 

                 No data available.

 

       9.2 Chronic poisoning 

                         

           9.2.1 Ingestion

 

                 The only route of administration.  Dose-related adverse 

                 effects are therefore only from oral ingestion of 

                 clofazimine.

                 

                 Adverse reactions are dose-related with daily doses of 

                 300 mg or more, and more than three months of intake. 

 

           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 exposure

 

                 No data available.

 

           9.2.6 Other

                                                  

                 No data available.

 

       9.3 Course, prognosis, cause of death

 

           Adverse effects of clofazimine were generally well tolerated 

           and no patient stopped treatment because of them. However, 

 

           there was a report of fatal syndrome of abdominal pain, 

           malabsorption, intra-abdominal deposition of clofazimine 

           crystals in one patient.  There was also noted splenic 

           infarction and tissue accumulation of clofazimine in a 

           patient receiving clofazimine for the treatment of pyoderma 

           gangrenosum (Reynolds, 1989). 

 

       9.4 Systematic description of clinical effects

 

           9.4.1 Cardiovascular

 

                 Arrhythmia secondary to hypokalaemia (PDR, 1990).

                 

                 Its cardiotoxicity has been postulated (Choudhri et 

                 al., 1995). 

 

           9.4.2 Respiratory

 

                 Discolouration of the sputum.

 

           9.4.3 Neurological

 

                 9.4.3.1 Central nervous system (CNS)

 

                         Headache, dizziness, drowsiness, fatigue, taste 

                         disorder, depression. 

 

                 9.4.3.2 Peripheral nervous system

 

                         Not relevant.

 

                 9.4.3.3 Autonomic nervous system

 

                         Not relevant.

 

                 9.4.3.4 Skeletal and smooth muscle

 

                         Not relevant.

 

           9.4.4 Gastrointestinal

 

                 Nausea, vomiting, abdominal pain, diarrhoea, 

                 discolouration of the faeces.  There was even note of 

                 splenic infarction seen in a patient receiving 

                 clofazimine for the treatment of pyoderma gangrenosum.

 

           9.4.5 Hepatic

 

                 Elevated albumin, bilirubin, SGOT.

 

           9.4.6 Urinary

 

                 9.4.6.1 Renal

 

                         Discolouration of urine.

 

                 9.4.6.2 Other

 

                         No data available.

 

           9.4.7 Endocrine and reproductive systems

 

                 Urinary-oestrogen excretion, which can be used as an 

                 index of foeto-placental function, was reduced in women 

                 with lepromatous leprosy receiving clofazimine 

                 (Reynolds, 1989).

                 

                 Thyroid: no data available.

 

           9.4.8 Dermatological

 

                 Bilateral pedaloedema developed in five men and one 

                 woman who were treated with clofazimine, rifampicin and 

                 dapsone for multibacillary leprosy. The bilateral 

                 pedaloedema was symmetrical, pitting, nontender and 

                 progressive and developed after about 3 month's 

                 therapy.  Symptoms developed only in patients receiving 

                 all 3 drugs and not in patients who received only 

                 rifampicin and dapsone. It appears that this oedema is 

                 due to clofazimine (Oommen T, 1990).

                 

                 Pink to brownish-black discolouration of the skin, 

                 dryness, ichthyosis, pruritus, rashes, acneform 

                 eruptions, photosensitivity reactions. 

 

           9.4.9 Eye, ear, nose, throat: local effects

 

                 Bull's eye pigmentary maculopathy and widespread 

                 retinal damage were observed in a 37-year-old man with 

                 AIDS after 8 months therapy with clofazimine 20 mg/day 

                 for disseminated Mycobacterium avium complex infection. 

                 The patient was also receiving isoniazid rifabutin, 

                 ethambutol, ganciclovir, pyrimethamine + sulfadoxine 

                 and prednisone. Clofazimine therapy was withdrawn and 

                 no change was observed after 6 weeks. Long term follow-

                 up was not possible as the patient died 3 months later. 

                 The authors suggest that all AIDS patients receiving 

                 this drug be closely followed for the development of 

                 macular pigmentary changes (Cunningham, 1990).

                 

                 Reddish-brown discolouration of the cornea conjunctiva, 

                 lacrimal fluid, occasional dryness, itchiness 

                 irritation, burning and watering of the eyes. 

 

          9.4.10 Haematological

 

                 Eosinophilia, elevated ESR.

 

          9.4.11 Immunological

 

                 No data available.

 

          9.4.12 Metabolic

 

                 9.4.12.1 Acid-base disturbances

 

                          No data available.

 

                 9.4.12.2 Fluid and electrolyte disturbances

 

                          Hypokalaemia (PDR, 1990).

 

                 9.4.12.3 Others

 

                          No data available.

                          

          9.4.13 Allergic reactions

 

                 Pruritus, skin rashes.

 

          9.4.14 Other clinical effects

 

                 No data available.

 

          9.4.15 Special risks

 

                 Pregnance

                 

                 It has been found that clofazimine crosses the human 

                 placenta.  The skin of infants born to women who had 

                 received the drug during pregnancy was noted to be 

                 deeply pigmented at birth. However, no evidence of 

                 teratogenicity was noted.  There are no adequate and 

                 well controlled studies in pregnant women, but 3 

                 neonatal deaths had been reported in 15 pregnancies in 

                 patients given clofazimine.  Further evaluation of the 

                 perinatal consequences of clofazimine therapy in 

                 patients with leprosy is needed (McEvoy, 1990; 

                 Reynolds, 1989; PDR, 1990).

                 

                 Urinary oestrogen excretion, which can be used as an 

                 index of foeto-placental function, was reduced in women 

                 with lepromatous leprosy receiving Clofazimine 

                 (Reynolds, 1989).

                 

                 Breastfeeding

                 

                 Clofazimine is excreted in breastmilk.

                 

                 Enzyme deficiencies

                 

                 No data available.

                 

       9.5 Other

 

           No data available.

 

       9.6 Summary

 

           Not relevant

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Acute poisoning

             

             No data are available.

             

             Chronic poisoning

             

             Symptomatic therapy.  ECG for detecting hypokalaemia.

 

        10.2 Relevant laboratory analyses

 

             10.2.1 Sample collection

 

                    Blood samples for levels of Clofazimine can be 

                    collected in heparinized tubes.  The volume is about 

                    1 ml.  Then the blood sample is to be centrifuges so 

                    that plasma could be separated and transferred into 

                    a plastic tube.  It will be kept frozen at -20°C 

                    until required for analysis with the use of the 

                    thin-layer chromatographic method (Hauffe et al., 

                    1986).

                    

                    High pressure liquid chromatography and thin-layer 

                    chromatography can be used. 

 

             10.2.2 Biomedical analysis

 

                    No data available

 

             10.2.3 Toxicological analysis

 

                    Clofazimine concentration could be analyzed with the 

                    use of blood samples collected in heparinized tubes. 

                    The samples collected are then centrifuged and the 

                    separated plasma is analyzed with the use of thin-

                    layer chromatographic method or HPLC (Moffat, 1986). 

 

             10.2.4 Other investigations

 

                    No data available.

 

        10.3 Life supportive procedures and symptomatic/specific 

             treatment 

 

             ECG for detecting hypokalaemia.

          

        10.4 Decontamination

 

             Gastric lavage (preferably with activated charcoal), or 

             inducing emesis may be useful, if the patient is seen early 

             after the ingestion.  The use of a cathartic is no longer 

             recommended.

 

        10.5 Elimination

 

             No data available.

 

        10.6 Antidote treatment

 

             10.6.1 Adults

 

                    No antidote available.

 

             10.6.2 Children

 

                    No antidote available.

 

        10.7 Management discussion

 

                  No data available

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             A 46 year-old woman experienced weight loss, diarrhoea, and 

             abdominal pain 10 months after receiving a 6 month course 

             of clofazimine 300 mg given daily for prurigo nodularis.  

             Abdominal symptoms were initially relieved by a gluten-free 

             diet, but returned 22 months after withdrawal of 

             clofazimine.  Laparotomy showed crystal deposition in the 

             chorion of intestinal villi and in the mesenteric lymph 

             nodes (Reynolds, 1989).

             

             Splenic infarction and tissue accumulation of clofazimine 

             in a patient receiving clofazimine for the treatment of 

             pyoderma gangrenosum (Reynolds, 1989).

             

             Although 2 pregnant patients received clofazimine without 

             any adverse effects to the fetus, 2 neonatal deaths had 

             been reported in 13 pregnancies in patients given 

             clofazimine (Farb et al., 1982; Reynolds, 1989). 

 

        11.2 Internally extracted data on cases

 

             No data available.

 

        11.3 Internal cases

 

             To be completed by each Centre using local data

 

  1. ADDITIONAL INFORMATION

 

        12.1 Availability of antidotes

 

             To be completed by each Centre using local data

 

        12.2 Specific preventive measures

 

             Clofazimine should be stored at 23 °C.  It should be 

             protected from heat and moisture.  If the capsules are 

             sticking together, then do not use them.  When the 

             preceding adverse effects are noted, discontinue the use of 

             the drug.  The drug should not be given to pregnant or 

             nursing mothers, unless absolutely necessary.  Refrain from 

             using the drug in patients with liver function 

             disturbances.  It should be used with caution with 

             diuretics.  The drug should be used with Dapsone or 

             Rifampicin in treating leprosy.  At present, it has no 

             potential of becoming a drug of abuse. 

 

        12.3 Other

 

             No data available.

 

  1. REFERENCES

 

        Alford R (1989)  Antimycobacterial agents, principles and 

        practice of infectious diseases,  3rd ed., pp 358-359.

        

        de Bergeyck E, Janssens PG,  & de Muynck A (1980) Radiological 

        abnormalities of the ileum associated with the use of 

        clofazamine (Lamprene: B.663) in the treatment of skin 

        ulceration due to Mycobacterium ulcerans. Leprosy Review, 51: 

        221-228.

        

        Budavari S ed. (1989) Merck index, an encyclopedia of chemicals, 

        drugs and biologicals ,11th ed. Rahway, New Jersey, Merck and 

        Co., Inc. pp 370-371.

        

        Choudhri SH, Harris L, Butany JW, & Keystone JS 

        (1995)Clofazimine induced cardiotoxicity: a case report. Lepr 

        Rev 66(1): 63-68.

        

        Cunningham CA, Friedberg DN, & Carr RE (1990) Clofazimine-

        induced generalized retinal degeneration.  Retina, 10: 131-134.

        

        Das RK & Roy B (1990)  Evaluation of genotoxicity of 

        Clofazamine, an antileprosy drug in mice in vivo. I. Chromosomal 

        analysis in bone marrow and spermatocytes.  Mutation Research, 

        241: 161-168.

        

        Dollery ed. (1991)  Therapeutic drugs. Churchill & Livingstone, 

        Edinburgh.

 

        Farb H, West DP, & Pedvis-Leftick A (1982) Clofazimine in 

        pregnancy complicated by leprosy.  Obstetrics & Gynecology, 

        59: 122-123.

        

        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 1160-1162.

        

        Harvey RF Harman RRM, Black C, et al. (1977) Abdominal pain and 

        malabsorption due to tissue deposition of clofazimine (Lamprene) 

        crystals. Brit J of Dermatology, 97 (suppl) l5: 19

        

        Hauffe et al. (1986) CIBA-Geigy Pharma Research and Development 

        Pharmacological Chemistry.

        

        Jopling WH (1976)  Editorial. Complications of treatment with 

        clofazimine (Lamprene: B.663).  Leprosy Review, 47: 1-3.

        

        Mason GH, Ellis-Pegler RB, Arthur JF (1977)  Clofazamine and 

        eosinophilic enteritis.  Leprosy Review, 48: 175-180.

        

        McDougal AC, Horsfall WR, Hede JE, Chaplin AJ (1980)  Splenic 

        infarction and tissue accumulation of crystals associated with 

        the use of clofazimine (Lamprene: B.663) in the treatment of 

        pyoderma gangrenosum.  Brit J of Dermatology, 102: 227-230

        

        McEvoy GK ed. (1990) American Hospital Formulary Service, Drug 

        Information. American Society of Hospital Pharmacists. Bethesda, 

        MD, American Society of Hospital Pharmacists,  pp 442-446.

        

        Moffat, AC ed. (1986) Clarke's Isolation and Identification of 

        Drugs, 2nd ed. London, The Pharmaceutical Press, pp 476-477.

        

        Oommen T (1990) Clofazimine-induced lymphoedema. Leprosy Review, 

        61: 289.

        

        PDR - Physicians' Desk Reference (1990)  44th ed., Ordell NJ, 

        Medical Economics, pp 980-981.

        

        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 

        29th ed. London, The Pharmaceutical Press, pp 556-557.

        

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 

        30th ed. London, The Pharmaceutical Press, pp 151-152.

        

        Roy B & Das RK (1990)  Evaluation of genotoxicity of 

        clofazamine, an antileprosy drug in mice in vivo.  II. 

        Micronucleus test in bone marrow and hepatocytes.  Mutation 

        Research, 241: 169-173.

        

        von den Driesch, Mielke V, Simon M Jr, Staib G, Tacke J, & 

        Sterry W (1994) "Granulomatous slack skin" - cutaneous 

        elastolytic lymphoma. Hautarzt, 45(12): 861-865.

        

        Weber & Kop (1987)  CIBA-Geigy Pharma Analytical Development, 

        Basle. Pharmaceutical Documentation.

        

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 

        index. Oslo, WHO Collaborating Centre for Drug Statistics 

        Methodology, p 61.

        

        WHO (1988)  Guide to Leprosy Control, 2nd Edition.  World Health 

        Organization, Geneva, pp 34-36.

        

        WHO (1992) International nonproprietary names (INN) for 

        pharmaceutical substances. Geneva, World Health Organisation,  

        p 130. 

        

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

        ADDRESS(ES)

 

        Author        Dr Diana Jacinto Gascon

                      National Poisons Control and Information Service

                      UP, College of Medicine - Philippine General

                      Hospital

                      547 Pedro Gil Street

                      Ermita

                      Manila

                      Philippines 1000

        

        Date          January 1992

        

        Updated by 

             author   May 1992

        

        Peer Review   Newcastle-upon-Tyne, United Kingdom, February 1992

        

                           London, United Kingdom, September 1992

    

    

 

Dapsone

  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

  1. 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

  1. 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 Bioavailability

      3.4.5 Specific properties and composition

  1. USES

   4.1 Indications

   4.2 Therapeutic dosage

      4.2.1 Adults

      4.2.2 Children

   4.3 Contraindications

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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

  1. 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 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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. Additional information

   12.1 Availability of antidotes

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    PHARMACEUTICALS

  1. NAME

     1.1 Substance

       Dapsone

     1.2 Group

       Dihydrofolate reductase inhibitor

     1.3 Synonyms

       Avlosulfon

       Avlosulphone

       Croysulfone

       DADPS

       DDS

       Diaphenylsulfone

       Diphenasone

       Diphone

       Disulone

       Dumitone

       Eporal

       Novophone

       Sulfona-Mae

       Sulphadione

       Udolac

     1.4 Identification numbers

       1.4.1 CAS number

             80-08-0

       1.4.2 Other numbers

             1358F 

             NCI-CO1718

             NSC 6091D

             RTECS: BY892500

             WR 488

     1.5 Brand names, Trade names

       Avlosulfon (ICI, Ayerst), DAPS (Sintyal), Dapsone USP (Jacobus 

       Pharmaceutical), Disulone 100 (Specia), Dubronax (Kela), 

       Maloprim (Burroughs Wellcome), Sulfona oral (Esteve), Udolac 

       (ICI).

     1.6 Manufacturers, Importers

       Disulone (Specia)

  1. SUMMARY

     2.1 Main risks and target organs

       Methaemoglobinaemia and haemolysis are the main risks of acute 

       intoxication. Haemolytic anaemia, agranulocytosis, aplastic 

       anaemia and other blood dyscrasias may occur in chronic 

       poisoning.

       

       Target organs are central and peripheral nervous systems, 

       blood, liver and skin.

     2.2 Summary of clinical effects

       Acute poisoning

       

       Methaemoglobinaemia is the principal and constant feature of 

       dapsone poisoning. Clinical features may include headache, 

       dizziness, agitation, restlessness, nausea, vomiting, 

       abdominal pain, bluish-grey cyanosis, tachycardia, 

       hyperventilation, stupor, convulsions, coma, jaundice, and 

       intravascular haemolysis.

