MONOGRAPH FOR UKPID DOTHIEPIN HYDROCHLORIDE HY Allen ZM Everitt AT Judd National Poisons Information Service (Leeds Centre) Leeds Poisons Information Centre Leeds General Infirmary Leeds LS1 3EX UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. MONOGRAPH FOR UKPID Drug Name Dothiepin hydrochloride Chemical group Tricyclic antidepressant Origin Synthetic Name UKBrand name(s) Prothiaden(R), Dothapax(R), Prepadine(R). Synonyms Dosulepin hydrochloride (INN). Common names Product licence number(s) Prothiaden(R) 25 mg: 00169/0086 Prothiaden(R) 75 mg: 00169/0087 CAS number 7081-53-0 Manufacturer Prothiaden(R), Knoll Ltd, 9 Castle Quay, Castle Boulevard, Nottingham, Nottinghamshire NG7 1FW Tel no. 0115 912 5000 APS, Ashbourne (Dothapax(R)), Berk (Prepadine(R)), Cox, Generics, Hillcross, Kent, Pharm and Norton. Presentation Form Capsules, tablets. Formulation details Capsules of 25mg. Tablets of 75mg. Pack size(s) 25mg capsules - packs of 100 and 600. 75mg tablets - packs of 28 and 500. Generics or branded generics may have different pack sizes. Packaging Prothiaden(R) 25mg - red/brown capsules marked P25 Prothiaden(R) 75 mg - red sugar-coated tablets marked P75 Generic formulations or branded generics will differ in presentation. Properties Chemical structure C19H21NS.HCl = 331.9 Chemical name 11-(3-Dimethylaminopropylidene)-6,-11- dihydrodibenz [b,e]thiepin hydrochloride Indications Depressive illness especially where an anti-anxiety effect is required. Therapeutic Dosage ADULTS: 50 mg - 150 mg daily in either divided doses or as a single dose at night. In severely depressed patients, doses of up to 225 mg daily have been used. CHILD: Not recommended. Contra-indications Recent myocardial infarction, heart block or other cardiac arrhythmia, mania, severe liver disease. Abuses Epidemiology Over a four year period between 1989 and 1992 there were over 600 deaths from dothiepin overdose (ONS 1996). Tricyclic fatalities tend to occur in older rather than in younger patients. In both fatal and non-fatal overdose, there are a greater number of tricyclic ingestions in females than in males (Crome 1986). The overall incidence of serious cardiac complications in patients who are admitted to hospital following tricyclic overdose is reported to be less than 10%. Some degree of coma occurs in about 50% of cases, but is only unresponsive to painful stimuli in about 10-15% of cases (Crome 1986). Convulsions occur in approximately 6% of patients (Taboulet 1995). The death rate in patients admitted to hospital is estimated to be 2%-3% (Dziukas & Vohra 1991). Adverse effects Antimuscarinic effects, sedation, arrhythmias, postural hypotension, tachycardia, sweating, tremor, rashes, hypomania or mania, confusion, interference with sexual function, weight gain, convulsions, hepatic and haematological reactions. Interactions Pharmacodynamic: a) A potentially hazardous interaction may occur between a tricyclic antidepressant and a MONOAMINE OXIDASE INHIBITOR (including moclobemide and selegiline) resulting in increased amounts of noradrenaline and serotonin at the synapse. Coma, hyperthermia, hypertension, convulsions, delirium, or death may result (Lipman 1981, White & Simpson 1984). b) There is an increased risk of cardiotoxicity when administered with other DRUGS WHICH PROLONG THE QT INTERVAL e.g. anti-arrhythmics, astemizole, halofantrine, or terfenadine. c) The pharmacology of dothiepin suggests that concomitant ingestions of SELECTIVE SEROTONIN REUPTAKE INHIBITORS, PHENOTHIAZINES, SYMPATHOMIMETICS, or OTHER TRICYCLIC ANTIDEPRESSANTS will enhance its toxicity. Pharmacokinetic: a) The metabolism of tricyclic antidepressants is inhibited by most SELECTIVE SEROTONIN REUPTAKE INHIBITORS, resulting in elevated tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and paroxetine appear to exert a greater effect than sertraline. Limited data suggest that citalopram does not inhibit tricyclic metabolism (Baettig et al. 1993, Taylor 1995). b) As the metabolism of dothiepin is mediated by cytochrome P450 microsomal enzymes, the potential exists for interactions with other drugs which are substrates of this system. c) CIMETIDINE reduces the metabolic clearance of tricyclic antidepressants by inhibition of liver enzymes, resulting in higher plasma tricyclic concentrations (Stockley 1996). Ethanol Information about any interaction between dothiepin and ethanol is lacking. Two other tricyclic antidepressants (amitriptyline, doxepin) are known to interact with ethanol resulting in an increased impairment of psychomotor