Data Sheet
DOPRESS
Dothiepin (dosulepin) hydrochloride
Presentation
DOPRESS 25 mg capsules: Brown OP body, Scarlet OP cap, size 4, containing a white powder. Each capsule contains 25 mg dothiepin (dosulepin) hydrochloride.
DOPRESS 75 mg tablets: Dark red, film coated biconvex tablets, 11/32" diameter, imprinted DN75 on one side. Each tablet contains 75 mg dothiepin (dosulepin) hydrochloride.
Uses
Actions
Dothiepin (dosulepin) hydrochloride is a tricyclic antidepressant. It is a thioanalogue of amitriptyline. In antireserpine activity it is generally equivalent to amitriptyline but less potent than imipramine.
Site and Mode of Action
The site of action is thought to be in the CNS, but the mechanism by which this medicine 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.
Pharmacokinetics
Absorption
Dothiepin is well absorbed from the small intestine. There are substantial inter-individual variations in plasma concentrations after a single dose and concentration in plasma can be quite dynamic and unpredictable, leading to extremely large inter-individual differences in steady state drug concentrations in plasma. 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).After a single oral dose of 150 mg, a maximum concentration of 30.4 nanogram/mL to 278.8 nanogram/mL was achieved within 2 to 3 hours. Steady state concentrations appear to be reached after 10 to 14 days.
Distribution
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.
Protein Binding
Unchanged drug is about 84% bound to serum protein.
Metabolism
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.
Excretion
71% of a 50mg labelled dose is excreted in the urine and faeces within 4 days, 56% being by the renal route.
Half-life
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.
Indications
Depression of any aetiology and the anxiety frequently associated with depressive illness.
Dosage and Administration
Adults
75 mg daily in divided doses or as a single dose at night increasing to 150 mg daily. In certain circumstances, e.g. in hospital use, dosages up to 225 mg daily have been used.
Elderly
50-75 mg daily initially. Half the normal adult dose may be sufficient to produce a satisfactory clinical response.
Adolescent Depression
Not recommended for use in adolescent patients 13-18 years of age for the treatment of depression, unless under the supervision of a specialist.
Instructions to Patients
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.
Contraindications
- Dothiepin is contraindicated for the treatment of depression in patients 12 years of age and under.
- Dothiepin is contraindicated for the treatment of nocturnal enuresis.
- Epilepsy; seizure thresholds may be lowered by the medicine.
- Tricyclic antidepressants should not be used concomitantly or within 14 days of treatment with MAOIs since the combination may cause cerebral excitation followed by coma and dangerous hyperthermia.
- Acute recovery phase following myocardial infarction; tricyclic antidepressants may produce conduction defects and arrhythmias.
- Hepatic failure.
- Hypersensitivity to dothiepin.
Warnings and Precautions
Due to its toxicity in overdose, dothiepin should only be used in patients intolerant of, or unresponsive to, alternative treatment options.
Toxicity in overdose
Dothiepin is associated with high mortality in overdose. There is a low margin of safety between the (maximum) therapeutic dose and potentially fatal doses. Onset of toxicity occurs within 4-6 hours.
- A limited number of tablets should be prescribed to reduce the risk from overdose for all patients and especially for patients at risk of suicide.
- A maximum prescription equivalent to two weeks supply of 75 mg/day should be considered in patients with increased risk factors for suicide at initiation of treatment, during any dosage adjustment and until improvement occurs.
- Avoid concomitant medications that may increase the risk of toxicity associated with dothiepin (see Interactions)
- Patients should be advised to store the medicines securely, out of sight and reach of children.
- In cases of overdose, patients should seek IMMEDIATE MEDICAL ATTENTION (see Overdosage).
Clinical Worsening and Suicide Risk
Patients of any age with Major Depressive Disorder may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Patients should be closely monitored, especially at the beginning of therapy or when the dose is changed, until such improvement occurs.
There has been a long-standing concern that some antidepressants may have a role in the emergence of suicidality in some patients. The possible risk of increased suicidality in patients applies to all classes of antidepressant medicines, as available data are not adequate to exclude this risk for any antidepressant. Therefore, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Generally, when stopping an antidepressant, doses should be tapered rather than stopped abruptly.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and paediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.
