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Tablets, 75 mg (red sugar coated, overprinted "P 75" in white).
Capsules, 25 mg (red/brown, overprinted "P 25" in white).
Dothiepin is a tricyclic antidepressant. It is a thioanalogue of amitriptyline. In antireserpine activity it is generally equivalent to amitriptyline but less potent than imipramine.
The site of action is thought to be in the CNS, but the mechanism by which this drug and all tricyclic antidepressants produce an antidepressant effect is unknown. Dothiepin possesses anticholinergic, antihistamine and central sedative properties. It is postulated that the aetiology of depression is associated with a functional abnormality of one or more of the biogenic amines, particularly the catecholamines, in the brain. The tricyclics inhibit uptake of noradrenaline and 5-hydroxytryptamine from the nerve endings thus increasing their availability at central noradrenergic synapses.
Well absorbed. Animal studies show dothiepin is absorbed from the small intestine. After a single 50 mg oral dose in one patient, a peak level of 20 nanogram/mL was achieved after 3 hours, falling to 10 nanogram/mL at 6 hours. There are substantial interindividual variations in steady state concentrations. In 10 patients taking 100 mg/day for two weeks, the serum concentration ranged from 18 to 84 nanogram/mL (mean 41 ± 7 nanogram/mL). After increasing the dose to 175 mg/day for a further two weeks the concentration ranged from 43 to 196 nanogram/mL (mean 96 ± 15 nanogram/mL). Steady state concentrations appear to be reached after 10 to 14 days.
Dothiepin is present in low concentrations in breast milk. It crosses the placental and blood-brain barriers in animals. Animal studies in the dog and cat show maximal concentration after 24 hours in liver, uveal tract of the eye, lung, kidney, pituitary and thyroid in descending order. In dogs, the tissue/plasma ratio for uveal tract tissue was 257:1.
Unchanged drug is about 84% bound to serum protein.
Dothiepin is metabolised in the liver and in man 12 basic metabolites were found in the urine, the bulk of which are northiaden sulphoxide and dothiepin sulphoxide. The metabolic pathways are thought to consist of N-demethylation, S-oxidation and glucuronic acid conjugation. There is active enterohepatic circulation in animals but this has not been studied in humans.
71% of a 50 mg labelled dose is excreted in the urine and faeces within 4 days, 56% being by the renal route.
The elimination half-life is biphasic; the first phase is 15 hours, the second 56 hours. Mean whole body elimination half-life is 51 hours.
Depression of any aetiology and the anxiety frequently associated with depressive illness.
75 mg daily in divided doses or as a single dose at night increasing to 150 mg daily. In certain circumstances, eg. in hospital use, dosages up to 225 mg daily have been used.
50-75 mg daily initially. Half the normal adult dose may be sufficient to produce a satisfactory clinical response.
Not recommended for use in children under 16 years since safety and efficacy in this age group has not been established.
The main dose may be taken at night as it may produce drowsiness. Ability to drive or operate machinery may be impaired. Do not abruptly discontinue the medicine. Warn patient about OTC preparations containing sympathomimetic medicines particularly patent cold remedies, cough syrups and weight reducing tablets.
The hazards of ECT may be increased as the drug lowers the convulsive threshold.
The drug should be withdrawn prior to surgery as anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.
In patients with severe depression, the possibility of suicide using this drug exists and hence they should be closely supervised during early therapy. These patients should not receive large quantities of the drug.
The drug may provide a shift towards the manic phase.
Do not prescribe dothiepin concurrently or within 14 days of MAOIs (see Contraindications). After withdrawal of MAOIs, initiate therapy at low doses and gradually increase to the normal range.
Use with caution as the drug may provoke conduction defects and arrhythmias.
Closely supervise these patients as the drug may provoke cardiac arrhythmias or conduction defects.
Dothiepin has an anticholinergic action and can exacerbate glaucoma and urinary retention and potentiate anticholinergics.
Tricyclic antidepressants have been reported to produce possible dangerous potentiation of the effects of sympathomimetic drugs.
Latent schizophrenia may be activated by dothiepin.
Psychotic manifestations, including mania and paranoid delusions, with or without associated hostility, may be exaggerated during treatment with tricyclic antidepressants.
Use with care as toxic blood levels may develop.
Eyes should be examined regularly for visual acuity and colour fields checked during prolonged therapy since the drug or its metabolites may accumulate in the pigmented area of the eye in experimental animals.
Ability to drive or operate machinery may be impaired as alertness is decreased.
Use with care as confusional states may occur.
Dependency potential is unknown.