 

         

       Chronic poisoning

       

       Haemolytic anaemia and agranulocytosis may occur with the 

       relatively low doses used for leprosy and malaria, whereas 

       peripheral neuropathy and hepatitis are only observed with the 

       higher doses used in the treatment of dermatitis herpetiformis 

       (Scholer et al., 1984). Deficiency of glucose-6-phosphate 

       dehydrogenase, and administration in combination with 

       primaquine are predisposing factors for the occurrence of 

       haemolytic anaemia.  Concurrent administration of primaquine 

       also predisposes to agranulocytosis (Chernof 1967; Hutchinson 

       et al., 1986).

     2.3 Diagnosis

       Nausea, vomiting, abdominal pain, features of 

       methaemoglobinaemia (cyanosis, headache, lethargy, syncope 

       etc), anaemia and jaundice are the features suggesting acute 

       dapsone poisoning when there is a history of exposure. In 

       severe cases there may be convulsions and coma.

       

       If methaemoglobinaemia is present the patient's blood will be 

       chocolate brown in colour. 

       

       Laboratory analysis of blood for methaemoglobin levels is 

       useful for the diagnosis. Methaemoglobin level correlates well 

       with symptoms. 

       

       Dapsone plasma concentrations are usually higher than 10 mg/l 

       in patients with methaemoglobinaemia.

       

       Other useful laboratory analyses include blood count, 

       reticulocytes, haptoglobin, bilirubin, plasma haemoglobin, 

       sulphaemoglobin, transaminases, arterial blood gases.

       

       Clinical features of chronic dapsone poisoning are haemolytic 

       anaemia, agranulocytosis, peripheral neuropathy and hepatitis. 

     2.4 First aid measures and management principles

       Patients with acute dapsone poisoning should be admitted to an 

       intensive care unit.

       

       Monitor respiration, blood pressure and urine output.

       

       Treatment may include:

         

       Gastric lavage or emesis

       

       Repeated oral activated charcoal

       

       Oxygen therapy and antidotes (methylene blue) for 

       methaemoglobinaemia.

       

       Haemodialysis in severe cases.

       

       Dapsone toxicity is due both to the parent drug and its 

       metabolites. Therefore aggressive therapy may be indicated to 

       enhance elimination of dapsone and its metabolites when 

 

       features of severe poisoning persist despite adequate 

       supportive, antidotal and charcoal therapy.

  1. PHYSICO-CHEMICAL PROPERTIES

     3.1 Origin of the substance

       Synthetic

       

       Manufacturing : Reaction of excess sodium sulfide with 1-

       chloro-4-nitrobenzene followed by acetylation, oxidation with 

       hydrogen peroxide, reduction and acidic or basic hydrolysis; 

       amination of bis(4-chlorophenyl) sulfone.

     3.2 Chemical structure

       4,4'-Sulfonylbisbenzeneamine; 4,4'-sulfonyldianiline; bis(4-

       aminophenyl)sulfone; 4,4'-diaminodiphenyl sulfone.

       

       C12H12N2O2S

     3.3 Physical properties

       3.3.1 Properties of the substance

             Dapsone is a white or slightly yellowish-white, 

             odourless, crystalline powder with a slightly 

             bitter taste. Dapsone is practically insoluble 

             in water (1 in 7000 of water), soluble in 

             alcohol (1 in 30), methanol and freely soluble 

             in acetone.  Dapsone is also soluble in diluted 

             hydrochloric acid (Reynolds & Prasad, 1982). 

             

             Melting point: 175 - 176° C 

             also a higher melting form, m.p. 180.5°

       3.3.2 Properties of the locally available formulation

             To be completed 

     3.4 Other characteristics

       3.4.1 Shelf-life of the substance

             To be completed 

       3.4.2 Shelf-life of the locally available formulation

             To be completed 

       3.4.3 Storage conditions

             Protect from light

       3.4.4 Bioavailability

             To be completed

       3.4.5 Specific properties and composition

             To be completed

  1. USES

     4.1 Indications

       Dapsone is the drug of choice for the treatment of 

       dermatitis herpetiformis.  It is an antibacterial drug used in 

       the treatment of leprosy.  Dapsone has also been used in malaria

       prophylaxis and in the treatment of relapsing polychondritis, 

       Pneumocystis carinii pneumonia, Kaposi's sarcoma and various other

       dermatoses.  It is also used in veterinary medicine. 

       

       Veterinary medicine: in streptococcal mastitis and coccidiosis of 

       cattle.  Topically in infectious keratitis of cattle and sheep and

       otitis externa of dogs.  Used experimentally to suppress 

       toxoplasmosis in swine.  

       

       Former use (non pharmaceutical) : hardening agent for epoxy resins.

     4.2 Therapeutic dosage

 

       4.2.1 Adults

             Leprosy: 50 to 100 mg per day (6 to 10 mg/kg per week). 

             Treatment may be continued for several years. 

             Dermatitis herpetiformis: 100 to 300 mg per day.

       4.2.2 Children

             Leprosy: 6 to 10 mg/kg per week

     4.3 Contraindications

       Hypersensitivity to dapsone.  Dapsone should be administered 

       with caution in patients with renal or hepatic failure and in 

       patients with glucose-6-phosphate dehydrogenase deficiency. 

       

       Dapsone levels are influenced by acetylation rates. Patients 

       with genetically determined slow acetylation rates, or who are 

       receiving treatment affecting acetylation, may require an 

       adjustment in dosage.

  1. ROUTES OF ENTRY

     5.1 Oral

       This is the only route of exposure.

     5.2 Inhalation

       No data available.

     5.3 Dermal

       No data available.

     5.4 Eye

       No data available.

     5.5 Parenteral

       No data available.

     5.6 Other

       No data available.

  1. KINETICS

     6.1 Absorption by route of exposure

       70 to 80% of a single oral dose of 100 mg is absorbed (Zuidema 

       et al., 1986) and most is recovered in the urine (Israili et 

       al., 1973).  The maximum plasma concentration is reached 

       within 3 - 6 hours.

     6.2 Distribution by route of exposure

       70 to 80% is bound to plasma proteins (Zuidema et al., 1986). 

       Dapsone is widely distributed with concentrations in most 

       organs similar to plasma concentrations.

       

       The apparent volume of distribution is 0.5 to 1 L/kg (Gelber 

       et al., 1971). Red cell concentrations are higher than those 

       in plasma (Scholer et al., 1984).  Dapsone crosses the 

       placenta (Zuidema et al., 1986).

     6.3 Biological half-life by route of exposure

       Plasma half-lives range between 21 and 30 hours (Gelber et al.,

        1971). Zuidema et al (1986) reported a mean elimination half-

       life of 30 hours (range: 14 to 83 hours) with a clearance of 

       about 0.038 L/kg/hr.

       

       

       The following half-lives of dapsone were reported after 

       overdose:

       

       Authors                 Dose ingested Plasma

                                  (g)         half-life (h)

       ------------------------------------------------------

 

       Woodhouse et al., 1983      2.5 29.8

       Neuvonen et al., 1983       7 109

                                  70            88

                                   1            33

       Berlin et al., 1984        15 24

       ------------------------------------------------------

     6.4 Metabolism

       The principal metabolite in plasma is mono-N-acetyl dapsone, 

       which is 97 to 100% bound to plasma proteins and has an 

       elimination half-life of 30.5 hours. The proportion of this 

       metabolite in plasma is dependent on the acetylator phenotype. 

       The dapsone/mono-N-acetyl dapsone ratio is about 1 in slow 

       acetylators and about 0.2 in rapid acetylators (Gelber et al., 

       1971).

       

       Another metabolic pathway is the N-oxidation of dapsone to 4-

       amino-4'-hydroxamine-diphenylsulphone.  This metabolite may be 

       responsible for the haematological toxicity in overdose 

       (Zuidema et al., 1986).

       

       The kinetics of the main metabolite, mono-N-acetyl dapsone 

       (MADDS) after overdose have been reported: 

       

       Authors                Dapsone ingested MADDS T1/2 (h)

       ---------------------------------------------------------

       Woodhouse et al., 1983         2.5 29.9

       Neuvonen et al., 1983          7 50.0

                                     10             70.0

                                      1             33.8

       ---------------------------------------------------------

     6.5 Elimination by route of exposure

       After oral exposure the drug is eliminated mainly by kidneys.

       

       Kidney:  Urinary excretion is the main route of elimination 

       and 20% of the drug is excreted unchanged and 80% as 

       derivatives, namely 20% glucuronide, 1.5% mono-N-acetyl, 1.5% 

       mono-acetyl glucuronide and 57% sulphamate derivatives 

       (Scholer et al., 1984).

       

       Faeces:  Only minor amounts of dapsone are excreted in faeces 

       (Zuidema et al., 1986).

       

       Bile:  10% of an oral dose was found in the bile (Lang,1979).

       

       Breast-milk:  Dapsone is excreted in breast milk (Sanders et 

       al., 1982; Zuidema et al., 1986).

  1. PHARMACOLOGY AND TOXICOLOGY

     7.1 Mode of action

       7.1.1 Toxicodynamics

             Dapsone produces methaemoglobinaemia by oxidizing the 

             iron in haemoglobin from its ferrous to its ferric form. 

             This renders haemoglobin unable to carry oxygen to 

             tissues. Furthermore, haemolysis and changes in oxygen 

             affinity may occur, increasing the toxic symptoms more 

             than would be expected from the methaemoglobin 

             concentrations alone (Jaeger et al., 1987). The 

 

             hydroxylated metabolite of dapsone, T-amino-4'-

             hydroxamine-diphenylsulphone, is probably responsible 

             for methaemoglobinaemia and haemolysis (Israili et 1973; 

             Zuidema et al., 1986). 

             

             In vitro, this metabolite forms methaemoglobin (Kramer 

             et al., 1972) and induces haemolysis (Glader 1973). In 

             vitro, it generates hydrogen peroxide (Weetman et al,

             1980) and depletes cellular glutathione (Glader 1973; 

             Weetman et al., 1980). However, this metabolite has not 

             been detected in plasma of patients receiving dapsone.

       7.1.2 Pharmacodynamics

             The mechanism of the bacteriostatic action of dapsone is 

             probably similar to that of the sulphonamides as both 

             are inhibited by para-aminobenzoic acid (Lang, 1979). 

             Dapsone is bacteriostatic against Mycobacterium leprae. 

             It is also active against Plasmodium spp. In the mouse, 

             the minimum inhibitory concentration for M. leprae is 

             less than 10 mcg/l. In man, it has been estimated to be 

             up to 30 mcg/l. (Reynolds, 1989).

     7.2 Toxicity

       7.2.1 Human data

             7.2.1.1 Adults

                     The toxic dose of dapsone is close to its 

                     therapeutic dose.  Severe poisonings have been 

                     observed after doses of 1 g in adults (Neuvonen 

                     et al., 1983). Recovery without sequelae has 

                     been reported in adults after ingestion of doses 

                     up to 15 g (Berlin et al., 1985).

             7.2.1.2 Children

                     The toxic dose of dapsone is close to its 

                     therapeutic dose.  Severe poisonings have been 

                     observed after doses of 100 mg in children 

                     (Reigart et al., 1982). Sturt (1967) reported a 

                     fatal poisoning in a 16-year-old boy who 

                     developed methaemoglobinaemia, jaundice, 

                     haematuria and coma after ingestion of 1.46 g.

       7.2.2 Relevant animal data

             Oral rat : LDLo: 1000 mg/kg

             Oral rat : TDLo: 20 mg/kg

             Oral mouse : LD50: 496 mg/kg  (NIOSH)

       7.2.3 Relevant in vitro data

             No data available.

     7.3 Carcinogenicity

       There are no case reports of carcinogenicity in humans. In 

       experimental animals dapsone has been shown to be carcinogenic 

       at doses much larger than those used therapeutically (Lang 

       1979).

     7.4 Teratogenicity

       No teratogenicity has been reported

     7.5 Mutagenicity

       No data available

     7.6 Interactions

       Probenecid increases serum dapsone levels by reducing the 

       renal elimination of dapsone and its metabolites (Goodwin and 

       Sparell 1969).

 

       

       Rifampicin lowers dapsone serum levels 7- to 10-fold by 

       accelerating plasma clearance.

       

       Folic acid antagonists such as pyrimethamine and primaquine 

       may increase the likelihood of haematologic reactions. 

     7.7 Main adverse effects

       The following adverse effects after therapeutic doses have 

       been reported: (Dukes 1976-1984, Drugdex 1990).

       

       Blood - agranulocytosis, haemolytic anaemia, 

       methaemoglobinaemia, pseudoleukaemia, aplastic anaemia, 

       mononucleosis with lymphadenopathy

       

       Nervous system -    psychosis, peripheral neuropathy

       

       Kidney - acute renal failure following intravascular 

       haemolysis, nephrotic syndrome, renal papillary necrosis

       

       Liver - hepatitis and jaundice with increased levels of 

       transaminases

       

       Skin - exfoliative dermatitis, toxic erythema, erythema 

       multiforme, urticaria, erythema nodosum

       

       Hypersensitivity reactions - leprotic reactions may occur in 

       leprosy if the low initial dose is increased too rapidly.

  1. 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

  1. CLINICAL EFFECTS

     9.1 Acute poisoning

       9.1.1 Ingestion

             Symptoms may appear from a few minutes to 24 hours 

             following ingestion. Methaemoglobinaemia is the 

             principal feature of dapsone poisoning. Clinical 

             symptoms may include: headache, dizziness, agitation, 

             restlessness, nausea, vomiting, abdominal pain, bluish-

             grey cyanosis, tachycardia, hyperventilation, stupor, 

             convulsions, coma, jaundice, and intravascular 

             haemolysis.

       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

             No data available.

     9.2 Chronic poisoning

       9.2.1 Ingestion

             Haemolytic anaemia and agranulocytosis may occur at the 

             relatively low doses used for leprosy and malaria, 

             whereas peripheral neuropathy and hepatitis are only 

             observed at the higher doses used in the treatment of 

             dermatitis herpetiformis (Scholer et al., 1984).  

             Deficiency in glucose-6-phosphate dehydrogenase, and 

             combination with primaquine are predisposing factors for 

             the occurrence of haemolytic anaemia, and concurrent 

             therapy with primaquine may be associated with 

             agranulocytosis (Chernof, 1967; Hutchinson et al., 

             1986).

       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 exposure

             No data available.

       9.2.6 Other

             No data available.

     9.3 Course, prognosis, cause of death

       Methaemoglobinaemia may last for up to 10 days. Haemolysis is 

       usually delayed but it may persist for 14 days, returning to 

       normal within 3 to 4 weeks.

       

       With adequate treatment the prognosis is usually good, but a 

       death has been reported (Sturt 1967).

     9.4 Systematic description of clinical effects

       9.4.1 Cardiovascular

             Acute

             

             Tachycardia and hypotension may be observed and are 

             secondary to the hypoxaemia following 

             methaemoglobinaemia (Lambert et al., 1982; Berlin et al.,

              1985; Neuvonen et al., 1983).

             

             Chronic: No data available.

       9.4.2 Respiratory

             Acute

             

             Tachypnoea and hyperventilation may occur (Lambert et 

             al., 1982; Berlin et al., 1984).

             

             Cyanosis is due to methaemoglobinaemia

              

             Chronic: No data available.

       9.4.3 Neurological

             9.4.3.1 CNS

                     Headache, dizziness, restlessness, agitation and 

                     confusion are common in moderately severe acute 

                     poisonings.  In severe poisoning, uncoordinated 

                     movements, stupor, convulsions and coma have 

                     been reported (Schvartsman 1979;

                     Sturt 1967; Woodhouse et al., 1983).  Psychosis 

                     has been reported during therapeutic use (Lang 

                     1979).

             9.4.3.2 Peripheral nervous system

                     Sirsat et al (1987) reported three cases of 

                     motor neuropathy following acute ingestion.

                     

                     Peripheral motor neuropathy may develop in 

                     patients treated for several years at doses of 

                     300 mg/day or greater (Snavely and Hodges 1984). 

                     Slow acetylators are more likely to develop 

                     neuropathy.

             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

             Acute

 

             

             Nausea, vomiting and abdominal pain are usually the 

             first signs which appear.

             

             Chronic: No data available.

       9.4.5 Hepatic

             Acute

             

             Jaundice, elevated bilirubin and moderate increase of 

             transaminases have been reported (Berlin et al., 1984; 

             Sturt 1967).

             

             Chronic

             

             Jaundice and an increase of transaminases may occur 

             (Scholer 1984; Johnson et al., 1986).