skills, whilst a number of other tricyclics appear to interact with ethanol only minimally (Stockley 1996). Mechanism of action The precise mechanism of antidepressant action is unclear, but results from the inhibition of noradrenaline and serotonin reuptake into presynaptic neurones, and adaptive changes in receptor sensitivity. In addition to inhibiting the reuptake of noradrenaline and serotonin, dothiepin is also an antagonist of muscarinic cholinergic receptors, histamine receptors, and to a lesser extent alpha1 adrenergic receptors (Rudorfer et al. 1994). These antagonist actions account for its anticholinergic, sedative, and hypotensive properties. The contributions of the metabolites nordothiepin and the combined sulphoxides to the total antidepressant activity are similar to that of dothiepin itself (Rees 1981). Mechanism of toxicity The toxicity of dothiepin in overdose results from depression of the myocardial function (a quinidine-like effect), anticholinergic activity, alpha adrenergic receptor blockade, and respiratory insufficiency. The risk of toxicity is greatest 2-4 hours after ingestion when plasma levels are at the highest. Pharmacokinetics ABSORPTION Dothiepin is rapidly absorbed after oral administration with maximum plasma concentrations being reached after approximately 3 hours (Maguire et al. 1983). Extensive first-pass metabolism occurs (Rees 1981), the estimated oral bioavailability of dothiepin being approximately 30% (Yu et al. 1986). DISTRIBUTION Dothiepin is widely distributed throughout the body with an apparent volume of distribution of over 10 L/kg (Rees 1981). Dothiepin is 80-90% bound to plasma proteins at therapeutic concentrations (Dollery 1991). The plasma protein binding of tricyclic antidepressants is pH sensitive with a small reduction in plasma pH being associated with large increases in unbound (pharmacolgically active) drug (Nyberg & Martensson 1984). METABOLISM The metabolic profile of dothiepin varies widely between individuals. Dothiepin is metabolised by demethylation and S-oxidation in the liver, resulting in the active metabolites, nordothiepin (also known as northiaden or desmethyldothiepin), dothiepin sulphoxide and nordothiepin sulphoxide, all of which contribute to the antidepressant effect (Rees 1981). Inactive conjugated glucuronide metabolites have also been isolated (Rees 1981). ELIMINATION The major route of excretion is in urine, although significant faecal elimination also occurs. Less than 0.5% of a dose is excreted as unchanged dothiepin in urine (Rees 1981). Enteroenteric and enterohepatic recycling of dothiepin and its metabolites is considered to occur (Pimentel & Trommer 1994, Rees 1981). HALF LIFE Dothiepin: 20 hours (Yu et al. 1996). Active metabolites: 24-40 hours (Yu et al. 1996). SPECIAL POPULATIONS ELDERLY: Metabolic changes in the elderly result in higher plasma concentrations, longer half-lives, and reduced clearance than in younger populations (Ogura et al. 1983). LIVER IMPAIRMENT: Reduced metabolic capacity in liver disease suggests that accumulation of dothiepin will occur, but the clinical implications are unclear due to a corresponding reduction in active metabolite production. RENAL IMPAIRMENT: Reduced clearance in renal impairment suggests that accumulation of active metabolites will occur. GENDER: Elimination half-lives for dothiepin and nordothiepin are reported to be several hours longer in females than in males (Maguire et al. 1983). BREAST MILK Dothiepin and its active metabolites are excreted into human breast milk. In an early study, a patient treated with dothiepin 25 mg three times daily for 3 months had milk and serum dothiepin concentrations of 0.011 and 0.033 mg/L respectively (Rees et al. 1976). These data suggest that a baby would ingest less than 0.2% of the maternal dothiepin dose based on a daily milk intake of 150 ml/kg, but in this study no account was taken of active metabolites. A later study considered both the excretion of dothiepin and its active metabolites into breast milk. Concentrations of dothiepin, nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide were measured in blood and milk samples from five breast feeding women, and in plasma samples from their infants. The data show that the mean total infant daily dose is 4.5% of the maternal dothiepin dosage in dothiepin equivalents (Ilett et al. 1992). Toxicokinetics Absorption Distribution Metabolism Elimination Half life Dothiepin: 11-29 hours (Ilett et al. 1991) Special populations Breast milk Summary TYPE OF