SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dosulepin Tablets 75 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 75 mg Dosulepin Hydrochloride

3 PHARMACEUTICAL FORM

Tablets.

Red, film-coated tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Dosulepin is indicated in the treatment of symptoms of depressive illness, especiallywhere 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.

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 nighttime 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.

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.

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 and 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 tri/tetracyclic 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.

On stopping treatment, it is recommended that antidepressants should be withdrawn gradually, wherever possible.

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 coadministration 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 tri/tetracyclic antidepressant therapy may increase the risk of arrhythmias and hypotension.

Dosulepin has quinidine-like actions on the heart. For this reason, its concomitant use with other drugs which may affect cardiac conduction (e.g. sotalol, terfenadine, astemizole, halofantrine) should be avoided.

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.

Barbiturates may decrease and methylphenidate may increase the serum concentration of dosulepin and thus affect its antidepressant action.

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. There is inadequate evidence of safety of the drug during human pregnancy.

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

Initially, dosulepin may impair alertness; 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 including dry mouth, disturbances of accommodation, tachycardia, constipation and hesitancy of micturition are common early in treatment, but usually lessen.

Other adverse effects include drowsiness, sweating, postural hypotension, tremor and skin rashes. Interference with sexual function may occur.

Potentially serious adverse effects are rare. These include depression of the bone marrow, agranulocytosis, hepatitis (including altered liver function), cholestatic jaundice, convulsions and inappropriate ADH secretion.

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

Withdrawal symptoms may occur on abrupt cessation of tricyclic therapy and include insomnia, irritability and excessive perspiration. Similar symptoms in neonates whose mothers received tricyclic antidepressants during the third trimester have also been reported.

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

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

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.

4.9 Overdose

•    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.

Signs of Overdosage

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

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.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Dosulepin is a tricyclic antidepressant which acts by increasing transmitter levels at central synapses, so producing a clinical antidepressant effect.

Dosulepin, in common with other tricyclics, inhibits the reuptake of noradrenaline and 5-hydroxytryptamine, with a significantly greater action on the reuptake of noradrenaline. In addition, dosulepin inhibits the neuronal uptake of dopamine.

As a consequence of its effects on monoamine levels, dosulepin appears to produce adaptive changes in the brain by reducing or down-regulating both noradrenaline receptor numbers and noradrenaline-induced cyclic-AMP formation.

5.2. Pharmacokinetic Properties

Dosulepin is readily absorbed from the gastrointestinal tract and extensively

metabolised in the liver. Metabolites include northiaden, dosulepin-S-oxide and northiaden-S-oxide. Dosulepin is excreted in the urine, mainly in the form of metabolites; appreciable amounts are also excreted in the faeces. A half-life of about 50 hours has been reported for dosulepin and its metabolites.

5.3. Preclinical Safety Data

There is no pre-clinical data of relevance to a prescriber which is additional to that already included in other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core: Tricalcium phosphate, maize starch, povidone, magnesium stearate.

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

36 months.

6.4.    Special precautions for storage

None

6.5.    Nature and contents of container

PVC/aluminium blister pack containing 14 or 28 tablets.

6.6.    Instruction for use and handling

None.

7.    MARKETING AUTHORISATION HOLDER

Waymade PLC t/a Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex SS14 3FR

United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 06464/0770

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/03/2009

10    DATE OF REVISION OF THE TEXT

23/01/2012