       9.4.6 Urinary

             9.4.6.1 Renal

                     Acute: Haematuria has been reported (Sturt 

                     1967).

                     

                     Chronic

                     

                     Acute renal failure secondary to intravascular 

                     haemolysis has been reported after therapeutic 

                     doses in two patients (Chugh et al., 1977).  One 

                     case each of nephrotic syndrome (Hoffbrand 1978) 

                     and renal papillary necrosis have been reported 

                     (Belmont 1967).  

             9.4.6.2 Other

                     No data available.

       9.4.7 Endocrine and reproductive systems

             No data available

       9.4.8 Dermatological

             Acute

             

             Blue-grey cyanosis is due to methaemoglobinaemia

              

             Chronic

             

             Several dermatological reactions have been observed.  

             They were: exfoliative dermatitis, toxic erythema, 

             erythema multiforme, urticaria, and erythema nodosum.

       9.4.9 Eye, ear, nose, throat: local effects

             No data available.

       9.4.10 Haematological

              Acute

              

              Methaemoglobinaemia is the principal and consistent 

              feature of dapsone poisoning. Pronounced 

              methaemoglobinaemia exceeding 50 to 60% is associated 

              with serious clinical features (Schvartsman 1979); 

              haemolysis is usually severe in such cases. Cyanosis 

              and methaemoglobinaemia may persist for 8 to 10 days 

              following ingestion (Elonen et al., 1979; Lambert et 

              al., 1982; Neuvonen et al., 1983; Stanfield 1963).

 

              

              The following levels of methaemoglobin have been 

              reported:

              

              Authors             Dose ingested Methaemoglobin (%)

                                      (g)

              

              Reigart et al., 1983      0.1 27

              Lambert et al., 1983      3 41.5

              Berlin et al., 1984      15 48

              Neuvonen et al., 1983     7 62

                                       10                   36

                                        1                   45

              Woodhouse et al., 1983    2.5 22

              

              

              Methaemoglobin levels correlate well with symptoms in 

              most cases (Hall et al., 1986):

              

              15-20% clinical cyanosis, patient usually asymptomatic

              20-45% headache, lethargy, dizziness, syncope, dyspnoea

              45-55% increasing CNS depression

              55-70% coma, convulsions, shock

              > 70%  high mortality

              

              Haemolytic anaemia with Heinz bodies and  

              teticulocytosis is common in cases with severe 

              methaemoglobinaemia (Lambert et al., 1982; Berlin et 

              al., 1984; Neuvonen et al., 1983). Low haptoglobin and 

              elevated unconjugated bilirubin have been observed 

              (Lambert et al., 1982). Usually laboratory evidence 

              indicating haemolysis is apparent after 2 - 3 days and 

              reaches a maximum in 7 - 14 days after ingestion, the 

              evidence of haemolysis disappears within 3 - 4 weeks 

              (Neuvonen et al., 1983).

              

              Sulphaemoglobinaemia has been reported in a 22-year-old 

              man after an acute overdose with 3 g of dapsone. 

              Sulphaemoglobinaemia was maximal (9%) between days 4 

              and 8 (Lambert et al., 1982).

              

              Chronic

              

              Methaemoglobinaemia is also a frequent toxic side 

              effect during dapsone treatment and has been observed 

              in patients treated for malaria prophylaxis with 25 

              mg/day (Willerson et al., 1972). The incidence of 

              methaemoglobinaemia is even much higher when dapsone is 

              used in large doses in the treatment of leprosy or 

              dermatitis herpetiformis (Scholer et al., 1984).

              

              Haemolytic anaemia is dose related but may occur with 

              the relatively low doses used for leprosy and malaria 

              (Scholer et al., 1984).

              

              Agranulocytosis, neutropenia and thrombocytopenia have 

 

              also been reported (Leoung et al., 1986; Potter et al., 

              1989).

              

              Deficiency in glucose-6-phosphate dehydrogenase, and 

              combination with primaquine are predisposing factors 

              for the occurrence of haemolytic anaemia and concurrent 

              therapy with primaquine may cause agranulocytosis 

              (Chernof 1967; Hutchinson et al., 1986).

       9.4.11 Immunological

              Acute: No data available.

              

              Chronic

              

              Hypersensitivity reaction may be observed

              

              Sulfone syndrome : this is a hypersensitivity reaction 

              which includes fever, malaise, exfoliative dermatitis, 

              jaundice with liver necrosis, lymphadenopathy, 

              methaemoglobinaemia, and anaemia (Allday and Baines, 

              1951).

       9.4.12 Metabolic

              9.4.12.1 Acid-base disturbances

                       Acute

                       

                       Respiratory alkalosis or metabolic acidosis 

                       with impaired oxygenation has been reported 

                       (Berlin et al., 1984; Reigart et al., 1982).

              9.4.12.2 Fluid and electrolyte disturbances

                       No data available.

              9.4.12.3 Others

                       No data available.

       9.4.13 Allergic reactions

              Acute:  No data available.

              

              Chronic

              

              Hypersensitivity reactions may be observed. They 

              include: exfoliative dermatitis, toxic erythema, 

              erythema multiforme, urticaria, erythema nodosum.

       9.4.14 Other clinical effects

              No data available.

       9.4.15 Special risks

              Pregnancy:     Overdose of dapsone during pregnancy has 

              not been reported. The fetus may be at risk because of 

              the hypoxemia due to methaemoglobinaemia and 

              haemolysis.

               

              Breast feeding: Two cases of neonatal haemolytic 

              anaemia presumed to be due to dapsone in breast milk 

              have been reported (Zuidema et al., 1986).

              

              Enzyme deficiencies: Deficiency in glucose-6-phosphate 

              dehydrogenase is a predisposing factor for the 

              occurrence of haemolytic anaemia (Chernof, 1967).

     9.5 Other

       No data available.

 

     9.6 Summary

  1. MANAGEMENT

      10.1 General principles

         Patients with acute dapsone poisoning should be admitted to 

         an intensive care unit.

         

         Monitor respiration, blood pressure and urine output.

         

         Treatment may include:

           

         Symptomatic measures, especially oxygen therapy

         Gastric lavage or emesis. Repeated oral activated charcoal

         Antidotes for methaemoglobinaemia: methylene blue

         

         Haemodialysis may be considered in severe cases.

         

         Given that dapsone toxicity is not only related to the 

         parent drug but also to its metabolites, aggressive therapy 

         in order to enhance elimination of dapsone and its 

         metabolites may be indicated when severe poisoning persists 

         despite adequate supportive, antidotal and charcoal therapy.

         

         Patients may require several days of observation.

      10.2 Relevant laboratory analyses

         10.2.1 Sample collection

                Collect blood and urine for analysis.

         10.2.2 Biomedical analysis

                The most relevant investigation in dapsone poisoning 

                is methaemoglobinaemia which correlates well with 

                symptoms.  The level of methaemoglobin should be 

                monitored.

                

                Other relevant laboratory analyses : blood count, 

                reticulocytes, haptoglobin, bilirubin, plasma 

                haemoglobin, sulphaemoglobin, transaminases, arterial 

                blood gases.

                 

                Urine analysis

         10.2.3 Toxicological analysis

                Dapsone plasma concentrations higher than 10 mg/l are 

                likely to be associated with features of 

                methaemoglobin-aemia. Therapeutic plasma levels are 1-

                3.5 mg/l. 

                     

                Monitoring of dapsone serum concentrations is not 

                necessary for treatment unless haemodialysis is 

                contemplated.

                               

                In acute poisoning, dapsone plasma concentrations of 

                10-150 mg/l have been reported (Berlin et al., 1985; 

                Elonen et al., 1979; Neuvonen et al., 1983; Woodhouse 

                et al., 1983).

                

                Table: plasma concentrations of dapsone following 

                acute overdose

                

 

                Authors               Age Dose ingested Dapsone 

                conc

                                            (year) (g)       (mg/ml)

                

                Berlin et al., 1984     2 15.0 80.0

                Neuvonen et al., 1983  27 7.0 28.0

                                       45          10.0 23.6

                                       21           1.0 17.5

                Endre et al., 1983                  4.0 22.3

                Elonen et al., 1979  child ?     150.0

                                     child ?                   73.0

                Szajewski et al.,1979  18 10.0 12.0

                Linakis et al., 1989                3.5 3.9

                Woodhouse et al., 1983 57           2.5 18.8

         10.2.4 Other investigations

                No data available.

      10.3 Life supportive procedures and symptomatic/specific 

         treatment

         Monitor blood pressure, respiration and urine output.  

         Oxygen therapy is indicated if there are clinical signs of 

         methaemoglobinaemia. 

         

         Methylene blue is indicated when methaemoglobinaemia is 

         present. A dose of 1 to 2 mg/kg intravenously is 

         administered over a few minutes and may be repeated every 4 

         hours as needed. Because of the relapsing course of 

         methaemoglobinaemia due to the long half-life of dapsone, 

         repeated administration of methylene blue is sometimes 

         necessary (Berlin et al., 1984, Elonen et al., 1979, Lambert 

         et al., 1982). Berlin et al, (1984) recommended continuous 

         administration of methylene blue in order to avoid 

         overdosage. Monitoring of methaemoglobin is mandatory for 

         adjustment of the infusion rates: cyanosis is an unreliable 

         guide especially when anaemia is also present and methylene 

         blue may cause a bluish-grey discoloration of the skin 

         (Berlin et al., 1984). Methylene blue therapy should be 

         continued until the methaemoglobin level is below 10%.

         

         Supportive measures include treatment of respiratory failure,

          shock, acid-base disturbances, and convulsions.

      10.4 Decontamination

         Gastric lavage is indicated in recent ingestion, up to 6 

         hours.

         

         Repeated doses (20 g 4 times a day) of oral activated 

         charcoal are indicated because it enhances the total body 

         clearance and elimination of dapsone and its principal 

         metabolite, monoacetyldapsone. In patients receiving 

         therapeutic dosages of dapsone, the mean serum half-life was 

         decreased from 20.5 to 10.8 hours by charcoal (Neuvonen et 

         al., 1983). In three intoxicated patients, activated 

         charcoal decreased the mean dapsone and monoacetyldapsone 

         half-lives from 77 to 12.7 hours and from 51 to 13.3 hours,  

         respectively (Neuvonen et al., 1983). In these patients 

         charcoal did not prevent the primary absorption of dapsone, 

         but increased the elimination rates of dapsone and 

 

         monoacetyldapsone by adsorbing drugs secreted into the 

         gastrointestinal tract.

      10.5 Elimination

         Forced diuresis 

         

         No data indicating the benefit of forced diuresis are 

         available. However, in one case of poisoning with 15 g of 

         dapsone, 20% of the amount ingested was excreted in urine 

         (Berlin et al., 1984).

         

         Haemodialysis 

         

         Haemodialysis removes dapsone from the body. In one patient 

         who had ingested 7 g dapsone, haemodialysis decreased the 

         half-life of dapsone from 109 to 10.4 hours and the half-

         life of monoacetyldapsone from 50 to 10.9 hours (Neuvonen et 

         al., 1983). Szajewski et al, (1972) reported  a case of 

         severe dapsone poisoning in which haemodialysis was 

         successful with rapid correction of methaemoglobinaemia. In 

         these 2 patients a subsequent rebound of plasma dapsone 

         concentrations was observed.

         

         Haemoperfusion

         

         Endre et al (1983) reported a case of successful treatment 

         using charcoal haemoperfusion.

              

         Plasma exchange  

         

         Berlin et al (1984) treated a patient with plasma exchange. 

         Five plasma exchanges were performed on days 3 to 7 with a 

         total of 15.5 l. plasma exchanged. Only 2% of the amount 

         ingested was removed by plasma exchange. 

         

         Exchange transfusion

         

         Exchange transfusion has also been suggested (Schvartsman 

         1979; Stanfield 1963). Because of the low volume which can 

         be exchanged, this therapy is ineffective for drug removal. 

         However, it may be indicated when severe intravascular 

         haemolysis is associated with methaemoglobinaemia (Jaeger et 

         al., 1987).

      10.6 Antidote treatment

         10.6.1 Adults

                There is no specific antidote.

         10.6.2 Children

                There is no specific antidote.

      10.7 Management discussion

         Given that dapsone toxicity is not only related to the 

         parent drug but also to its metabolites, aggressive therapy 

         in order to enhance the elimination of dapsone and its 

         metabolites may be indicated when severe poisoning persists 

         despite adequate supportive, antidotal and charcoal therapy.

         

         After a bolus dose of methylene blue (1 to 2 mg/kg), a 

         continuous infusion at an initial rate of 0.1 to 0.5 mg/kg 

 

         has been recommended. The dose of methylene blue should be 

         titrated against the concentration of methaemoglobin (Dawson 

         and White, 1989)

  1. ILLUSTRATIVE CASES

      11.1 Case reports from literature

         Lambert et al (1979) reported a case of acute poisoning in a 

         22 year-old man who had ingested 3 g dapsone and developed 

         headache, dizziness, nausea, bluish-grey cyanosis and 

         methaemoglobinaemia (41.5%). Methaemoglobinaemia improved 

         with methylene blue. Subsequently, significant 

         sulphaemoglobinaemia (9% from day 4 to day 8) caused 

         prolonged cyanosis and mild haemolytic anaemia.

         

         An 18 month-old child developed methaemoglobinaemia (27%) 

         after ingestion of 100 mg dapsone. Activated charcoal was 

         administered orally (10 g every 6 hours). Treatment included 

         1 mg/kg methylene blue; the methaemoglobin level was 2.3%, 

         66 hours after ingestion (Reigart et al., 1982).

         

         A 57 year-old man was admitted 20 hours after ingestion of 

         2.5 g dapsone. Examination showed cyanosis with a 

         methaemoglobinaemia of 22% and an anaemia of 11.5 g/l 

         haemoglobin. The methaemoglobin level fell to 1% over 7 days 

         without specific treatment. The kinetics of dapsone and 

         monoacetyldapsone showed half-lives of 29.7 and 29.9 hours 

         respectively (Woodhouse et al., 1983).

         

         Neuvonen et al (1983) reported 3 cases of dapsone poisoning 

         in adults with doses of 7, 10 and 1 g, respectively, and 

         methaemoglobin concentrations of 36 - 62%. The elimination 

         half-lives were 109, 88 and 33 hours (mean 77) for dapsone 

         and 50, 70, and 33.8 hours (mean 51) for monoacetyldapsone. 

         With activated charcoal treatment, the plasma half-life was 

         12.7 hours for dapsone and 13.3 hours for monoacetyldapsone. 

         One patient underwent haemodialysis three times. During 

         haemodialysis, plasma half-lives of dapsone and 

         monoacetyldapsone decreased from 109 to 10.4 hours and from 

         50 to 10.9 hours, respectively.

         

         Berlin et al (1984) described a 28-year-old man who ingested 

         15 g dapsone and developed a methaemoglobin level of 50%. 

         The dapsone concentration rose to a peak of 80 mg/l on the 

         second day and then decreased with a half-life of 24 hours. 

         The patient was treated with activated charcoal, forced 

         diuresis and plasma exchange (5 exchanges on days 3 to 7 

         with a total of 15.5 l plasma exchanged. Of the amount 

         ingested, 25% was recovered in urine and only 2% was removed 

         by plasma exchange.

      11.2 Internally extracted data on cases

         To be added by the centre.

      11.3 Internal cases

         To be added by the centre.

  1. Additional information

      12.1 Availability of antidotes

         No antidote is available.

      12.2 Specific preventive measures

 

         No data available.

      12.3 Other

         No data available.

  1. REFERENCES

    Belmont A (1967). Dapsone-induced nephrotic syndrome. Journal of 

    American Medical Association 200:262-263.

    

    Berlin G, Brodin B, Hilden JO, Märtensson J (1984). Acute dapsone 

    intoxication: a case treated with continuous infusion of 

    methylene blue, forced diuresis and plasma exchange. Clinical 

    Toxicology 22:537-548.

    

    Chernof D (1967). Dapsone-induced haemolysis in G6PD deficiency. 

    Journal of the American Medical Association 201:122-125.

    

    Chugh KS et al (1977). Acute renal failure due to intravascular 

    haemolysis in the North indian patients. American Journal of 

    Medical Science 274:139-146.

    

    Cooke TJL (1970). Dapsone poisoning. Medical Journal of Australia 

    23:1158-1159.

    

    Davies R (1950). Fatal poisoning with undolac (diaminodiphenyl-

    sulphone). Lancet 1:905-906.

    

    Dawson AH & Whyte IM (1989). Management of dapsone poisoning 

    complicated by methaemoglobinaemia. Medical Toxicology and 

    Adverse Drug Exp. 4: 387 - 392. 