PRODUCT A tricyclic antidepressant. INGREDIENTS Dothiepin capsules: 25 mg Dothiepin tablets: 75mg SUMMARY OF TOXICITY Patients presenting with only mild signs of toxicity may rapidly develop life-threatening complications. Where major toxic events occur these usually develop within 6 hours of overdose, the risk of toxicity being greatest 2-4 hours after ingestion. Dothiepin overdose should be managed on a clinical basis rather than on the amount ingested, but as a guide, doses of 1 g in adults have been associated with severe toxicity. Ingestions of tricyclic antidepressants in children indicate that doses of 15 mg/kg may prove fatal to a child, although recovery has followed reported ingestions of over 100 mg/kg. Sinus tachycardia, hypotension, and anticholinergic symptoms are common features. Cardiotoxicity, impaired consciousness, seizures, acidosis, and respiratory insufficiency are associated with severe toxicity. The occurrence of seizures may precipitate the onset of cardiac arrhythmias and hypotension. Delirium may be a complication on recovery. FEATURES Dry mouth, blurred vision, dilated pupils, urinary retention, sinus tachycardia, drowsiness, hypothermia, and confusion. Hypoxia, acidosis, hypotension, convulsions, cardiac arrhythmias, and coma. UNCOMMON FEATURES Skin blisters, rhabdomyolysis, disseminated intravascular coagulation, adult respiratory distress syndrome, and absent brain stem reflexes. SUMMARY OF MANAGEMENT: SUPPORTIVE 1. Maintain a clear airway and adequate ventilation if consciousness is impaired. 2. If within 1 hour of the ingestion and more than 300 mg has been taken by an adult, or more than 1mg/kg by a child, give activated charcoal. 3. Carry out arterial blood gas analysis, and correct any acidosis and hypoxia. 4. Monitor the cardiac rhythm and blood pressure. 5. Single, brief convulsions do not require treatment but if they are prolonged or recurrent, they should be controlled with intravenous diazepam. 6. Ventricular arrhythmias should be managed with intravenous sodium bicarbonate and supportive measures. Where these measures fail and an anti-arrhythmic is considered essential, lignocaine is the preferred drug. 7. Other measures as indicated by the patient's clinical condition. Clinical Features ACUTE INGESTION Mild to moderate toxicity: dilated pupils, sinus tachycardia, drowsiness, dry mouth, blurred vision, urinary retention, absent bowel sounds, confusion, agitation, body temperature disturbances, twitching, delirium, hallucinations, nystagmus, and ataxia. Increased tone and hyperreflexia may be present with extensor plantar responses. (Callaham 1979, Crome 1986, Dziukas & Vohra 1991, Noble & Matthews 1969). Severe toxicity: coma, hypotension, convulsions, supraventricular and ventricular arrhythmias, hypoxia, metabolic and/or respiratory acidosis, and cardiac arrest (Crome 1986, Dziukas & Vohra 1991). ECG changes (in the usual order of appearance) include non-specific ST or T wave changes, prolongation of the QT, PR, and QRS intervals, right bundle branch block, and atrioventricular block. The terminal 0.04 second frontal plane QRS axis often shows a right axis deviation (Dziukas & Vohra 1991). Delayed features: adult respiratory distress syndrome (Varnell et al. 1989). Uncommon features: skin blisters, rhabdomyolysis, disseminated intravascular coagulation, gaze paralysis, and absent brain reflexes (Dziukas & Vohra 1991, White 1988). INHALATION DERMAL OCULAR OTHER CHRONIC INGESTION INHALATION DERMAL OCULAR OTHER At risk groups ELDERLY There is an increased risk of toxicity resulting from impaired drug metabolism and elimination. The elderly are also particularly susceptible to the central anticholinergic effects such as confusion, disorientation, acute psychosis and hallucinations (Nolan & O'Malley 1992). PREGNANCY The safety of dothiepin (or tricyclic antidepressants in general) during pregnancy has not been established. A handful of cases were reported in the early 1970's linking tricyclic antidepressant administration during pregnancy to birth defects, particularly limb deformities. Retrospective studies, subsequently reported, showed no correlation between tricyclic antidepressant use and increased malformations. However, a more recent report of a large case-controlled study found a greater occurrence (not quantified) of congenital malformation with tricyclic antidepressants than in control groups (Schardein 1993). Fetal tachyarrhythmia has been reported where dothiepin has been given in pregnancy - see case report 1. CHILDREN Comparison