4.1. Therapeutic indications

Dosulepin is indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required.

Due to its toxicity in overdose, dosulepin should only be used in patients intolerant of, or unresponsive to, alternative treatment options (see sections 4.4 and 4.9).

Initiation of treatment for patients who have not previously received dosulepin should be restricted to specialist care providers.

4.2. Posology and method of administration

For oral administration

Adults: Initially 75 mg/day in divided doses or as a single dose at night, increasing to 150 mg/day. In certain circumstances, e.g. in hospital use, dosages up to 225 mg daily have been used.

Suggested regimens: 25 or 50 mg three times daily or, alternatively, 75 or 150 mg as a single dose at night. Should the regimen of 150 mg as a single night-time dose be adopted, it is better to give a smaller dose for the first few days.

Elderly: 50 to 75 mg daily initially. As with any antidepressant, the initial dose should be increased with caution under close supervision. Half the normal adult dose may be sufficient to produce a satisfactory clinical response.

Children: Not recommended.

4.3. Contraindications

Dosulepin is contra-indicated following recent myocardial infarction, and in patients with any degree of heart block or other cardiac arrhythmias. It is also contra-indicated in mania and severe liver disease and in patients with known hypersensitivity to dosulepin or any of the ingredients.

4.4. Special warnings and precautions for use

It may be two to four weeks from the start of treatment before there is an improvement in the patient's depression; the subject should be monitored closely during this period. The anxiolytic effect may be observed within a few days of commencing treatment.

Toxicity in overdose

Dosulepin 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 75mg/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 which may increase the risk of toxicity associated with dosulepin (see section 4.5).

• Patients should be advised to store the tablets securely, out of sight and reach of children.

• In cases of overdose, patients should seek IMMEDIATE MEDICAL ATTENTION (see section 4.9).

The elderly are particularly liable to experience adverse effects with antidepressants, especially agitation, confusion and postural hypotension.

Dosulepin should be avoided in patients with a history of epilepsy.

Administration should be avoided if possible in patients with narrow-angle glaucoma or symptoms suggestive of prostatic hypertrophy.

Dosulepin 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 dosulepin in the elderly and in patients with suspected cardiovascular disease (see Section 4.3).

Tricyclic antidepressants potentiate the central nervous depressant action of alcohol.

Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that a patient is being so treated.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Dosulepin is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Dosulepin should be avoided in patients with a history of epilepsy.

Care should be taken where there is a history of mania or psychoses. Dosulepin may aggravate psychotic symptoms. Patients posing a high suicidal risk require close supervision.

Conduction defects or cardiac arrhythmias may occur in hyperthyroid patients.

Toxic levels of dosulepin may develop in patients with severe renal disease.

On stopping treatment, it is recommended that antidepressants should be withdrawn gradually, wherever possible as withdrawal reactions may occur.

Patients posing a high suicidal risk require close supervision.

Dosulepin hydrochloride should be given with caution to patients with a history of mania, history of urinary retention, or in patients with hepatic impairment, phaeochromocytoma, porphyria, and used with caution in patients having concurrent electroconvulsive therapy.

Blood sugar concentrations may be altered and as such dosulepin should be used in caution in diabetic patients.

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.

Contains Ponceau 4R (E124); which may cause allergic reactions in some people.

4.5. Interaction with other medicinal products and other forms of interaction

Dosulepin should not be given concurrently with a monoamine oxidase inhibitor, nor within fourteen days of ceasing such treatment.

The concomitant administration of Dosulepin and SSRIs should be avoided since increases in plasma tricyclic antidepressant levels have been reported following the co-administration of some SSRIs.

Dosulepin may alter the pharmacological effect of some concurrently administered drugs including CNS depressants such as alcohol and narcotic analgesics; the effect of these will be potentiated as will be the effects of adrenaline and noradrenaline (some local anaesthetics contain these sympathomimetics).

Anaesthetics given during tricyclic antidepressant therapy may increase the risk of arrhythmias and hypotension. If surgery is necessary, the anaesthetist should be informed that the patient is being so treated.

Drugs which prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, some antipsychotics (notably pimozide and sertindole), cisapride, halofantrine and sotalol may increase the likelihood of ventricular arrhythmias when taken with tricyclic antidepressants and concurrent use should be avoided. The problem may be exacerbated where the interacting drug (such as quinidine or some antipsychotics) also reduces tricyclic metabolism.

Antimuscarinic side effects may be enhanced by concurrent use with antimuscarinic drugs.

Antidepressants may antagonise the activity of antiepileptics by lowering the convulsive threshold.

Oral contraceptives may antagonise the antidepressant effect but side effects may be increased due to increased plasma concentrations of tricyclics.