    

    Dukes MNG (1976-84). Side effects of drugs. Excerpta Medica.

    

    Ellenhorn MJ, Barceloux DF (1988). Diagnosis and treatment of 

    human poisoning. Medical Toxicology, Elsevier, New York, pp. 353-

    358

    

    Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ (1979). Acute 

    dapsone intoxication: a case with prolonged symptoms. Clinical 

    Toxicology 14:79-85.

    

    Endre ZH, Charlesworth JA, MacDonald GJ, Woodbridge L (1983). 

    Successful treatment of acute dapsone intoxication using charcoal 

    hemoperfusion. Australia and New Zealand Journal of Medicine 

    13:509-512.

    

    Gelber R, Peters JH, Gordon GR, Glazko AJ, Levy L (1971). The 

    polymorphic acetylation of dapsone in man. Clinical Pharmacology 

    and Therapeutics 12:225-238.

    

    Glader BE (1973). Haemolysis by diphenylsulphones : comparative 

    effects of DDS and hydroxylamine D. Journal of Laboratory and 

    Clinical Medicine 81:267:272.

    

    Goodwin CS and Sparell G (1969). Inhibition of dapsone excretion 

    by probenecid. Lancet 2:884-885.

    

    Hall AH, Kulig KW, Rumack BH (1986). Drug-and chemical-induced 

 

    methaemoglobinaemia. Medical Toxicology 1:253-260.

    

    Hoffbrand BI (1978). Dapsone and renal papillary necrosis. 

    British Medical Journal 1:78.

    

    Hutchinson DBA, Whiteman PD, Farquhar JAV (1986). Agranulocytosis 

    associated with Maloprim : review of cases. Human Toxicology 

    5:221-227.

    

    Israili ZH, Cucinel SA, Vaught J, Davis E, Lesser JM et al 

    (1973). Studies of the metabolism of dapsone in man and 

    experimental animals : formation of N-hydroxy metabolites. 

    Journal of Pharmacology and Experimental Therapeutics 187:138-

    151.

    

    Jaeger A, Sauder P, Kopferschmitt J, Flesch F (1987). Clinical 

    features and management of poisoning due to antimalarial drugs. 

    Medical Toxicology 2:242:273.

    

    Kramer PA, Glader BE, Li TK (1972). Mechanism of methaemoglobin 

    formation by diphenylsulphones:effects of 4-amino-4'hydroxy-

    aminodiphenylsulphone and other p-substituted derivatives. 

    Biochemical Pharmacology 21:1265-1274.

    

    Lambert M, Sonnet J, Mahieu P, Hassoun A (1982). Delayed 

    sulfhemoglobinemia after acute dapsone intoxication. Journal of 

    Toxicology, Clinical Toxicology 19:45-50.

    

    Lang PG (1979). Sulfones and sulfonamides in dermatology today. 

    Journal of American Academy of Dermatology 1:479-492.

    

    Lee BL, Medina I, Benowitz NL et al (1989). Dapsone, trimethoprim 

    and sulfamethoxazole plasma levels during treatment of 

    pneumocystis pneumonia in patients with acquired immunodeficiency 

    syndrome (AIDS). Annals of Internal Medicine 110:606-611.

    

    Leoung GS, Mills J, Hopewell PC et al (1986). Dapsone-

    trimethoprim for pneumocystis carinii pneumonia in the acquired 

    immunodeficiency syndrome. Annals of Internal Medicine 105: 45-

    48.

    

    Linakis JG, Shannon M, Woolf A et al (1989). Recurrent 

    methemoglobinemia after acute dapsone intoxication in a child. J 

    Emerg Med, 7, 477-480, 

    

    Manfredi G, de Panfilis G, Zampetti M, Allegra F (1979) Studies 

    on dapsone induced haemolytic anaemia. British Journal of 

    Dermatology 100:427.

    

    Neuvonen PJ, Elonen E, Haapanen EJ (1983). Acute dapsone 

    intoxication: clinical findings and effect of oral charcoal and 

    haemodialysis on dapsone elimination. Acta Medica Scandinavica 

    214:215-220.

    

    Pengelly CD (1963). Dapsone-induced haemolysis. British Medical 

    Journal 246:660-664.

 

    

    Potter MN, Yates P, Slade R et al (1989). Agranulocytosis caused 

    by dapsone therapy for granuloma annulare. Journal of American 

    Academic Dermatology 20:87-88.

    

    Reigart JR, Harold LT, Lindsey JM (1982). Repetitive doses of 

    activated charcoal in dapsone poisoning in a child. Journal of 

    Toxicology, Clinical Toxicology, 19:1061:1066.

    

    Reynolds JEF and Prasad AB (eds.) (1982). Martindale, The Extra 

    Pharmacopoeia, 28th ed. The Pharmaceutical Press, London, pp. 

    1489-1492.

     

    Reynolds JEF ed (1989). Martindale, The Extra Pharmacopoeia, 29th 

  1. London, The Pharmaceutical Press. 

    

    Sanders SW, Zone JJ, Foltz RL et al (1982). Hemolytic anemia 

    induced by dapsone transmitted through breast milk. Annals of 

    Internal Medicine 96: 465-466.

    

    Scholer HJ, Leimer R, Richle R (1984). Sulphonamides and 

    sulphones. Handbook of Experimental Pharmacology 68:123-206.

    

    Schvartzman S (1979). Sulfone methemoglobinemia. Clinical 

    Toxicology 15:468. 

    

    Sirsat AM, Lalitha VS, Pandya SS (1987). Dapsone neuropathy-

    report of three cases and pathologic features of a motor nerve. 

    International Journal of Leprosy 55:23-29.

    

    Snavely SR and Hodges GR (1984). The neurotoxicity of 

    antibacterial agents. Annals of Internal Medicine 101:92-104.

    

    Szajewski JM, Dorywalski T, Tomecka Z et al (1972). Przypadek 

    cieskiego zatrucia preparatem przoeiwtradowym 

    dwuaminodwufenylsulfonem (DDS). Pol Arch Med Wewn ,49, 181-186.

    

    Stanfield JP (1963). A case of acute poisoning with dapsone. 

    Journal of Tropical Medicine and Hygiene 66:292-295.

    

    Sturt J (1967). Too much of a good thing. Papua New Guinea 

    Medical Journal 10:97.

    

    Weetman RM, Boxer LA, Brown MP, Mantich NM, Baehner RL (1980). In 

    vitro inhibition of granulopoeisis by 4-amino-4'hydroxylamino-

    diphenylsulphone. British Journal of Haematology 45:361-370.

    

    Willerson D, Rieckmann KH, Kass L, Carson PE, Frischer H et al 

    (1972). The chemoprophylactic use od fiformyldiamino-

    diphenylsulfone (DFD) in falciparum malaria. American Journal of 

    Tropical Medicine Hygiene 21:138:143.

    

    Woodhouse KW, Henderson DB, Charlton B, Peaston RT, Rawlins MD 

    (1983). Acute dapsone poisoning : clinical features and 

    pharmacokinetic studies. Human Toxicology 3:507-510.

    

 

    Zuidema J, Hilbers-Modderman ESM and Merkus FWHM (1986). Clinical 

    pharmacokinetics of dapsone. Clinical Pharmacokinetics 11:299-315.

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

    ADDRESS(ES)

    Author:   J. Higa de Landoni

              Jefa Seccion Toxicologia

              Hospital de Clinicas "Jose de San Martin"

              Facultad de Medicina

              Universidad de Buenos Aires

              Cordoba 2351

              Buenos Aires

              Argentina

    

    Tel: 54-1-9621280

    Fax: 54-1-3318605

    

    Reviewed and rewritten: 

    

              Drs A. Jaeger, P. Sauder, J. Kopferschmitt, F. Flesch

              Service de Reanimation Medicale 

                et Centre Anti-poisons

              Hospice Civil de Strasbourg

              Pavillon Pasteur

              1 place de l'Hopital

              67091 Strasbourg Cedex

              France

    

    Tel: 33 88161144

    Fax: 33 88161330

    

    Date:          January 1991

    

    Peer Review: Newcastle-upon-Tyne, United Kingdom, January 1991

    

    Review:   IPCS, May 1993





See Also:

        Dapsone (IARC Summary & Evaluation, Supplement 7, 1987)

        Dapsone (IARC Summary & Evaluation, Volume 24, 1980)

 

    

 

Ethambutol

  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

   1.7 Presentation, Formulation

  1. 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

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Properties of the substance

         3.3.1.1 Colour

         3.3.1.2 State/Form

         3.3.1.3 Description

      3.3.2 Properties of the locally available formulation(s)

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance unknown

      3.4.2 Shelf-life of the locally available formulation(s)

      3.4.3 Storage conditions

      3.4.4 Bioavailability

      3.4.5 Specific properties and composition

  1. 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

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

   8.1 Sample

      8.1.1 Collection

      8.1.2 Storage

      8.1.3 Transport

   8.2 Toxicological analytical methods

      8.2.1 Test for active ingredient

      8.2.2 Test for biological analyses

   8.3 Other laboratory analyses

      8.3.1 Haematological investigations

      8.3.2 Biochemical investigations

         8.3.2.1 Blood

         8.3.2.2 Urine

      8.3.3 Arterial blood gas analysis

      8.3.4 Other relevant biomedical analyses

   8.4 Interpretation

   8.5 References

  1. 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 systems

         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 Hematological

      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

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. ADDITIONAL INFORMATION

   12.1 Availability of antidotes

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S), (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




  1. NAME

 

        1.1  Substance

 

             Ethambutol               (INN) 

 

             (WHO, 1992) 

 

        1.2  Group

 

             ATC classification index 

 

 

             Antimycobacterials (J04)/ 

             Drugs for treatment of tuberculosis (J04A)/ 

             Other drugs for treatment of tuberculosis (J04AK) 

 

             (WHO, 1992) 

 

        1.3  Synonyms

 

             CL-40881

 

             (Reynolds, 1993) 

 

             (To be completed by each Centre using local data) 

 

        1.4  Identification numbers

 

             1.4.1                 CAS number

 

                   Ethambutol                 74-55-5

 

                   Ethambutol hydrochloride   1070-11-7

 

             1.4.2            Other numbers

 

                   RTECS            EL3640000

 

        1.5  Brand names, Trade names

 

             Ethambutol (Argentina); Myambutol (Australia, Belgium, 

             Canada, Denmark, France, Germany, Netherlands, South Africa, 

             Spain, Sweden, Switzerland, UK, USA)

             

             Mynah (UK)

             

             Etibi (Canada)

             

             Dexambutol (France)

             

 

 

 

             EMS-Fasol (Germany)

             

             Etambutyl, Etapiam, Miambutol, Mycobutol and Tibutolo (Italy)

             

             Afimocil, Anvital, Cidanbutol, Etambin, Farmabutol, Fimbutol, 

             Inagen and Tisiobutol (Spain).

             

             (To be completed by each Centre using local data)

 

        1.6  Manufacturers, Importers

 

             Northia (Argentina), Lederle (UK, both Myambutol and Mynah). 

 

             (To be completed by each Centre using local data)

 

        1.7  Presentation, Formulation

 

             Myambutol is available as powder (50 g per bottle) and 

             as tablets of 100 and 400 mg; Mynah is available as tablets 

             containing ethambutol and isoniazid.  Mynah 200, Mynah 250, 

             Mynah 300 and Mynah 365 contain 200, 250, 300 and 365 mg of 

             ethambutol hydrochloride respectively, with 100 mg of 

             isoniazid.

             

             (To be completed by each Centre using local data)

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             During chronic treatment ethambutol may produce visual 

             and neurological disturbances, allergic reactions, 

             gastrointestinal symptoms, psychiatric symptoms and transient 

             impairment of liver function.  This last event has a very low 

             incidence.

             

             Increased serum uric acid levels and acute gouty arthritis 

             have been reported.

 

        2.2  Summary of clinical effects

 

             Acute overdosage may cause gastrointestinal symptoms, 

             hallucinations and optic neuritis.  Acute overdosage symptoms 

             include nausea, abdominal pain, fever, mental confusion, 

             visual hallucinations, and optic neuropathy (retrobulbar 

             neuritis) with doses over 10 g.

             

             The effects of overdosage are not well established.  During 

             chronic treatment the following have been reported:

             

 

 

 

             Visual disturbances

             

             Ethambutol may produce a reduction of visual acuity which 

             appear to be due to optic neuritis.  Central scotoma and 

             green-red colour blindness may also occur.

             

             Allergic reactions

             

             Rash, anaphylactoid reactions, dermatitis, pruritus.

             

             Gastrointestinal symptoms

             

             Abdominal pain, anorexia, nausea, vomiting.

             

             Neurological disturbances and psychiatric symptoms

             

             Headache, peripheral neuritis, dizziness, mental confusion, 

             disorientation, hallucinations.

             

             Other side-effects

             

             Jaundice, transient impairment of liver function, fever, 

             increase of serum uric acid levels, joint pain, acute gouty 

             arthritis,malaise. Ethambutol may diffuse into milk.

 

        2.3  Diagnosis

 

             Clinical diagnosis is difficult, but the diagnosis of 

             poisoning with ethambutol should be considered as 

             differential in patients presenting with hallucinations, 

             visual disturbances and gastrointestinal symptoms.

             

             The following laboratory tests may be performed to detect 

             side effects:

             

             Serum uric acid levels;

             

             Liver and renal function tests; and

             

             Haematological examinations (neutropenia has been reported in 

             patients treated with rifampicin, isoniazid and 

             ethambutol).

 

        2.4  First aid measures and management principles

 

             In cases of overdosage with ethambutol gastric lavage or 

             inducing emesis should be considered, if seen 1 to 2 hours 

             after ingestion. Activated charcoal may be reasonably left in 

             the stomach after gastric lavage.

 

 

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Ethambutol is a synthetic oral antibiotic derivative of 

             ethylenediamine which contains two imine radicals and two 

             butanol radicals.

 

        3.2  Chemical structure

 

             CH3CH2CH(CH2OH)NHCH2CH2NHCH(CH2OH)CH2CH3

             

             Molecular formula

             

             Ethambutol base               C10H24N2O2

             

             Ethambutol hydrochloride      C10H24N2O2,2HCl

             

             Molecular weight

             

             Ethambutol base               204.3

             

             Ethambutol hydrochloride      277.2

             

 

             Chemical names 

 

              (S,S)-N,N'-Ethylenebis(2-aminobutan-1-ol)dihydrochloride

             

             2,2'-(1,2-ethanediyldiimino)bis-l-butanol

             

             (+)- (R,R)-NN'-Ethylenebis(2-aminobutan-1-ol)dihydrochloride

             

             (+)-2,2'-(ethylenediimino)di-1-butanol

             

             d-N,N'-bis(1-hydroxymethylpropyl)ethylenediamine

             

             (Reynolds, 1982,1993; Budavari, 1989) 

 

        3.3  Physical properties

 

             3.3.1 Properties of the substance

 

                   3.3.1.1 Colour

 

                           White

 

                   3.3.1.2 State/Form

 

                           Crystalline hygroscopic powder

 

                   3.3.1.3 Description

 

 

 

                           Odourless or almost odourless

                           

                           Bitter taste

                           

                           Melting point 199 °C to 204 °C

                           

                           Soluble 1 in 1 of water, 1 in 4 of alcohol, 1 

                           in 850 of chloroform, and 1 in 9 of methyl 

                           alcohol; very slightly soluble in ether.

                           

                           A solution in water is dextrorotatory. 

                           

                           Solutions are stable when heated at 121 °C for 

                           10 minutes.

                           

                           (Reynolds, 1993; Windholz, 1983)

 

             3.3.2 Properties of the locally available formulation(s)

 

                   (To be completed by each Centre using local data)

 

        3.4  Other characteristics

 

             3.4.1 Shelf-life of the substance unknown

 

             3.4.2 Shelf-life of the locally available formulation(s)

 

                   To be completed by each Centre using local data.

 

             3.4.3 Storage conditions

 

                   Store in airtight containers between 15 to 30°C.

 

             3.4.4 Bioavailability

 

                   To be completed by each Centre using local data.

 

             3.4.5 Specific properties and composition

 

                   To be completed by each Centre using local data.

 

  1. USES

 

        4.1  Indications

 

             4.1.1 Indications

 

 

 

             4.1.2 Description

 

                   For the treatment of tuberculosis in conjunction 

                   with at least one other antituberculous drug.