with other tricyclic antidepressants would suggest that ingestions in children result in symptoms typical of tricyclic antidepressant overdose in adults (Crome & Braithwaite 1978, Goel & Shanks 1974). See case report 2 for clinical details of dothiepin ingestion in a young child. ENZYME DEFICIENCIES Dothiepin is metabolised by microsomal enzymes in the liver which may be subject to genetic polymorphism. ENZYME INDUCED The metabolism of dothiepin is likely to be increased in the presence of enzyme inducing drugs, but is of doubtful clinical relevance as the metabolites formed also have antidepressant activity. OCCUPATIONS OTHERS RENAL IMPAIRMENT: increased risk of toxicity due to accumulation of metabolites. HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired metabolism. CARDIAC DISEASE: increased risk of toxicity due to underlying disease. EPILEPSY: increased risk of seizures. Management Decontamination If within one hour of ingestion, and more than 300mg has been taken by an adult or more than 1mg/kg by a child, activated charcoal should be given to reduce the absorption. ADULT DOSE; 50 g, CHILD DOSE; 1 g/kg. If the patient is drowsy this should be administered via a nasogastric tube, and if there is no gag reflex present, using a cuffed endotracheal tube to protect the airway. Supportive care GENERAL MANAGEMENT OF THE SYMPTOMATIC PATIENT Clear and maintain the airway, and give cardiopulmonary resuscitation if necessary. Evaluate the patient's condition and provide support for vital functions. 1. Administer intravenous sodium bicarbonate to correct any acidosis. ADULT DOSE: 50 ml of 8.4% sodium bicarbonate by slow intravenous injection; CHILD DOSE: 1 ml/kg of 8.4% sodium bicarbonate by slow intravenous injection. Subsequent bicarbonate therapy should be guided by arterial blood pH which should be monitored frequently. 2. Maintain adequate ventilation to prevent hypoxia with supplemental oxygen or artificial ventilation as appropriate. 3. Carefully maintain plasma potassium levels to prevent hypokalaemia. IN MIXED OVERDOSES WHERE A BENZODIAZEPINE HAS ALSO BEEN INGESTED, THE USE OF THE COMPETITIVE BENZODIAZEPINE ANTAGONIST FLUMAZENIL IS CONTRA-INDICATED (Mordel et al. 1992). Where symptoms develop following mild to moderate overdose, they may persist for 24 hours. Prolonged or delayed complications following severe toxicity may require the patient to be hospitalised for several days. SPECIFIC MANAGEMENT OF THE SYMPTOMATIC PATIENT 1. CARDIOTOXICITY GENERAL NOTE: in practice it is seldom necessary or advisable to use specific drug treatment for arrhythmias. If hypoxia and acidosis are reversed and adequate serum potassium levels maintained, then the majority of patients show improvement with supportive measures. SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment required (Pimentel & Trommer 1994). VENTRICULAR ARRHYTHMIAS: give intravenous sodium bicarbonate (even in the absence of acidosis) before considering antiarrhythmic drug therapy. Where an antiarrhythmic is considered necessary, lignocaine is the preferred drug (Pimentel & Trommer 1994). ADULT DOSE: 50-100 mg lignocaine by IV bolus over a few minutes, followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2 mg/minute for 2 hours, then 1 mg/minute (BNF 1998). The use of quinidine, disopyramide, procainamide, and flecainide are all contra-indicated as they depress cardiac conduction and contractility. The use of beta-blockers should also be avoided as they decrease cardiac output and exacerbate hypotension. The efficacy of other antiarrhythmic agents (e.g bretylium, amiodarone, calcium channel blockers) has not been studied in tricyclic antidepressant poisoning (Pimentel & Trommer 1994). BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited success as the cardiotoxicity of dothiepin results from depression of contractility rather than failure of cardiac pacemakers. CARDIAC ARREST: manage in the standard manner but with continuing resuscitative measures as some patients have recovered after receiving several hours of external cardiac massage (Orr & Bramble 1981). 2. COMA Good supportive care is essential. 