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.
Mania and Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with any antidepressant alone may increase the likelihood of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that dothiepin is not approved for use in treating bipolar depression.
Information for Patients and Families
Patients and their families should be alerted about the need to monitor for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's doctor, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
The patient has the right to treatment meeting appropriate ethical and professional standards, and the patient needs to be fully informed with frank discussion of risk/benefit issues relating to the medicines efficacy and safety when used in the treatment regimen proposed.
Electroconvulsive Therapy
The hazards of ECT may be increased as the medicine lowers the convulsive threshold.
Elective Surgery
The medicine should be withdrawn prior to surgery as anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.
Monoamine Oxidase Inhibitors
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.
Cardiovascular Disorders
Dothiepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse), especially in the elderly. Caution should be exercised in using dothiepin in the elderly and in patients with suspected cardiovascular disease (see Contraindications).
Hyperthyroidism or Patients Being Treated with Thyroid Hormone
Closely supervise these patients as the medicine may provoke cardiac arrhythmias or conduction defects.
Glaucoma, Prostatic Hypertrophy, Urinary Retention and Concurrent Anticholinergic Therapy
Dothiepin has an anticholinergic action and can exacerbate glaucoma and urinary retention and potentiate anticholinergics.
Concurrent Therapy with Sympathomimetic Medicines
Tricyclic antidepressants have been reported to produce possible dangerous potentiation of the effects of sympathomimetic medicines.
Renal or Hepatic Impairment
Use with care as toxic blood levels may develop.
Ophthalmological Examination
Eyes should be examined regularly for visual acuity and colour fields checked during prolonged therapy since the medicine or its metabolites may accumulate in the pigmented area of the eye in experimental animals.
Impairment of Motor Co-ordination
Ability to drive or operate machinery may be impaired as alertness is decreased.
Elderly Patients
Use with care as confusional states may occur.
Dependence and Withdrawal
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.
Use in Pregnancy
Category C.
Withdrawal symptoms in newborn infants have been reported with prolonged maternal use of this class of medicines. 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.
Use in Lactation
Small amounts of dothiepin have been observed in breast milk and its possible effect on the child must be carefully considered if it is necessary to give the medicine to breastfeeding mothers.
Effect on Ability to Drive or Operate Machinery
Because alertness is decreased whilst using dothiepin, the ability to drive or operate machinery may be impaired.
Adverse Effects
These occur in about 30% of patients and may be severe enough to discontinue the medicine in 10% of patients.
More Common Reactions
Central Nervous System, Neuromuscular
Drowsiness, dizziness, tremor, extrapyramidal symptoms, confusional states, paraesthesia, alterations to EEG patterns, disorientation.
Anticholinergic
Dry mouth, urinary retention, sweating.
Cardiovascular
Hypotension, postural hypotension, tachycardia, arrhythmias, conduction defects, palpitations.
Endocrine
Increased or decreased libido in either sex.
Gastrointestinal
Nausea, vomiting, constipation.
Ocular
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.
Less Common Reactions
Central Nervous System, Neuromuscular
Disturbed concentration, delusions, hallucinations, excitement, anxiety, hypomania, restlessness, insomnia, nightmares, peripheral neuropathy, ataxia, incoordination, seizures, fatigue, headaches.
Anticholinergic
Paralytic ileus.
Cardiovascular
Hypertension, myocardial infarction, heart block, stroke.
Endocrine
Males: Gynaecomastia, testicular swelling, impotence; Females: Galactorrhoea.
Gastrointestinal
Epigastric distress, abdominal cramps, stomatitis, black tongue, peculiar taste sensations, parotid swellings, diarrhoea.
Haematological
Bone marrow depression including agranulocytosis, thrombocytopenia, eosinophilia.
Hepatic
Cholestatic jaundice, hepatitis, altered liver function.
Allergic
Skin rash, urticaria, angioneurotic oedema, photosensitisation, skin blisters.
Other
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.