Abrupt withdrawal may produce headache, nausea, convulsions, insomnia, irritability, excessive perspiration and the possibility of thrombotic episodes. It is recommended that antidepressants be withdrawn gradually. Symptoms similar to insomnia, irritability and excessive perspiration in neonates whose mothers received tricyclic antidepressants during the third trimester also have been reported.
Drug interactions may occur with several drugs (see Interactions).
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of drugs. Tricyclic antidepressants have not been shown to be associated with an increased incidence of birth defects. However, there is evidence of interference with central monoamine neurotransmission in rats. Care should be taken that there are sound indications for the use of these antidepressants during pregnancy.
Small amounts of Prothiaden have been observed in breast milk and its possible effect on the child must be carefully considered if it is necessary to give the drug to nursing mothers.
Occur in about 30% of patients and may be severe enough to discontinue the drug in 10% of patients.
Drowsiness, dizziness, tremor, extrapyramidal symptoms, confusional states, paraesthesia, alterations to EEG patterns, disorientation.
Dry mouth, urinary retention, sweating.
Hypotension, postural hypotension, tachycardia, arrhythmias, conduction defects, palpitations.
Increased or decreased libido in either sex.
Nausea, vomiting, constipation.
Disturbance of accommodation (blurred vision).
Several of the following reactions have not yet been reported with dothiepin but must be borne in mind because of its similarity to other antidepressants.
Disturbed concentration, delusions, hallucinations, excitement, anxiety, hypomania, restlessness, insomnia, nightmares, peripheral neuropathy, ataxia, incoordination, seizures, fatigue, headaches.
Paralytic ileus.
Hypertension, myocardial infarction, heart block, stroke.
Males: Gynaecomastia, testicular swelling, impotence; Females: Galactorrhoea.
Epigastric distress, abdominal cramps, stomatitis, black tongue, peculiar taste sensations, parotid swellings, diarrhoea.
Bone marrow depression including agranulocytosis, thrombocytopenia, eosinophilia.
Cholestatic jaundice, hepatitis, altered liver function.
Skin rash, urticaria, angioneurotic oedema, photosensitisation, skin blisters.
Weight loss, urinary frequency, mydriasis. Increased appetite and weight gain have been reported but it is not known whether it is due to relief of depression or to the drug.
The effect of alcohol may be potentiated by dothiepin. One death has been associated with this combination.
The sedative effect may be potentiated.
The sedative effect may be potentiated.
The antihypertensive effect may be blocked by dothiepin.
The sympathomimetic effect may be dangerously potentiated by dothiepin.
A potentially lethal interaction can occur between MAOIs and tricyclic antidepressants (see CONTRAINDICATIONS and WARNINGS).
Dothiepin may potentiate their anticholinergic effects.
May be potentiated.
No information available.
No interference reported with laboratory tests.
The toxicity of tricyclic antidepressants is attributed mostly to their anticholinergic effects which produce dry mouth, blurred vision, mydriasis, ileus and urinary retention. Common CNS symptoms are agitation, delirium, ataxia, hyperpyrexia, convulsions, respiratory depression and coma. Cardiovascular symptoms include cyanosis, hypotension, shock, tachycardia and cardiac arrhythmias which are often the major cause of death.
Individual response varies, e.g. death has resulted from overdosage with 0.75 to 1 g of dothiepin (30 to 40 capsules) but recovery has occurred after as much as 2 g (80 capsules).
Serious overdosage with tricyclic antidepressants in children occurs more easily with a relatively small total dosage because the dose per weight ratio is higher.
Gastric lavage. Induce emesis with syrup of ipecacuanha. In the unconscious patient with no cough reflex, the lungs should be protected with a cuffed endotracheal tube. As the drug is thought to undergo enterohepatic circulation, repeated aspiration may be of benefit by removing the drug and its metabolites excreted into the gut via the bile. Haemodialysis is not recommended as the absorbed drug rapidly enters the tissue compartment and is very slowly eliminated (Whole body elimination half-life = 51 hours).
General support of the circulation and respiration may be required. ECG monitoring is required. Propranolol and xylocaine may be useful in controlling arrhythmias.
Convulsions may be controlled with diazepam. Due to their respiratory depressant effects, barbiturates should be avoided especially if the patient is thought to have been on MAOIs or if barbiturates have been taken in association with the antidepressant in the overdose.
Prescription medicine.
25 mg x 50
75 mg x 30
Nil.
Abbott Laboratories (NZ) Ltd
227 Cambridge Terrace
NAENAE
Telephone (04) 567 0039
January 2002