 

        4.2  Therapeutic dosage

 

             4.2.1 Adults

 

                   Treatment (oral) 

 

                   Initial phase (8 weeks) 25 mg/kg per day as a single 

                   dose in continuous regimens; or 30 to 40 mg/kg three 

                   times weekly in intermittent regimens.

                   

                   Continuation phase: 15 mg/kg daily

                   

                   Prophylaxis (oral)

                   

                   15 mg/kg per day

                   

                   Note:

                   

                   The dose of ethambutol should be reduced or dosage 

                   interval should be adjusted in patients with impaired 

                   renal function.

                   

                   A dose supplement should be given to patients 

                   undergoing haemodialysis or peritoneal dialysis.

                   

                   Ethambutol is usually given with isoniazid, rifampicin 

                   and pyrazinamide in the initial 8 week phase 

                   (Reynolds,1993)

 

             4.2.2 Children

 

                   Ethambutol is not recommended for use in 

                   children under thirteen years of age since safe 

                   conditions for use have not been established (PDR, 

                   1989).  However, children over the age of 6 years have 

                   been given doses similar to those used for adults 

                   (Reynolds, 1989).

 

        4.3  Contraindications

 

             Ethambutol hydrochloride is contraindicated in patients 

             who are known to be hypersensitive to this drug.  Renal 

             impairment, old age and optic neuritis are relative 

             contraindications (PDR, 1989).

 

 

 

  1. ROUTES OF ENTRY

 

        5.1  Oral

 

             Ethambutol is only available for oral use.  Data about 

             other  routes of entry are not available.

 

        5.2  Inhalation

 

             Not relevant

 

        5.3  Dermal

 

             Not relevant

 

        5.4  Eye

 

             Not relevant

 

        5.5  Parenteral

 

             Not relevant

 

        5.6  Other

 

             Not relevant

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Ethambutol hydrochloride, following a single oral dose 

             of 25 mg/kg of body weight, attains a peak of up to 5 œg/mL 

             in serum within 4 hours after administration and is less than 

             1 ug/ml by 24 hours.  When the drug is administered daily for 

             longer periods of time at this dose, serum levels are 

             similar.

             

             About 80% of an oral dose of ethambutol is absorbed from the 

             gastro-intestinal tract, and the remainder appears in the 

             faeces unchanged. Absorption is not significantly impaired by 

             food.

 

             (Reynolds, 1993) 

 

        6.2  Distribution by route of exposure

 

             Ethambutol diffuses readily into red blood cells and 

             into the cerebrospinal fluid when the meninges are inflamed. 

             The concentration in erythrocytes at steady state is 

             approximately twice the plasma concentration.

             

 

 

 

             Protein binding is less than 5%; the volume of distribution 

             is 1.6 L/kg (Gilman et al., 1990)

             

             It has been reported to cross the placenta and is excreted in 

             breast milk (Reynolds, 1989).  The concentration of 

             ethambutol in one sample of breast milk collected during a 2 

             hour period after a dose of 15 mg per kg body-weight was 1.4 

             mcg/mL. Another woman had simultaneous concentrations of 4.62 

             and 4.60 œg/mL in plasma and milk respectively, but no dose 

             had been specified (Reynolds, 1989).

 

        6.3  Biological half-life by route of exposure

 

             The serum half-life in therapeutic doses is 3 hours, 

             increasing in renal failure, as 80% is excreted renally 

             (Gilman et al., 1990).

             

             In 6 healthy subjects given a single dose of ethambutol 15 

             mg/kg bodyweight as an aqueous solution and as a commercial 

             tablet preparation the apparent mean elimination half-life 

             was 4.78  and 4.06 hours respectively, for plasma 

             concentration measured up to 12 hours after administration. 

             It was increased to about 10 hours for 24 to 72 hour 

             samplings.  The serum levels of ethambutol falls to 

             undetectable levels by 24 hours after the last dose, except 

             in some patients with abnormal renal function.

 

        6.4  Metabolism

 

             The main path of metabolism appears to be an initial 

             oxidation  of the alcohol to an aldehydic intermediate, 

             followed by conversion to a dicarboxylic acid (PDR, 

             1989).

 

        6.5  Elimination by route of exposure

 

             During the 24-hour period following oral administration 

             of ethambutol, approximately 50% of the initial dose is 

             excreted unchanged in the urine, while an additional 8% to 

             15% appears  in the form of metabolites.  From 20 to 22% of 

             the initial dose is excreted in the faeces as unchanged drug 

             (PDR, 1989).

             

             No drug accumulation has been reported with consecutive 

             single daily doses of 25 mg/kg in patients with normal kidney 

             function, although marked accumulation has been demonstrated 

             in patients with renal insufficiency (PDR, 1989).

             

             The intrinsic total body clearance is 9 mL/min/kg (Gilman et 

             al., 1990).

 

 

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             7.1.1 Toxicodynamics

 

                   The underlying cause of visual alterations 

                   appears to be  a disturbance of metabolism due to 

                   depletion of copper and zinc which serve as prosthetic 

                   groups for many enzymes.  The eye normally contains a 

                   considerable store of zinc, amounting to 0.5% of the 

                   weight of the eyeball.  Much of the zinc is in the 

                   pigmented cells of the outer zone of the retina, where 

                   it serves as a metal prosthetic group for retinol 

                   (alcohol) dehydrogenase.

 

             7.1.2 Pharmacodynamics

 

                   Ethambutol is an oral chemotherapeutic agent 

                   which is specifically effective against actively 

                   growing microorganisms of the genus Mycobacterium, 

                   including M. tuberculosis (PDR,1989). Ethambutol is 

                   bacteriostatic and appears to inhibit the synthesis of 

                   one or more metabolites, thus causing impairment of 

                   cell metabolism, arrest of multiplication, and cell 

                   death.  No cross resistance with other available 

                   antimycobacterial agents has been demonstrated. 

                   Ethambutol has been shown to be effective against 

                   strains of mycobacterium tuberculosis but does not seem 

                   to be active against fungi, viruses, or other bacteria. 

                   Ethambutol is also active against some atypical 

                   mycobacteria including M. kansasii.  Primary resistance 

                   to ethambutol is uncommon in developed countries but 

                   resistant strains of M. tuberculosis are readily 

                   produced if the drug is used alone.

 

        7.2  Toxicity

 

             7.2.1 Human data

 

                   7.2.1.1 Adults 

 

                           Adverse effects to ethambutol appear 

                           to be uncommon with doses of 15 mg/kg body- 

                           weight (Reynolds, 1989). Optic neuropathy is 

                           virtually unknown when ethambutol is given in 

                           doses of up to 15 mg/kg body-weight and is rare 

                           at doses of up to 25 mg/kg.  However, a patient 

                           developed rapid progressive deterioration of 

                           vision only 3 days after beginning therapy with 

                           ethambutol 800 mg daily by mouth (about 15 

 

 

 

                           mg/kg body-weight) and this patient remained 

                           blind over one year after the initial reaction 

                           (Karnik et al., 1985).

                           

                           Subclinical impairment of colour discrimination 

                           was reported to be relatively common in 54 

                           patients receiving about 15 mg/kg body-weight 

                           of ethambutol daily as part of antituberculous 

                           chemotherapy when compared with 50 patients 

                           receiving other antituberculous agents 

                           (Reynolds, 1989).

                           

                           Peripheral neuropathy has been reported in 3 

                           tubercular patients who had received ethambutol 

                           13 to 50 mg/kg body-weight, among other drugs. 

                           It has been reported that a patient who took 

                           ethambutol 20 g, rifampicin 9 g and isoniazid 

                           6 g made an uneventful recovery after 

                           haemodialysis and treatment with pyridoxine 

                           (Reynolds, 1989).

 

                   7.2.1.2 Children

 

                           No available data.

 

             7.2.2 Relevant animal data

 

                   Toxicological studies in dogs on high prolonged 

                   doses, produced evidence of myocardial damage and 

                   failure, and depigmentation of the tapetum lucidum of 

                   the eyes, the significance of which is not known. 

                   Degenerative changes in the central nervous system, 

                   apparently not dose-related, have also been noted in 

                   dogs receiving ethambutol hydrochloride over a 

                   prolonged period (PDR, 1989). 

                   

                   In the rhesus monkey, neurological signs appeared after 

                   treatment with high doses given daily over a period of 

                   several months. These correlated with specific serum 

                   levels of ethambutol hydrochloride and with definite 

                   neuro-anatomical changes in the central nervous system. 

                   Focal interstitial carditis was also noted in monkeys 

                   which received ethambutol hydrochloride in high doses 

                   for a prolonged period (PDR, 1989).

 

             7.2.3 Relevant in vitro data

 

                   Information about in vitro toxicological tests 

                   is not available.

 

 

 

        7.3  Carcinogenicity

 

             No available data.  Tumour inducing effects are not known.

 

        7.4  Teratogenicity

 

             Although ethambutol may be teratogenic in animals, there 

             is no evidence of teratogencity in man (Reynolds, 

             1989).

 

        7.5  Mutagenicity

 

             No available data

 

        7.6  Interactions

 

             Results of a crossover study involving 13 tuberculous 

             patients suggest that concomitant administration of aluminium 

             hydroxide may delay and reduce absorption of ethambutol in 

             some patients (Mattila et al., 1978).

             

             Untoward effects may be enhanced when ethambutol is combined 

             with isoniazid or rifampicin (Dukes, 1984).

 

        7.7  Main adverse effects

 

             Ethambutol may produce decreased visual acuity which 

             appear to be due to optic neuritis and to be related to dose 

             and duration of treatment. The effects are generally 

             reversible when administration of the drug is discontinued 

             promptly (PDR, 1989).

             

             Ethambutol may produce constriction of visual field, central 

             and peripheral scotoma, and green-red colour blindness which 

             may be associated with retrobulbar neuritis (Dukes, 1984; 

             Reynolds, 1989). 

             

             Renal clearance of urate may be reduced in about 50% of 

             patients receiving ethambutol and acute gout has been 

             precipitated in patients with gout or impaired renal function 

             (Reynolds, 1989).

             

             Cholestatic jaundice has been reported (Gulliford et al., 1986).

 

  1. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

 

        8.1  Sample

 

             8.1.1 Collection

 

             8.1.2 Storage

 

             8.1.3 Transport

 

 

 

        8.2  Toxicological analytical methods

 

             An agar diffusion microbiological assay, based upon 

             inhibition of Mycobacterium smegmatis (ATCC 607) may be used to 

             determine concentrations of ethambutol hydrochloride in serum 

             and urine.  This technique has not been published. 

 

             8.2.1 Test for active ingredient

 

             8.2.2 Test for biological analyses

 

        8.3  Other laboratory analyses

 

             8.3.1 Haematological investigations

 

                   Full blood count might be convenient to detect 

                   adverse effects. Leucopenia with neutropenia and 

                   thrombocytopenia have been reported in patients treated 

                   with ethambutol, isoniazid and rifampicin.

 

             8.3.2 Biochemical investigations

 

                   8.3.2.1 Blood

 

                           The following laboratory test may be 

                           performed to detect side-effects: serum uric 

                           acid levels; liver function tests; serum urea 

                           and creatinine concentrations.

 

                   8.3.2.2 Urine

 

             8.3.3 Arterial blood gas analysis

 

             8.3.4 Other relevant biomedical analyses

 

        8.4  Interpretation

 

             Ethambutol may increase uric acid levels by reducing renal 

             clearance of urate.  Rarely, it might induce liver or renal 

             disfunction.

 

        8.5  References

 

             See Section 13

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1 Ingestion

 

                   The acute overdosage symptoms include nausea, 

                   abdominal pain, fever, mental confusion, visual 

                   hallucinations and optical neuropathy with doses above 

                   10 g.

 

 

 

                   

                   According to scarce available information about 

                   ethambutol overdosage in humans, no deaths due to 

                   ethambutol alone have been reported.  One fatal case of 

                   overdose with rifampicin and ethambutol has been 

                   reported (Jack et al., 1978).

                   

                   Ethambutol may induce many other side-effects which 

                   were mentioned as "Main adverse effects" in the item 

                   7.7.  Possible presentation of these signs and symptoms 

                   in an acute overdose with ethambutol is 

                   unknown.

 

             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

 

                   Not relevant.

 

             9.1.6 Other

 

                   Not relevant.

 

        9.2  Chronic poisoning

 

             9.2.1 Ingestion

 

                   Signs and symptoms reported in long-term 

                   treatments with ethambutol have been presented in item 

                   7.7.  Other data are not available in our 

                   centre.

 

             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

 

                   Not relevant.

 

        9.3  Course, prognosis, cause of death

 

             As it has been mentioned, no deaths due to ethambutol 

             have been reported.  Decrease in visual acuity induced by 

             ethambutol was reversible when administration of the drug was 

             discontinued.  In rare cases, recovery may be delayed for up 

             to one year or more and the effects may possibly be 

             irreversible in these cases.  Patients should be advised to 

             report promptly to their physician any change in visual 

             acuity (PDR,1989). If careful evaluation confirms the 

             magnitude of visual change and fails to reveal another cause, 

             ethambutol therapy should be discontinued and the patient 

             reevaluated at frequent intervals.  Patients developing 

             visual abnormality during ethambutol therapy may show 

             subjective visual symptoms before, or simultaneously with, 

             the demonstration of decreases in visual acuity, and all 

             patients receiving ethambutol should be questioned 

             periodically about blurred vision and other subjective eye 

             symptoms (PDR, 1989).  Recovery of visual acuity generally 

             occurs over a period of weeks or months after the drug has 

             been discontinued. Patients have then received ethambutol 

             again without recurrence of loss of visual acuity (PDR, 

             1989).

 

        9.4  Systematic description of clinical effects

 

             9.4.1 Cardiovascular

 

                   None reported.

 

             9.4.2 Respiratory

 

                   None reported

 

             9.4.3 Neurological

 

 

                   9.4.3.1 Central nervous system (CNS)

 

                           Confusion, disorientation, 

                           hallucinations, headache, dizziness, 

                           retrobulbar neuritis with a reduction in visual 

                           acuity, constriction of visual field, central 

                           or peripheral scotoma and green-red colour 

                           blindness have been reported as adverse-effects 

                           of ethambutol therapy. Retinal haemorrhage has 

                           occurred rarely (Reynolds, 1989).

 

 

 

                           

                           Mental confusion, visual hallucination and 

                           optical neuropathy have been reported in cases 

                           of acute overdosage. The incidence and severity 

                           of ocular damage appears to be dose-dependent. 

                           In severe cases even blue- yellow defects 

                           occurred which may result in achromatopsia 

                           (Dukes, 1986).  Visual-evoked potential testing 

                           is reported to be the most reliable method for 

                           early detection of ocular 

                           abnormalities.

 

                   9.4.3.2 Peripheral nervous systems

 

                           Peripheral neuritis may precede or 

                           accompany ocular damage.  Changes are more 

                           severe in the sensory than in the motor nervous 

                           system.

 

                   9.4.3.3 Autonomic nervous system

 

                           Unknown

 

                   9.4.3.4 Skeletal and smooth muscle

 

                           Joint pains can occur with ethambutol 

                           therapy.

 

             9.4.4 Gastrointestinal

 

                   Digestive disturbances may be present both in 

                   acute poisoning or in long-term therapy.  Metallic 

                   taste, nausea, vomiting, anorexia, and abdominal pain 

                   have been reported as adverse-effects to ethambutol 

                   treatment.

 

             9.4.5 Hepatic

 

                   Jaundice and transient liver dysfunction are not 

                   unusual findings during ethambutol treatment.

 

             9.4.6 Urinary

 

                   9.4.6.1 Renal

 

                           Renal clearance of urate may be 

                           reduced in about 50% of patients receiving 

                           ethambutol.  There are scarce reports about 

                           renal failure and acute diffuse interstitial 

                           nephritis related with ethambutol 

                           therapy.

 

                   9.4.6.2 Other

 

                           None reported.

 

 

 

             9.4.7 Endocrine and reproductive systems

 

                   Unknown

 

             9.4.8 Dermatological

 

                   Skin rashes and pruritus may occur.

 

             9.4.9 Eye, ear, nose, throat: local effects

 

                   Ocular disturbances as described in 

                   9.4.3.1.

 

             9.4.10 Hematological

 

                   Leucopenia is an unusual finding.