3. HYPOTENSION Hypotension should be managed by the administration of intravenous fluids and by physical means. The majority of patients ingesting dothiepin have otherwise healthy cardiovascular systems and providing cardiac output is good it is unnecessary to use specific drug therapy. If there is evidence of poor cardiac output (after correction of acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive agent may need to be considered. Noradrenaline has been shown to be helpful in a number of studies (including cases where dopamine therapy has failed) (Teba et al. 1988, Yang & Dantzker 1991). ADULT DOSE: IV infusion of noradrenaline acid tartrate 80 micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute adjusted according to response (BNF 1998). CHILD DOSE (unlicensed indication): IV infusion of noradrenaline acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1 microgram/kg/minute of noradrenaline base) in glucose 5% or glucose/saline via a central venous catheter (Guy's, Lewisham & St Thomas Paediatric Formulary, 1997). 4. SEIZURES Administer intravenous diazepam to control frequent or prolonged convulsions. ADULT DOSE: 10 mg CHILD DOSE: 0.25-0.4 mg/kg Both by slow IV injection preferably in emulsion form. Where seizure activity proves difficult to manage, paralyse and ventilate the patient. Continue to monitor the cerebral function to ensure the cessation of seizure activity. 5. OTHER Catheterisation may be required to relieve distressing urinary retention and to allow continuous monitoring of urine output as a means of assessing cardiac output (Crome 1986). Respiratory complications should be managed conventionally with early respiratory support. Control delirium with oral diazepam. Large doses may be required (20- 30mg two-hourly in adults). Monitoring Monitor the heart rate and rhythm, arterial blood gases, blood pressure, serum electrolytes, body temperature, respiratory rate and depth, and urinary output. Observe for a minimum of 6 hours post-ingestion where: i) more than 1mg/kg has been ingested by a child, ii) more than 300 mg is known to have been ingested by an adult, iii) the patient is symptomatic. Antidotes None available Elimination techniques Dialysis and haemoperfusion are ineffective as means of promoting drug or metabolite elimination. Investigations Following severe toxicity: i) a chest X-ray will be needed to exclude pulmonary complications, ii) measure serum creatine kinase and other skeletal muscle enzyme activity (e.g. AST, ALT, and lactic dehydrogenase), iii) assess renal function, iv) assess haematological status. Management controversies Gastric lavage is not recommended as the procedure may be associated with significant morbidity, and there is no evidence that it is of any greater benefit than activated charcoal used alone (Bosse et al. 1995). If the procedure is used (i.e. in cases where activated charcoal cannot be administered), a cuffed endotracheal tube should be used to protect the airway if the patient is drowsy, and activated charcoal left in the stomach following the lavage. Repeat doses of oral activated charcoal may prevent the reabsorption of tricyclic antidepressants and their metabolites secreted in gastric juices and bile (Swartz & Sherman 1984). However, it would not be expected from the large volume of distribution of the tricyclics that clinically significant increases in body clearance would result. Physostigmine salicylate is a short acting reversible cholinesterase inhibitor which has been used historically in the management of tricyclic overdoses to reverse coma and antimuscarinic effects. Reports of serious complications from its use include severe cholinergic activity, convulsions, bradycardia, and asystole (Newton 1975, Pentel & Peterson 1980). The use of physostigmine is no longer recommended. The use of dopamine in the management of hypotension has been suggested, but the pressor effect of this indirect acting inotrope may be diminished in tricyclic overdosed patients due to depleted levels of noradrenaline (Buchman et al. 1990, Teba et al. 1988). The use of intravenous glucagon has been proposed in cases where hypotension is unresponsive to volume expansion and sodium bicarbonate administration, because of its positive inotropic effect and possible antiarrhythmic property. Its place in therapy has not been established (Sener et al. 1995). ADULT DOSE: 10 mg by IV bolus followed by an infusion of 10 mg over 6 hours (unlicensed indication and dose). There are a number of reports of severe arrhythmias or sudden death occurring up to 1 week after tricyclic overdose, but a review of the cases show that the patients had continuing toxicity, underlying disease or abnormalities (Stern et al. 1985). Several predictors of clinical severity in tricyclic overdoses have been suggested, including: 1. a maximal limb-lead QRS duration of 0.1 second or longer as a predictor of the risk of seizure (Boehnert & Lovejoy 1985), 2. a maximal