Adverse events have been reported during post-approval use of dothiepin. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to dothiepin exposure.
| Table1: Additional Adverse Effects from Postmarketing Surveillance | |
|---|---|
| System Organ Class | Adverse Effect |
| Immune system disorders | Hypersensitivity reactions |
| Endocrine disorders | Endocrine side effects |
| Metabolism and nutrition disorders | Hyponatremia |
| Nervous system disorders | Movement disorders |
| Investigations | Increased intraocular pressure, changes in blood sugar levels |
Interactions
Alcohol
The effect of alcohol may be potentiated by dothiepin. One death has been associated with this combination.
Other drugs
Barbiturates
The sedative effect may be potentiated.
Tranquillisers and CNS Depressants
The sedative effect may be potentiated.
Guanethidine and Other Adrenergic Neurone Blocking Drugs
The antihypertensive effect may be blocked by dothiepin.
Sympathomimetics
The sympathomimetic effect may be dangerously potentiated by dothiepin.
Monoamine Oxidase Inhibitors
A potentially lethal interaction can occur between MAOIs and tricyclic antidepressants (see Contraindications and Warnings and Precautions).
Anticholinergics
Dothiepin may potentiate their anticholinergic effects.
Antihistamines
May be potentiated.
Diuretics
There is an increased risk of postural hypotension when tricyclic antidepressants are given with diuretics.
Antiepileptics
Tricyclic antidepressants may also antagonise the anticonvulsant effect of antiepileptics (convulsive threshold decreased).
Food
No information available.
Interference with Clinical, Laboratory and Other Tests
No interference reported with laboratory tests.
Overdosage
The onset of toxicity occurs within 4-6 hours.
Patients ingesting >5 mg/kg should seek immediate medical attention.
All children ingesting dothiepin should be assessed by a physician.
Symptoms
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).
In children, serious overdosage with tricyclic antidepressants occurs more easily with a relatively small total dosage because the dose per weight ratio is higher.
Management
A clear airway and adequate ventilation should be ensured. Hypoxia and acid-based imbalances should be corrected by assisted ventilation and intravenous sodium bicarbonate as appropriate.
Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.
The use of activated charcoal should be considered as a preferred initial means of reducing absorption in patients presenting within 2 hours of ingestion.
Blood pressure, pulse and cardiac rhythm should be monitored for at least 6 hours after ingestion.
Arrhythmias are best treated by correcting hypoxia and acid-base disturbances. Specialist poisons advice should be sought before using any anti-arrhythmic agents as these may exacerbate the arrhythmia.
In cases of cardiac arrest, persist with prolonged CPR (for at least an hour).
Convulsions should be controlled with intravenous diazepam or lorazepam.
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.
In cases of overdosage, it is advisable to contact the National Poisons Information Centre on 0800 POISON or 0800 764 766 for recommendation on the management and treatment of overdosage.
Pharmaceutical Precautions
Store below 25°C.
Medicine Classification
Prescription Medicine.
Package Quantities
DOPRESS 25 mg capsules: Blister packs of 100 capsules.
DOPRESS 75 mg tablets: Blister packs of 100 tablets.
Further Information
The active ingredient in Dopress is dothiepin hydrochloride (also known as dosulepin hydrochloride). The structural formula for dothiepin (dosulepin) hydrochloride is:
Molecular formula: C19H21NS.HCl Molecular weight: 331.9 CAS Registry No: 897-15-4
Dothiepin (dosulepin) hydrochloride is a white or faintly yellow, crystalline powder. It is freely soluble in water, in alcohol and in methylene chloride.
Excipients
DOPRESS 25 mg capsules also contain lactose, maize starch, purified talc, colloidal silicon dioxide and magnesium stearate. The capsules shell contains gelatin, titanium dioxide, FD & C red 3, FD & C red 40, FD & C blue 1 and FD & C yellow 6.
DOPRESS 75 mg tablets also contain lactose, maize starch, povidone, purified talc, sodium starch glycollate, magnesium stearate, and film coat of diethyl phthalate, hypromellose, Opaspray Red K-1F-4972 (with colourants titanium dioxide and carmoisine aluminium lake), and carnauba wax as a polishing agent.
Name and Address
Mylan New Zealand Limited
PO Box 11-183
Ellerslie
AUCKLAND
Telephone 09-579-2792
Date of Preparation
21 September 2009