 

             9.4.11 Immunological

 

                   Acute thrombocytopenia, probably due to an 

                   immunological mechanism, has been described in a single 

                   patient (Dukes, 1984). Various exanthemas, Stevens- 

                   Johnson syndrome, "toxic" epidermal necrolysis, 

                   purpura-like vasculitis, acute thrombopenic purpura, 

                   joint pain, drug fever, and leukopenia have been 

                   attributed to hypersensitivity. These reactions may 

                   arise during combined treatment with other 

                   tuberculostatics and it is therefore difficult to 

                   determine which drug is responsible.

 

             9.4.12 Metabolic

 

                   Elevation of serum uric acid levels may occur 

                   during ethambutol treatment (Dukes, 1986) and 

                   precipitation of acute gout has been reported (PDR, 

                   1989).

 

                   9.4.12.1 Acid-base disturbances

 

                           Unknown

 

                   9.4.12.2 Fluid and electrolyte disturbances

 

                           No data available

 

                   9.4.12.3 Others

 

                           No data available

 

             9.4.13 Allergic reactions

 

                   Anaphylactoid reactions

 

 

 

             9.4.14 Other clinical effects

 

                   Fever has been reported as an adverse-effect. 

                   It has been attributed to hypersensitivity.

 

             9.4.15 Special risks

 

                   Pregnancy 

 

                   The effects of combination of ethambutol with other 

                   antituberculous drugs on the foetus is not known. 

                   While administration of this drug to pregnant human 

                   patients has produced no detectable effect upon the 

                   foetus, the possible teratogenic potential in women 

                   capable of bearing children should be weighed carefully 

                   against the benefits of therapy.  There are published 

                   reports of five women who received the drug during 

                   pregnancy without apparent adverse effect upon the 

                   foetus (PDR,1989).

                   

                   Breastfeeding 

                   

                   Ethambutol may diffuse into milk.

                   

                   Enzyme deficiencies

                   

                   No data available.

                   

                   Alcohol

                   

 

                   In alcoholics with liver damage, in patients with 

                   intercurrent or previous hepatitis or in diabetics with 

                   retinopathy, monthly controls of the pathological state 

                   are necessary (Dukes, 1984).

 

        9.5  Other

 

             No data available

 

        9.6  Summary

 

             Not relevant

 

  1. MANAGEMENT

 

        10.1  General principles

 

             Consider prevention of absorption by enemas or gastric 

             lavage, if patient seen within 1 to 2 hours after ingestion. 

             Otherwise treatment is supportive.

 

        10.2  Relevant laboratory analyses

 

             10.2.1 Sample collection

 

 

 

             10.2.2 Biomedical analysis

 

                   As with any potent drug, assessment of organ 

                   system functions, including renal, hepatic, and 

                   haematopoietic, should be made.

 

             10.2.3 Toxicological analysis

 

                   Ethambutol concentrations may be evaluated both 

                   in blood and urine.

 

             10.2.4 Other investigations

 

                   No data available.

 

        10.3  Life supportive procedures and symptomatic/specific 

              treatment

 

             Usual life-supportive and/or symptomatic measures, 

             depending on clinical presentation of the patient.

 

        10.4  Decontamination

 

             In case of overdosage, the common methods employed to 

             limit the absorption of the drug from the gastrointestinal 

             tract may be utilized. Activated charcoal suspension may be 

             left in the stomach after gastric lavage.

 

        10.5  Elimination

 

             Based on the low protein binding (<5%) and volume of 

             distribution (1.6 L/kg) haemodialysis may theoretically 

             remove significant amounts of ethambutol. However, the high 

             intrinsic clearance (9 mL/min/kg) and short half-life (3 

             hours) indicate that this procedure may only be considered if 

             renal failure develops. (Jacobsen, personal 

             communication).

 

        10.6  Antidote treatment

 

             10.6.1 Adults

 

                   Antidotes are not available

 

             10.6.2 Children

 

                   Antidotes are not available

 

        10.7  Management discussion

 

             There are no data about the efficacy of treatment in 

             cases of ethambutol overdosage.

 

 

 

  1. ILLUSTRATIVE CASES

 

        11.1  Case reports from literature

 

             Neutropenia in a 75-year-old man treated with isoniazid, 

             ethambutol, and rifampicin.  Neutropenia was induced, on 

             challenge, by each of the 3 agents (Jenkins et al., 1980).  A 

             patient who took ethambutol 20 g, rifampicin 9 g, and isoniazid 

             6 g made an uneventful recovery after haemodialysis and 

             treatment with pyridoxine (Ducobu et al., 1982).

             

             Substitution of ethambutol by isoniazid was considered to be 

             responsible for thrombocytopenia in a 71 year-old woman who had 

             been receiving isoniazid and rifampicin for tuberculosis 

             (Rabinovitz et al., 1982).

             

             A patient developed rapid progressive deterioration of vision 

             only 3 days after beginning therapy with ethambutol 800 mg 

             daily by mouth (about 15 mg/kg body-weight) as part of 

             combination chemotherapy for pulmonary tuberculosis.  The 

             patient remained blind over one year after the initial reaction 

             (Karnik et al., 1985).

             

             Ethambutol might have caused renal failure in 2 patients 

             (Collier et al., 1976).

             

 

             A report of acute diffuse interstitial nephritis in 3 patients 

             attributed to antituberculous therapy and especially isoniazid 

             and/or ethambutol (Stone et al., 1976).

             

             Ethambutol was considered to be the cause of jaundice which 

             developed in a patient also receiving isoniazid and 

             streptomycin.  Rechallenge was positive for ethambutol or 

             ethambutol and streptomycin (Gulliford et al., 1986).

             

             A report of toxic epidermal necrolysis associated with the use 

             of ethambutol in one patient (Pegram et al., 1981).

             

             Hyperuricaemia has been found in up to 66% of patients 

             receiving ethambutol (Postlethwaite et al, 1972) and there have 

             been reports of acute gouty arthritis precipitated by 

             ethambutol in some patients (Self et al., 1977).

             

             An acute overdose of isoniazid (7.l g), rifampicin (15 g) and 

             ethambutol(20 g) produced seizures with loss of consciousness 

             and full extension of all four extremities in a 21-year-old 

             female who had ingested the medication 3.5 hours earlier. 

             Neurological examination revealed no focal or lateralizing 

             defects.  Convulsions resisted conventional treatment with 

             diazepam and phenytoin, but did not recur following 

             approximately 8.0 g pyridoxine and haemodialysis for 4 hours. 

             Pancuronium (2 mg intravenously) was also administered under 

             intubation of the patient.  A severe metabolic acidosis, 

 

 

 

             typical of acute overdosage with isoniazid was treated with 

             sodium bicarbonate infusion.  The patient's SGOT and SGPT 

             peaked on day 3 and declined rapidly thereafter.  She was 

             released on day 9 with no significant complications.  (Spalding 

             & Buss, 1986).

             

             A fatal case of overdose with both rifampicin and ethambutol 

             has been reported.  A man was found lying in the street and was 

             dead on admission to hospital.  He had been receiving 

             rifampicin and ethambutol. At necropsy, a pink discoloration of 

             the skin and internal organs was noted.  The dead man's urine 

             was bright red.  Blood and urine concentrations of rifampcin 

             and ethambutol were respectively 182 œg/ml and 3.3 mg/ml and 84 

             œg/ml and 6.8 œg/ml.  These levels may correlate with acute 

             overdosage with both drugs. Alcohol concentrations were very 

             low. Discolouration of skin, mucous membranes, and urine is 

             typical of rifampicin treatment, since the drug and its 

             metabolites are deep-red (Jack et al., 1978).

 

        11.2  Internally extracted data on cases

 

             No data available

 

        11.3  Internal cases

 

             To be completed by each Centre using local data

 

  1. ADDITIONAL INFORMATION

 

        12.1  Availability of antidotes

 

             Antidotes are not available.

 

        12.2  Specific preventive measures

 

             Ethambutol should be given in reduced dosage to patients 

             with impaired kidney function; it should be used with great 

             care in patients with visual defects, the elderly, and in 

             children in whom evaluation of changes in visual acuity may be 

             difficult; it should not be used in children under at least 6 

             years and some consider it should not be used in patients with 

             visual defects; ocular examinations are recommended before 

             treatment with ethambutol and some consider that regular 

             examinations are necessary during treatment especially in 

             children; patients should be advised to report visual 

             disturbances immediately and ethambutol should be withdrawn if 

             vision deteriorates; desensitization may be attempted following 

             hypersensitivity reactions if the use of ethambutol is 

             considered essential for provision of adequate 

             chemotherapy.

 

        12.3 Other

 

             No data available.

 

 

 

  1. REFERENCES

 

        Budavari S ed. (1989) The Merck index, an encyclopedia of 

        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 

        Merck and Co., Inc.  p 587.

        

        Collier J, Joekes AM, Philalithis PE, & Thompson FD (1976) Two cases 

        of ethambutol nephrotoxicity. Br Med J, 2:1105-6.

        

        Dictionnaire Vidal (1987) Vidal 1987. Editions du Vidal, Paris.

        

        Ducobu J, Dupont P, Laurent M, & Bruart J (1982) Acute 

        isoniazid/ethambutol/rifampicin overdosage (letter). Lancet, 

        1: 632.

        

        Dukes MNG ed. (1984) Meyler's Side Effects of Drugs, Volume 10. 

        Amsterdam, Elsevier.

        

        Dukes MNG ed. (1986) Meyler's Side Effects of Drugs Annual 10. 

        Amsterdam, Elsevier, p 270.

        

        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 1152-1153,1679.

        

 

        Gulliford M, Mackay AD, & Prowse K (1986) Cholestatic jaundice 

        caused by ethambutol. Br Med J, 292: 866.

        

        Jack et al (1978)  Fatal Rifampicin-ethambutol overdosage.  Lancet, 

        2: 1107-8.

        

        Jenkins PF, Williams TD, & Campbell IA (1980) Neutropenia with each 

        standard antituberculosis drug in the same patient. Brit Med J, 

        280: 1069-70.

        

        Karnik AM, Al Shamali MA, & Fenech FF (1985) A case of ocular 

        toxicity to ethambutol--an idiosyncratic reaction? Postgrad Med J, 

        61: 8ll-813.

        

        Mattila MJ, Linnoila M, Seppala T, & Koskinen R (1978) Effect of 

        aluminium hydroxide and glycopyrrhonium on the absorption of 

        ethambutol and alcohol in man.  Brit J Clin Pharmacol, 

        5: 161-166.

        

        Pegram PS Jr, Mountz JD, & O'Bar PR (1981) Ethambutol-induced toxic 

        epidermal necrolysis. Arch Intern Med, 141: 1677-8.

        

        Physician's Desk Reference (1989) 43rd ed. Ordell NJ, Medical 

        Economics, p 560.

        

        Postlethwaite AE, Bartel AG, & Kelley WN (1972) Hyperuricemia due to 

        ethambutol. New Engl J Med, 286: 761-762.

        

 

 

 

        Rabinovitz M, Pitlik SD, Halevy J, & Rosenfeld JB (1982) Ethambutol- 

        induced thrombocytopenia.  Chest, 81: 765-6.

        

        Reynolds JEF ed. (1982) Martindale, the extra pharmacopoeia, 28th 

  1. London, The Pharmaceutical Press, pp 1569-1570.

        

        Reynolds JEF ed. (1989) Martindale, 29th ed. The Pharmaceutical 

        Press, pp 560-563.

        

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th 

  1. London, The Pharmaceutical Press. pp 164-165

        

        Self TH, Fountain FF, Taylor WJ, & Sutliff WD (1977) Acute gouty 

        arthritis associated with ethambutol. Chest, 71(4): 561-2.

        

        Spalding CT & Buss WC (1986) Toxic overdose of isoniazid, rifampicin 

        and ethambutol. Eur J Clin Pharmcol, 30: 381-382.

        

        Stone WJ, Waldron JA, Dixon JH, Primm RK, & Horn RG (1976) Acute 

        diffuse interstitial nephritis related to chemotherapy of 

        tuberculosis. Antimicrob Agents Chemother, 10(1): 164-172.

        

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 

        index. Oslo, WHO Collaborating Centre for Drug Statistics 

        Methodology, p 61.

        

        WHO (1992) International nonproprietary names (INN) for 

        pharmaceutical substances. Geneva, World Health Organisation,  p 

        207.

        

        Windholz M ed. (1983)  The Merck index, an encyclopedia of 

        chemicals, drugs, and biologicals, 10th ed. Rahway, New Jersey, 

        Merck and Co., Inc, p 539.

 

  1. AUTHOR(S), REVIEWER(S), DATE(S), (INCLUDING UPDATES), COMPLETE 

         ADDRESS(ES)

 

        Co-authors  Dr Julia Higa de Londoni

                         Professor and Chief

                         Toxicology Section

                         Department of Internal Medicine

                         Hospital de Clínicas José de San Martín

                         Av Córdoba 2351

                         1120 Buenos Aires

                         Argentina

        

                         Dr Roberto Juan Gabach

                         Toxicology Section

                         Department of Internal Medicine

                         Hospital de Clínicas José de San Martín

                         Av Córdoba 2351

                         1120 Buenos Aires

                         Argentina

        

 

 

 

        Date             January 1990

        

        Reviewer         Dr R. Ferner Newcastle-upon-Tyne

        

        Peer Review      Strasbourg, France, April 1990

 




Ethionamide

  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

   1.7 Presentation, Formulation

  1. 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

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Properties of the substance

         3.3.1.1 Colour

         3.3.1.2 State/Form

         3.3.1.3 Description

      3.3.2 Properties of the locally available formulation(s)

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Shelf-life of the locally available formulation(s)

      3.4.3 Storage conditions

      3.4.4 Bioavailability

      3.4.5 Specific properties and composition

  1. 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

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Other

  1. 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

  1. 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

  1. 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 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 Advance quantitative method(s)

      8.2.2 Test 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 Advance quantitative method(s)

         8.2.2.5 Other dedicated method(s)

      8.2.3 Interpretation of toxicological analyses

   8.3 Interpretation of toxicological analyses

      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

  1. 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, and 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 Others

   9.6 Summary

  1. 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

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. ADDITIONAL INFORMATION

   12.1 Availability of antidotes

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




  1. NAME

 

       1.1 Substance 

 

           Ethionamide   (INN)

 

           (WHO, 1992)

 

       1.2 Group

 

           ATC classification index

 

           Antimycobacterials (J04)/Drugs for the treatment of

           tuberculosis (J04A)/Thiocarbamide derivatives(J04AD).

 

           (WHO, 1992)

 

       1.3 Synonyms

 

           Etionamide

           1314-TH

           Amidazine

           Ethioniamide 

 

           (Budavari, 1989)

 

           (To be completed by each Centre using local data)

 

       1.4 Identification numbers

 

           1.4.1 CAS number

 

                 536-33-4

 

           1.4.2 Other numbers

 

                 RTECS

 

                 NS0350000

 

       1.5 Brand names, Trade names

 

           Ethatyl (SCS, S. Afr.)

           Etiocidan (Cidan, Spain)

           Panathide (Propan, S. Afr.)

           Regenicide (Gedeon, Richter)

           Thioniden (Kaken, Jpn)

           Trecator (Belg., Theraplix, Fr)

           Trecator-SC (Wyeth, USA)

           Trescatyl (May & Baker, S. Afr; May & Baker, UK)

           Tubenamide (Meiji. Jpn)

           Resitran (Mla. Phil.)

 

           (To be completed by each Centre using local data)

 

       1.6 Manufacturers, Importers

 

           To be completed by each Centre using local data

 

       1.7 Presentation, Formulation

 

           Tablets 250 mg, in packs of 100  (PDR, 1992)

 

           (To be completed by each Centre using local data)

 

  1. SUMMARY

 

       2.1 Main risks and target organs

 

           Most common adverse reactions are gastrointestinal 

           disturbances including anorexia, nausea, vomiting, excessive 

           salivation, a metallic taste, stomatitis and diarrhoea and 

           hepatitis. Central nervous system effects include dizziness, 

           drowsiness, headaches, convulsions, peripheral neuropathy, 

           tremors and paraesthesias. 

 

           There is no experience in acute overdose of ethionamide. One 

           of the metabolites resembles isoniazid and one should watch 

           for similar symptoms. 

 

       2.2 Summary of clinical effects

 

           TOXIC REACTIONS FROM ETHIONAMIDE

 

           SITE               REACTIONS

         

           Gastrointestinal   Anorexia, vomiting, stomatitis, diarrhoea, 

           System             excessive salivation, metallic taste, 

                              hepatotoxicity. 

                              

           Central Nervous    Mental depression, anxiety or psychosis, 

           System             encephalopathy with pellagra-like 

                              symptoms, dizziness, drowsiness, headache, 

                              convulsion, peripheral neuropathy, 

                              tremors, paraesthesias. 