The hypotensive activity of certain antihypertensive agents (e.g. betanidine, debrisoquine, guanethidine) may be reduced by dosulepin. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

There is an increased risk of postural hypotension when tricyclic antidepressants are given with diuretics.

Tricyclic antidepressants may also antagonise the anticonvulsant effect of antiepileptics (convulsive threshold decreased).

Barbiturates and other enzyme inducers such as rifampicin and some antiepileptics may increase the metabolism of tricyclic antidepressants and result in lowered plasma concentrations and reduced antidepressant response. Cimetidine, methylphenidate, antipsychotics and calcium channel blockers (eg diltiazem, verapamil) may reduce the metabolism and increase plasma levels of tricyclics.

There is no evidence that dosulepin interferes with standard laboratory tests.

4.6. Pregnancy and lactation

Treatment with dosulepin should be avoided during pregnancy, unless there are compelling reasons. The safety of the drug during pregnancy has not been adequately studied.

There is evidence that dosulepin is secreted in breast milk but this is at levels which are unlikely to cause problems.

4.7. Effects on ability to drive and use machines

Dosulepin may cause drowsiness; patients likely to drive vehicles or operate machinery should be warned of this possibility.

4.8. Undesirable effects

The following adverse effects, although not necessarily all reported with dosulepin, have occurred with other tricyclic antidepressants:

Atropine-like side effects are common early in treatment, but usually lessen.

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Blood and lymphatic system disorders:

Rare: Bone marrow depression, thrombocytopenia, leucopenia, agranulocytosis, eosinophilia

Immune system disorders:

Hypersensitivity reactions (see Skin and subcutaneous tissue disorders)

Metabolism and nutrition disorders:

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant.

Increased appetite, weight gain, changes in blood sugar levels.

Psychiatric disorders:

Confusion, hypomania, nervousness

Psychotic manifestations; including mania and paranoid delusions may be exacerbated during treatment with tricyclic antidepressants.

Nervous system disorders:

Drowsiness, tremor, dyskinesia, movement disorders, convulsions (rare), epileptiform seizures, occasional extrapyramidal symptoms including speech difficulties

Eye disorders:

Disturbances of accommodation, increased intraocular pressure.

Cardiac disorders:

Tachycardia, ECG changes including conduction defects, dizziness

Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in deliberate overdosage. They may also occur in patients with pre-existing heart disease taking normal dosage.

Vascular disorders:

Postural hypotension, orthostatic hypotension, occasional hypertension

Gastrointestinal disorders:

Dry mouth, constipation, gastric irritation with nausea and vomiting

Hepatobiliary disorders:

Increased liver function test values, cholestatic jaundice, hepatitis (rare)

Skin and subcutaneous tissue disorders:

Rash, urticaria, photosensitivity, purpura, increased sweating, photosensitization

Renal and urinary disorders:

Urinary hesitation

Reproductive system and breast disorders:

Sexual dysfunction, testicular enlargement, gynaecomastia, galactorrhoea

Respiratory disorders

Idiosyncratic alveolitis which may prove fatal

General disorders:

Weakness, fatigue, ataxia, Weight loss may occur as may weight gain and the latter is sometimes associated with inappropriate appetite (carbohydrate craving).

Endocrine disorders:

Inappropriate ADH secretion

Withdrawal symptoms may occur on abrupt cessation of tricyclic therapy and include insomnia, irritability, headache, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration (see section 4.4). Similar symptoms in neonates whose mothers received tricyclic antidepressants during the third trimester have also been reported.

Cases of suicidal ideation and suicidal behaviours have been reported during dosulepin therapy or early after treatment discontinuation (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms of overdosage may include dryness of the mouth, excitement, ataxia, drowsiness, loss of consciousness, respiratory or metabolic alkalosis, muscle twitching, convulsions, widely dilated pupils, hyperreflexia, sinus tachycardia, cardiac arrhythmias, hypotension, hypothermia, depression of respiration, visual hallucinations, delirium, urinary retention and paralytic ileus.

• Patients ingesting >5mg/kg should seek immediate medical attention.

• All children ingesting dosulepin should be assessed by a physician.

• On set of toxicity occurs within 4-6 hours.

Management

• A clear airway and adequate ventilation should be ensured. Hypoxia and acid-base imbalances should be corrected by assisted ventilation and i.v. 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.

The benefit of gastric lavage is uncertain and the technique

• should be avoided in any patient with an impaired airway.

• 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 antiarrhythmic agents as these may exacerbate the arrhythmia.

• In cases of cardiac arrest, persist with prolonged CPR (for at least 1 hour).

• Convulsions should be controlled with i.v. diazepam or lorazepam.