limb-lead QRS duration of 0.16 second or longer as a predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy 1985), 3. plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart 1991), 4. the ECG terminal 40-ms frontal plane QRS axis of more than 120° (Wolfe et al. 1989), 5. plasma drug concentrations in excess of 2 mg/L as a predictor of the development of lung injury (Roy et al. 1989). Whilst none of these features in isolation are predictive of life-threatening toxicity, they may be helpful in assessing patient risk. Case data CASE REPORT 1 - Fetal tachyarrhythmia attributed to maternal drug treatment with dothiepin. A 26 year old woman was started on dothiepin 50 mg daily during the first trimester of pregnancy. This was increased to 75 mg daily at about 16 weeks of gestation and subsequently reduced to 50 and 25 mg daily at 30 and 34 weeks respectively. At 37 weeks there had been little growth over the previous three weeks, the patients weight remaining the same. The fetal heart rate was irregular with over 180 beats per minute. An ultrasound scan showed a normally grown fetus with no evidence of cardiac failure. The dothiepin was stopped after a few days. The frequency and the duration of the tachyarrhythmias decreased and within four days no abnormalities of the fetal heart rate were detected. At subsequent review in antenatal clinics no abnormalities were noted, and the patient delivered a healthy infant at term (Prentice & Brown 1989). CASE REPORT 2 - Dothiepin ingestion in an infant. An 11-month-old child weighing 9.7 kg ingested about 13 dothiepin 75 mg tablets (100 mg/kg). She was drowsy, had muscle twitching and a generalised convulsion. On admission to hospital one and a half hours later she was comatose and convulsing. Her pulse was 160 beats/minute, blood pressure 80/50 mm Hg, respirations regular, and pupils fixed and dilated. Electrocardiography showed sinus tachycardia. Her convulsions were controlled with 10 mg IV diazepam and 4 ml IM paraldehyde. She was intubated and her stomach emptied. She suddenly became bradycardic (pulse 50 beats/minute, blood pressure unrecordable), with wide QRS complexes showing on the ECG. Cardiac massage and assisted ventilation were started. She was unresponsive to IV atropine, and was given 5 mmol sodium bicarbonate and 50 ml plasma protein fraction. Blood gas analysis showed hypoxia with metabolic and respiratory acidosis. Further sodium bicarbonate was given (30 mmol) and hyperventilation started. One hour later blood gas analysis showed correction of her acidosis, her pulse returned to 104 beats/minute, and her blood pressure was 75 mm Hg systolic. Over the next few hours there was narrowing of the QRS complexes, some ST depression, and ventricular ectopic beats. She was responsive to pain ten hours after ingestion, and made an uneventful recovery (Hodes 1984). Analysis Agent/toxin/metabolite There is no clear relationship between plasma dothiepin concentration and clinical response or toxicity. Consequently the measurement of plasma drug concentration following overdose is not routinely advised, although it may have diagnostic value. Sample container Optimum storage Transport of samples Interpretation of data There is considerable variation in plasma concentration of dothiepin between individuals. As a guide, it has been suggested that therapeutic effect is associated with plasma dothiepin concentrations in excess of 0.1 mg/L (Rees 1981). Forensic studies have found lethal tricyclic antidepressant levels ranging from 1.1 mg/L to 21.8 mg/L (Frommer et al. 1987). Conversion factors 1 mg/L = 3.013 micromoles/L 1 micromole/L = 0.332 mg/L The molecular weight of dothiepin hydrochloride is 331.9 Other recommendations Prevention of poisoning Other toxicological data Carcinogenicity Genotoxicity Mutagenicity Reprotoxicity Teratogenicity Relevant animal data Animal tests show no evidence of carcinogenicity, teratogenicity, genotoxicity, or reprotoxicity (Dollery 1991, Goldstein & Claghorn 1980). Relevant in vitro data Laboratory tests involving mammalian cells, human lymphocytes, and bacteria show no evidence of genotoxicity (Dollery 1991). Other regulatory standards NA Environment NA Hazard NA Authors HY Allen ZM Everitt AT Judd National Poisons Information Service (Leeds Centre) Leeds Poisons Information Centre Leeds General Infirmary Leeds LS1 3EX UK This monograph was produced by the staff of the Leeds Centre of the National Poisons Information Service in the United Kingdom. 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