                              

           Eye                Optic neuritis, optic atrophy, diplopia. 

                              

           Nose               Olefactory disturbances

                              

           Ear                Deafness

                              

           Endocrine          Hypothyroidism, gynaecomastia, impotence, 

                              menorrhagia, hypoglycaemia 

                              

           Integumentary      Alopecia, acne, severe allergic rashes, 

                              photodermatitis. 

                              

           Haematology        Thrombocytopenia

                              

           Skeletal system    Rheumatic pains

                              

           Cardiovascular     Postural hypotension

 

           (Reynolds, 1989; Gilman et al., 1990)

               

       2.3 Diagnosis

 

           Clinical diagnosis is difficult to determine because of the 

           lack of history of toxic ingestions. 

 

           Quantitative Analysis

 

           Confirmatory tests can be used to document poisoning using 

           High Pressure Liquid Chromatography on plasma, serum or urine 

           or a colour reaction on urine; detection limit 10 ng/mL. 

 

           Qualitative Analysis

 

           Presence of sulphoxide derivative of ethionamide gives a 

           yellow colour in the acid extract. 

 

       2.4 First aid measures and management principles

 

           Whether the presentation of the patient is an overdose or an 

           adverse drug event, the first principle is to evaluate the 

           vital functions and provide life-support measures to 

           stabilize the victim.  Screening and confirmatory tests to 

           document poisoning in biological fluids should be done. (For 

           details, see 10.1) 

 

           Maintain patient airway, adequate breathing and circulation.  

           Decontaminate with activated charcoal and follow with 

           cathartic. 

                      

           Although the drug is extensively metabolised by the liver in 

           toxic doses, excretion may be enhanced with diuretics. 

 

           There are no known antidotes for ethionamide overdose. 

                      

  1. PHYSICO-CHEMICAL PROPERTIES

 

       3.1 Origin of the substance

 

           Synthesized from the interaction of 2-ethylisonicotinonitrile 

           and H2S in the presence of triethanolamine (Budavari, 1989).

 

       3.2 Chemical structure

 

           Structural formula

 

            

 

           Molecular formula

            

           C8H10N2S

 

           Molecular weight

 

           166.2

 

           Structural Chemical names

 

           2-Ethylpyridine-4-carbothioamide

           2-ethyl-4-pyridinecarbothioamide

           2-ethylththioisonicotinamide

           3-ethylisothionicotinamide

           2-ethylisothionicotinamide

           2-ethyl-4-thiocarbamoylpyridine

           alpha-ethylisonicotinoylthioamide

 

           (Reynolds, 1993; Budavari, 1989)

 

       3.3 Physical properties

 

           3.3.1 Properties of the substance

 

                 3.3.1.1 Colour

 

                         Yellow (darkens on exposure to light)

 

                 3.3.1.2 State/Form

 

                         Crystal or crystalline powder

 

                 3.3.1.3 Description

 

                         Slight sulphide-like odour.

 

                         Melting range   158°C to 164°C.

                

                         pH   6.0 to 7.0 in a 1 in 100 slurry in

                         water.

 

                         Soluble in 1 in 30 of alcohol. 

                         Very sparingly soluble in water.

                         Slightly soluble in chloroform (1 in 500) 

                         Slightly soluble in ether (1 in 320). 

                         Soluble in methyl alcohol. 

                         Sparingly soluble in propylene glycol.

 

                         (Reynolds 1993, Budavari 1989, European

                         Pharmacopoeia, 1986)

 

           3.3.2 Properties of the locally available formulation(s) 

 

                 It is stable at all ordinary temperatures and levels of 

                 humidity. 

 

                 (To be completed by each Centre using local data). 

 

       3.4 Other characteristics

 

           3.4.1 Shelf-life of the substance

 

                 No data available.

 

           3.4.2 Shelf-life of the locally available formulation(s) 

 

                 To be completed by each Centre using local data. 

                 

           3.4.3 Storage conditions

 

                 Preserve in air-tight containers at less than 40°C, 

                 preferably between 15 to 30°C. 

 

           3.4.4 Bioavailability

 

                 To be completed by each Centre using local data. 

 

           3.4.5 Specific properties and composition

 

                 To be completed by each Centre using local data

 

  1. USES

 

       4.1 Indications

 

           4.1.1 Indications

                      

                 For the treatment of pulmonary and extrapulmonary 

                 tuberculosis in conjunction with other antituberculous 

                 agents (when resistance to primary agents has 

                 developed). 

 

                 For the treatment of leprosy, as part of multi-drug 

                 regimens. 

 

                 In the treatment of pulmonary disease in Mycobacterium 

                 kansasii and other atypical mycobacteria. 

                      

           4.1.2 Description

 

                 Not applicable

 

       4.2 Therapeutic dosage

 

           4.2.1 Adults

 

                 Oral

                              

                  Tuberculosis 

 

                 0.5 to 1 g daily in divided doses (PDR, 1992) 

 

                 15 to 20 mg/kg (given as a single daily dose, up to 

                 maximum of 1 g (Reynolds, 1993). 

                              

                  Leprosy 

 

                 250 to 375 mg daily (Reynolds, 1989; Gilman et al., 

                 1990) 

 

                 5 mg/kg (as a single daily dose)(Reynolds, 1993) 

 

           4.2.2 Children

 

                 Oral

 

                  Tuberculosis

 

                 12 to 15 mg/kg body weight daily to a maximum of 750 mg 

                 daily in divided doses. 

 

                 Some children have received 20 mg/kg daily.

                 (Reynolds, 1989)

                      

                 15 to 20 mg/kg (given as a single daily dose) 

                 (Reynolds, 1993) 

 

                 Note: Optimum dose for children has not been 

                 established. A report showed the maximum daily dose as 

                 750 mg (Shirkey, 1977). 

 

       4.3 Contraindications

 

           Ethionamide should not be given to pregnant women unless the 

           benefits outweigh its possible risk. 

 

           To be used with caution in women of child-bearing age. 

 

           Severe liver disease.  

 

           Severe hypersensitivity.

 

           Note: Caution is necessary in administering ethionamide to 

           patients with depression or other psychiatric diseases, 

           chronic alcoholism, epilepsy, hypothyroidism or diabetes 

           mellitus.  

 

  1. ROUTES OF ENTRY

 

       5.1 Oral

 

           This is the usual route of administration for therapeutic 

           use. 

 

       5.2 Inhalation

 

           Unknown.

 

       5.3 Dermal

 

           Unknown.

 

       5.4 Eye

 

           Unknown.

 

       5.5 Parenteral

 

           Ethionamide hydrochloride has been given intravenously, but 

           there is no commercial preparation. 

 

       5.6 Other

 

           Ethionamide has been administered as rectal suppositories. 

 

  1. KINETICS

 

       6.1 Absorption by route of exposure

 

           Oral

 

           Approximately 80% of a gastrointestinal oral dose of 

           ethionamide is rapidly absorbed from the gastrointestinal 

           tract.  Following a single 1 g oral dose in adults, peak 

           plasma concentration of ethionamide averaging 20 ug/mL are 

           attained within 3 hours and less than 1 ug/mL at 24 hours. 

           Following a single 250 mg oral dose in adults, peak plasma 

           concentrations of ethionamide average 1-4 ug/ml (McEvoy, 

           1990). 

 

           After oral administration, the bioavailability is circa 100%. 

           (USPDI, 1993) 

 

           Rectal

 

           Relative bioavailability after rectal administration was 

           57.3% of that following oral administration. 

 

           Parenteral

 

           No data available.

 

       6.2 Distribution by route of exposure

 

           Oral

 

           It is widely distributed throughout body tissues and fluids. 

 

           It crosses the placenta and penetrates the meninges, 

           appearing in the CSF in concentrations equivalent to those in 

           the serum. 

 

           (Reynolds, 1989;  Gilman et al., 1990)

 

           Protein binding is low (10%) (USPDI, 1993).

 

       6.3 Biological half-life by route of exposure

 

           Oral

 

           Half-life is 2 to 3 hours (Reynolds, 1989).

 

       6.4 Metabolism

 

           Ethionamide is extensively metabolized, probably in the 

           liver, to ethionamide sulphoxide, 2-ethylisonicotinic acid 

           and 2-ethylisonicotinamide. The sulfoxide is the main active 

           metabolite (Moffat, 1986; McEvoy, 1993). 

 

       6.5 Elimination by route of exposure

 

           Less than 1% of a dose appears in the urine as unchanged 

           drug, the remainder is excreted in the urine as inactive 

           metabolites. 

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

       7.1 Mode of action

 

           7.1.1 Toxicodynamics

 

                 In view of the structural similarity of the metabolite 

                 2-methylisonicotinic acid to isoniazid, it has been 

                 suggested that toxicity is due to pyridoxine deficiency 

                 (Manapat, 1992). 

 

           7.1.2 Pharmacodynamics

 

                 Ethionamide inhibits the synthesis of mycolic acids and 

                 stimulates oxidation-reduction reactions. Treated cells 

                 lose acid-fastness, thus the mechanism of action 

                 appears to be similar to that of INH. Specific sites of 

                 action may be different, since strains of 

                 M.tuberculosis that are resistant to high 

                 concentrations of INH are susceptible to ethionamide. 

 

                 Both the drug and the sulphoxide metabolite are active 

                 against M.tuberculosis. 2-ethylisonicotinic acid and 2-

                 ethylisonicotinamide are not active metabolites. 

 

                 It is bacteriostatic against M. tuberculosis at 

                 therapeutic concentrations, but may be bactericidal at 

                 higher concentrations. The average MIC (Minimum 

                 Inhibitory Concentration) for Mycobacterium 

                 tuberculosis is 0.6 - 2.5 mg/mL (Lorian, 1980). Most 

                 susceptible organisms are inhibited by 10 ug/mL or 

                 less.  

 

                 It is bactericidal against M. leprae and a minimum 

                 inhibiting concentration (MIC) of 0.05 ug/mL has been 

                 reported in mice. 

 

                 Resistance develops rapidly if used alone and there is 

                 complete cross-resistance with prothionamide, 

                 thiacetazone and thiambutosine. (Reynolds, 1989) 

 

       7.2 Toxicity

 

           7.2.1 Human data

 

                 7.2.1.1 Adults

 

                         There is no experience with acute overdoses. 

                         Some of the adverse effects are dose-dependent 

                         and would be expected in an overdose situation. 

                         The most serious effects are neuropsychiatric 

                         symptoms and liver necrosis. 

 

                         In clinical use, neuropsychiatric symptoms, 

                         such as headache, sleeping, insomnia, 

                         depression and paraesthesia may occur. 

                         Elevation of liver transaminase enzymes has 

                         been known to develop. (British Tuberculosis 

                         Association, 1968). 

 

                         No special precautions are required due to age, 

                         as doses are adjusted according to patient 

                         response. However, dose should be modified 

                         depending on liver and renal status. (Dollery, 

                         1991) 

 

                 7.2.1.2 Children

 

                         No data available.

 

           7.2.2 Relevant animal data

 

                 A rat study showed the sublethal neurotoxicity level of 

                 ethionamide to be 1300 mg/kg. The principal signs were 

                 paralysis, loss of screen grip and decreased motor 

                 activity (Manapat et al., 1992). 

 

           7.2.3 Relevant in vitro data

 

                 No data available.

 

       7.3 Carcinogenicity

 

           No data available.

           

       7.4 Teratogenicity

 

           Teratogenic effects have been reported in rabbits, mice and 

 

           rats, in which high doses have led to abortions and some 

           malformations. 

           Conflicting reports exist in the literature concerning 

           congenital malformations in children when exposed to the drug 

           in utero. One observation attributes 7 malformations among 23 

           children exposed to ethionamide whereas in another study with 

           70 infants no such relationship to drug treatment during 

           pregnancy was found. (Dollery, 1991) 

 

       7.5 Mutagenicity

 

           Ethionamide was not found to be mutagenic as shown by Ames 

           Salmonella and Micronuclei Assay Test (Peters, 1983). 

 

       7.6 Interactions

 

           Ethionamide taken with pyrazinamide may lead to abnormalities 

           of liver function and the use of these two agents together 

           should be avoided (Reynolds, 1989). 

 

           The use of rifampicin with the thiomides (ethionamide or 

           prothionamide) as part of the regimens recommended by WHO for 

           the treatment of multibacillary leprosy has been associated 

           with an unexpectedly high incidence of hepatotoxicity (Pattyn 

           et al., 1984; Reynolds, 1989). 

 

           Adverse nervous system effects of ethionamide,

           cylcoserine and isoniazid may be additive (McEvoy, 1990).

 

           The side effects of other tuberculostatic agents may be 

           enhanced when ethionamide is administered concomitantly 

           (Griffin, 1988). 

 

           Alcohol may contribute to psychotropic reactions in an 

           ethionamide treated patient. More study is needed to clarify 

           the clinical significance of this interaction. (Griffin, 

           1988) 

 

       7.7 Main adverse effects

 

           The most common adverse effects are dose-related, viz: 

           gastrointestinal disturbances, including anorexia, excessive 

           salivation, a metallic taste, nausea, vomiting, stomatitis, 

           diarrhoea and hepatitis.  

 

           Dizziness, drowsiness, headache, postural hypotension and 

           asthenia may also occur occasionally. 

 

           Other side effects reported include acne, allergic reactions 

           alopecia, convulsions, deafness, dermatitis (including 

           photodermatitis), visual disturbances, tremors, 

           gynaecomastia, impotence, menstrual disturbances, olfactory 

           disorders, peripheral and optic neuropathy, thrombocytopenia 

           and rheumatic pains.  Mental disturbances, including 

           depression, anxiety and psychosis have been provoked.  A 

 

           pellagra-like syndrome with encephalopathy has been reported 

           rarely.  A tendency towards hypoglycaemia may occur and could 

           be of significance in patients with diabetes mellitus. 

           Hypothyroidism has also occurred.  Racial differences in 

           tolerance may occur, e.g. Chinese and Africans are often more 

           tolerant of ethionamide than are Europeans (Reynolds, 1989). 

 

           Note: Many patients cannot tolerate therapeutic doses of 

           ethionamide and have to discontinue treatment. 

 

  1. 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 Biomedical analyses

 

                 8.1.1.3 Arterial blood gas analysis

 

                 8.1.1.4 Haematological analyses

 

                 8.1.1.5 Other (unspecified) analyses

 

                         Plasma, serum, or urine may be used; however, 

                         blood is preferably collected on the third hour 

                         post-ingestion. 

 

           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

 

                         The blood obtained should be frozen at -20 to

                         -40°. 

 

           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

 

                         The blood sample should be transported, 

                         refrigerated and separated within 2 hours of 

                         collection. 

 

       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)

 

                         Description 

 

                         Yellow crystal or a yellow crystalline powder, 

                         darkening on exposure to light, with a slight 

                         sulphide-like odour. 

 

                         Identity Tests

 

                         The assay exhibits an absorbence maximum at 290 

                         +2 nm. 

 

                         Dissolve 1 g of ethionamide tablets in 50 ml of 

                         methanol and filter through a medium porosity 

                         sintered-glass funnel.  Evaporate the filtrate 

                         on a steam bath and the obtained residue melts 

                         between 155 and 164 (USP, 1985). 

 

                 8.2.1.2 Advanced qualitative confirmation test(s)

 

                 8.2.1.3 Simple quantitative method(s)

 

                 8.2.1.4 Advance quantitative method(s)

 

           8.2.2 Test for biological specimens

 

                 8.2.2.1 Simple qualitative test(s)

 

                         Qualitative analysis of urine based on a colour 

                         reaction. 

 

                 8.2.2.2 Advanced qualitative confirmation test(s)

 

                 8.2.2.3 Simple quantitative method(s)

 

                 8.2.2.4 Advance quantitative method(s)

 

                         Quantification analysis using High Pressure 

                         Liquid Chromatography on plasma, serum, or 

                         urine. 

 

                 8.2.2.5 Other dedicated method(s)

 

           8.2.3 Interpretation of toxicological analyses

 

                 Blood levels would peak by the third hour; levels at 6 

                 to 20 ug/ml are considered therapeutic. 

 

                  A yellow urine colour reaction detects the presence of 

                 a sulfoxide derivative. 

 

       8.3 Interpretation of toxicological analyses

 

           8.3.1 Biochemical analysis

 

                 8.3.1.1 Blood, plasma or serum

 

                         Liver function tests such as ALT, AST, Alkaline 

                         Phosphatase, Direct and Indirect Bilirubin; 

                         Prothrombin time; Blood Sugar; BUN, Creatinine 

 

                 8.3.1.2 Urine

 

                         Urinalysis to detect glucose, protein, and 

                         leucocytes; hourly urine output determination. 

 

                 8.3.1.3 Other fluids

 

           8.3.2 Arterial blood gas analyses

 

                 Not relevant.

 

           8.3.3 Haematological analyses

 

                 In severe cases of jaundice or suspected 

                 hepatotoxicity, a full blood count and prothrombin time 

                 must be monitored for coagulopathy. 

 

           8.3.4 Interpretation of biomedical investigations

 

                 Transient increase in serum bilirubin, AST (SGOT) and 

                 ALT (SGPT) concentrations have been reported in 

                 patients receiving ethionamide.  Hepatitis (with or 

                 without jaundice) has also been reported.  

                 Hepatotoxicity generally is reversible on 

                 discontinuation of the drug. 

 

       8.4 Other biomedical (diagnostic) investigations and their 

           interpretation 

 

           T3, T4; urinary coproporphyrin, ophthalmoscopy.

 

       8.5 Overall Interpretation of all toxicological analyses and 

           toxicological investigations 

 

       8.6 References

 

           United States Pharmacopeia, The National formulary (1985) 

 

           21st rev., 16th ed., Rockville MD, United States 

           Pharmacopeial Convention,,  pp 413. 

    

  1. CLINICAL EFFECTS

 

       9.1 Acute poisoning

 

           9.1.1 Ingestion

 

                 None reported.

 

           9.1.2 Inhalation

 

                 None reported.

                 

           9.1.3 Skin exposure

 

                 Not relevant.

 

           9.1.4 Eye contact

 

                 None reported.

 

           9.1.5 Parenteral exposure

 

                 None reported.

 

           9.1.6 Other

 

                 None reported.

 

       9.2 Chronic poisoning

 

           9.2.1 Ingestion

 

                 None reported.

 

           9.2.2 Inhalation

 

                 None reported.

 

           9.2.3 Skin Exposure

 

                 Not relevant.

 

           9.2.4 Eye contact

 

                 None reported.

 

           9.2.5 Parenteral exposure

 

                 None reported.

 

           9.2.6 Other

 

       9.3 Course, prognosis, cause of death

 

           None reported.

           

       9.4 Systematic description of clinical effects

 

           9.4.1 Cardiovascular

 

                 None reported.

 

           9.4.2 Respiratory

 

                 None reported.

 

           9.4.3 Neurological

 

                 9.4.3.1 Central nervous system (CNS)

 

                         May cause encephalopathy with pellagra-like 

                         symptoms; headaches; sleepiness, insomnia, 

                         depression, tremors, convulsions (British 

                         Tuberculosis Assn., 1968) 

 

                 9.4.3.2 Peripheral nervous system

 

                         Peripheral nerve symptoms consisting of 

                         paraesthesias, motor weakness or sensory 

                         impairment have been observed, following 

                         therapeutic doses (Snavely, 1984). 

 

                 9.4.3.3 Autonomic nervous system 

            

                         None reported.

 

                 9.4.3.4 Skeletal and smooth muscle 

 

                         None reported.

 

           9.4.4 Gastrointestinal

 

                  Dose-related 

 

                 Anorexia, excessive salivation, metallic taste, nausea, 

                 vomiting, stomatitis, and diarrhoea. 

 

           9.4.5 Hepatic

 

                 Although jaundice is rare, hepatitis may occur in about 

                 5% of patients. 

 

                 One study showed a 13% incidence of hepatitis when drug 

                 is combined with rifampicin and dapsone. The 

                 hepatocellular injury is non dose-related, especially 

                 among diabetics. 

 

           9.4.6 Urinary

 

                 9.4.6.1 Renal

 

                         None reported.

 

                 9.4.6.2 Other

 

           9.4.7 Endocrine and reproductive systems

 

                  Thyroid

 

                 May cause a disturbance in the synthesis of thyroid 

                 hormone resulting in hypothyroidism. 

 

                 Ethionamide inhibits the trapping of technetium and 

                 organification of iodine at concentration seen 

                 clinically (Drucker 1984). 

 

                  Other

 

                 Gynaecomastia

                 Menorrhagia

                 Impotence

                 Hypoglycaemia

 

           9.4.8 Dermatological

 

                 Dermatitis (photodermatitis)

                 Acne

                 Alopecia

 

           9.4.9 Eye, ear, nose, and throat: local effects 

 

                  Local effects

 

                 None reported.

 

                  Systemic effects

 

                 Optic neuritis, optic atrophy, degeneration of the 

                 chiasma, deafness, olefactory disturbances (Holdiness, 

                 1987). 

                 

           9.4.10 Haematological

 

                  May cause acute porphyria because it has been shown to 

                  be porphyrinogenic in animals. 

 

                  Thrombocytopenia

 

           9.4.11 Immunological

 

                  None reported.

 

           9.4.12 Metabolic

 

                  9.4.12.1 Acid-base disturbances

 

                           None reported.

 

                  9.4.12.2 Fluid and Electrolyte disturbances

 

                           None reported.

 

                  9.4.12.3 Others

 

                           Hypoglycaemia when given to diabetic 

                           patients. 

 

           9.4.13 Allergic reactions

 

                  Hypersensitivity reactions may occur.

 

           9.4.14 Other clinical effects

 

                  Rheumatic pains.

 

           9.4.15 Special risks

 

                  Pregnancy

 

                  CNS malformations have been reported (Schardein, 

                  1976). 

 

                  Conflicting reports exist for congenital malformations 

                  of children born to mothers receiving the drug during 

                  pregnancy. Therefore, it is suggested that the drug be 

                  avoided during pregnancy or in women of childbearing 

                  potential unless the benefits outweigh its possible 

                  hazard. (Dollery, 1991) 

                  

                  Breast-feeding

                  

                  As far as can be determined there are no data 

                  published indicating the secretion of ethionamide in 

                  breast milk in measurable quantities (Dollery, 1991). 

 

                  Enzyme deficiencies

 

                  None reported.

 

       9.5 Others

 

           No data available

 

       9.6 Summary

 

           Not applicable

 

  1. MANAGEMENT

 

        10.1 General  principles

 

             Whenever the presentation of the patient is an overdose or 

             adverse drug event, the first principle is to evaluate the 

             vital functions and provide life-support measures to 

             stabilize the victim. 

 

             Decontamination should be considered to reduce further 

             absorption, if patient seen early after poisoning.  

 

             There are no specific antidotes for ethionamide overdose; 

             however, high dose pyridoxine has been found to inhibit its 

             neurotoxic effects (Gennaro et al., 1985). 

 

             Pellagra-like symptoms can be reversed by niacin.

 

        10.2 Relevant laboratory analyses

 

             Bio-medical tests: (i.e., baseline liver function; platelet 

             count, blood sugar, prothrombin time). 

 

             10.2.1 Sample collection

 

                    Plasma, serum or urine may be used, however, blood 

                    is preferably collected on the third hour post-

                    ingestion.  Samples obtained should be frozen at  

                    -20 to -40 °C and separated within 2 hours of 

                    collection. 

 

             10.2.2 Biomedical analysis

 

                    Blood

 

                    Liver function tests such as ALT, AST, alkaline 

                    phosphatase, Direct and Indirect Bilirubin; 

                    Prothrombin time; Blood sugar; BUN, Creatinine. 

 

                    Urine

 

                    Urinalysis to detect glucose, protein, and 

                    leucocytes; hourly urine output determination. 

 

             10.2.3 Toxicological analysis

 

                    Blood levels taken on the third hour post-ingestion 

                    whose values are beyond 20 ug/ml are considered 

                    toxic. 

 

             10.2.4 Other investigations

 

                    Not relevant

 

        10.3 Life supportive procedures and symptomatic/specific 

             treatment 

 

             Treatment is mainly supportive.  If patient is in a 

             critical condition (i.e. cardiorespiratory distress) 

             maintain a clear airway, aspirate secretions if these are 

             present in the airway, administer oxygen, perform 

             endotracheal intubation if indicated, provide artificial 

             ventilation, if warranted. Maintain a patent intravenous 

             line to support circulation. Monitor vital signs 

             (sensorium, blood pressure, heart and respiratory rate) 

             regularly and correct hypotension with isotonic fluids or 

             inotropic agents.  Monitor fluids and electrolyte balance 

             (i.e., input and urine output). 

 

             If there are cardiac dysrhythmias, antiarrhythmic agents 

             are best avoided, especially if the "torsades de pointes" 

             type of arrhythmia is present. 

 

             If bleeding ensues, correct by doing appropriate component 

             transfusion only if indicated.  

 

             Reevaluate other drugs which patient may be taking and 

             which may interact with ethionamide. 

 

        10.4 Decontamination

 

             Methods to reduce gastrointestinal absorption consist of 

             inducing emesis or performing gastric lavage. 

 

             Perform gastric lavage if dose was high and ingestion was 

             recent. Protect airway if patient is unconscious. 

 

             Administer activated charcoal (1 mg/kg). (Note: The use of 

             cathartics is generally no longer recommended). 

 

        10.5 Elimination

 

             No documented information available.

 

        10.6 Antidote treatment

 

             10.6.1 Adults

 

                    There are no specific antidotes for ethionamide 

                    overdose. However, high dose pyridoxine may inhibit 

                    its neurotoxic effects (Gennaro et al., 1985) 

                    because of its similarity to isoniazid. This 

                    possible antidotal effect has not been documented. 

 

             10.6.2 Children

 

                    There is no specific antidote.  However, high dose 

                    pyridoxine may prevent neurotoxicities. 

 

        10.7 Management discussion

 

             Despite ethionamide's synthesis in 1956, there is still 

             paucity of both clinical and experimental data, 

             specifically in the management of acute poisoning overdose. 

 

             Drug induced hepatotoxicity was shown to be decreased by 

             pre-administration of methimazole (MMI)(Ruse, 1991). 

 

             High dose pyridoxine may prevent neurotoxicities.

 

             Pellagra-like symptoms can be reversed by niacin.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Abnormalities of liver function (but no jaundice) occurred 

             in 12 of 80 patients treated with ethionamide as part of 

             their antituberculous chemotherapy.  However, 10 of these 

             patients were also taking pyrazinamide.  The use of these 2 

             agents together may increase the risk of hepatotoxicity and 

             should be avoided (Reynolds, 1989). 

 

             A girl developed acute hepatic necrosis and died after 

             treatment with ethionamide, isoniazid and aminosalicylic 

             acid.  It was considered that ethionamide was the most 

             likely cause (Reynolds, 1989). 

 

             A report of encephalopathy with pellagra-like symptoms 

             occurring in association with ethionamide in 2 patients, 

             and with ethionamide and cycloserine in one patient. 

             Treatment was with nicotinamide and compound vitamin 

             preparations (Reynolds, 1989). 

 

        11.2 Internally extracted data on cases

 

             No data available.

 

        11.3 Internal cases

 

             To be completed by each Centre using local data.

 

  1. ADDITIONAL INFORMATION

 

        12.1 Availability of antidotes

 

             To be completed by each Centre using local data.

 

        12.2 Specific preventive measures

 

             Caution is necessary in administration ethionamide to 

             patients with depression or other psychiatric illnesses, 

             chronic alcoholism, or epilepsy. 

 

             As there have been reports of goitre and hypothyroidism 

             associated with the use of ethionamide it should  be 

             administered with care to patients requiring treatment for 

             hypothyroidism. 

 

             Difficulty may be experienced in controlling diabetes. 

             The side effects of other tuberculostatic agents may 

             be increased when ethionamide is used concurrently.

                      

             Ethionamide is contraindicated in pregnant and lactating 

             women, in patients with severe liver disease, and those 

             with severe hypersensitivity to the drug. 

         

        12.3 Other

 

             No data available.

 

  1. REFERENCES

            

        British Tuberculosis Association (1968) Comparison of toxicity 

        of prothionamide and ethionamide: a report from the research 

        committee of the british tuberculosis association. Tubercule, 

        49(2): 125-135 

 

        Budavari S ed. (1989) The Merck Index, an encyclopedia of 

        chemicals, drugs, and biologicals, 11th ed. Rahway,   New 

        Jersey, Merck and Co., Inc.  p 590. 

 

        Dollery C ed. (1991) Therapeutic Drugs, Volume 1. Edinburgh, 

        Churchill & Livingstone. 

 

        Drucker D et al. (1984) Ethionamide-induced goitrous 

        hypothyroidism. Ann Intern Med, 100(6): 837-9 

 

        European Pharmacopoeia (1980-1986) 2nd. ed., Maison Neuve, 

        Council of Europe, p 142. 

 

        Gennaro AR ed. (1985) Remington's pharmaceutical sciences, 17th 

  1. Easton, Pennsylvania,  Mack Publishing Company, p 1216. 

 

        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 1154-1155 

 

        Griffin JP, O,Grady J, Well FO,& D'Arcy (1988) A manual of 

        adverse drug interactions, Butterworth and Co Ltd. 

 

        Holdiness MR (1984) Clinical pharmacokinetics of antituberculous 

        drugs. A review. Clin Pharmacokinetics, 9(6): 571-574 

 

        Lorian V ed. (1980) Antibiotics in laboratory medicine, 

        Baltimore Press, Williams and Wilkins Company, pp 160-165. 

 

        McEvoy GK ed. (1990) American hospital formulary service, drug 

        information, Bethesda, American Society of Hospital Pharmacists, 

        pp 343-344. 

 

        McEvoy GK ed. (1993) American hospital formulary service, drug 

        information, Bethesda, American Society of Hospital Pharmacists, 

        pp 343-344. 

 

        Manapat BD et al. (1992) The effectiveness of pyridoxine in 

        modifying the neurotoxidome of ethionamide overdose in sprague-

        dawley rats. Manilla, Pharmacokinetic research paper, UP College 

        of Medicine-Department of Pharmacology. 

 

        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, pp 597-598. 

         

        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 

        29th ed. London, The Pharmaceutical Press, pp 562-563. 

        

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 

        30th ed. London, The Pharmaceutical Press, p 166. 

            

        Osol A et al. (1973)  The united states dispensatory, 27th ed. , 

        JB Lippincott Company,  p 509. 

 

        Pattyn SR et al. (1984) Hepatotoxicity of the combination of 

        rifampicin-ethionamide. Int J Lepr and Other Mycobacterial 

        Diseases, 1: 1-6 

 

        Peters JH (1983) Mutagenic activity of antileprosy drugs and 

        their derivatives. Int J Lepr and Other Mycobacterial Diseases, 

        51(1): 45-53 

 

        Physician's Desk Reference (1992) 46th ed. Ordell NJ, Medical

        Economics, p 2527.

 

        Ruse MJ (1991) The effect of methimazole on thioamide 

        bioactivation and toxicity. Toxicol Lett, 58(1): 37-41 

 

        Schardein JL (1976)  Drugs as teratogens. CRC Press, Inc,  

        p 202. 

 

        Shirkey HC (1984) Pediatric drug handbook , W B  Saunders 

        Company. 

 

        Snavely SR et al. (1984) The neurotoxicity of antibacterial 

        agents. Ann Intern Med, 100(1): 92-104 

 

        USPDI (1983) Drug Information for the Health Care Professional. 

        Vol. 1, Rockville MD, United States Pharmacopeial Convention,  

        pp 396-397. 

 

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 

        index. Oslo, WHO Collaborating Centre for Drug Statistics 

        Methodology, p 61. 

 

        WHO (1992) International nonproprietary names (INN) for 

        pharmaceutical substances. Geneva, World Health Organisation,  

        p 208. 

            

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

         

        Author       Dr Perlita Young, M.D.

                     National Poison Control and Information Service

                     University of the Philippines

                     College of Medicine

                     Philippine General Hospital

                     Ermita, Manila 1000

                     Philippines

 

                     Tel: 63-2-5218251

                     Fax: 63-2-501078

 

        Date         January 1992

 

        Reviewer     Dr M.C. Alonzo

                     CIAT 7- piso

                     Hospital de Clinicas

                     Av. Italia s/n

                     Montevideo

                     Uruguay

 

                     Tel: 598-2-804000

                     Fax: 598-2-470300

 

        Peer Review  Drs Maramba, Critchley, Caitens, Panganiban, 

                     Ombega, Ten Ham & Ms Kaye. Newcastle-upon-Tyne, 

                     United Kingdom, February 1992. 





See Also:

        Ethionamide (IARC Summary & Evaluation, Volume 13, 1977)