Summary of Product Characteristics (SmPC) - Dosulepin 25 mg capsules
1 NAME OF THE MEDICINAL PRODUCT
Dosulepin 25mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains dosulepin hydrochloride 25 mg.
Excipient(s) with known effect
Each capsule contains 153 mg of lactose monohydrate. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Size 4 orange/caramel capsules marked ‘MP75’ and ‘25mg’
4 CLINICAL PARTICULARS
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 prescribers.
4.2 Posology and method of administration
Posology
Adults
Initially 75 mg/day in divided doses or as a single dose at night. The dose may be increased to 150 mg daily after a few days if required. In certain circumstances, e.g. under hospital conditions, dosages up to 225 mg daily have been used. Suggested regimes: 25 or 50mg three times a day oralternatively, 75 or 150mg as a single dose at night. Should the regimes of 150mg as a single dose be adopted, it is betterto give a smaller dose for the first few days.
Paediatric population Not recommended.
Elderly:
50-75 mg daily initially. As with any antidepressant, the initial dose should be increased with caution under close supervision.
A satisfactory clinical response may be seen when half the normal adult dose is administered.
There may be a latent period of up to two to four weeks from the start of treatment, before any improvement in the patient’s depression occurs.
Method of
administration
For oral administration.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Dosulepin is contraindicated in patients who have had a recent myocardial infarction or in patients with heart block of any degree or other cardiac arrhythmias. It is also contraindicated in mania and in severe liver disease.
4.4 Special warnings and precautions for use
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 capsules 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 capsules securely, out of sight and reach of children.
In cases of overdose, patients should seek IMMEDIATE MEDICAL ATTENTION (see section 4.9).
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.
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 epileptic patients.
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). Administration should be avoided if possible in patients with narrow angle glaucoma and symptoms suggestive of prostatic hypertrophy. Care should be exercised if a patient receiving treatment undergoes surgery as anaesthetics may increase the risk of arrhythmias or hypotension. If surgery is required the anaesthetist should be informed that the patient is receiving dosulepin treatment.
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. The elderly are particularly susceptible to experience adverse reactions to antidepressants. In particular they may suffer from agitation, confusion and postural hypotension.
After initiating antidepressant therapy, it may be two to four weeks before there is an improvement in a patient's depression. It is important that the patient is carefully monitored during this period. The anxiolytic effect may be observed within a few days of commencing treatment.
It is recommended that antidepressants are withdrawn gradually, as withdrawal reactions may occur (see 4.8).
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.
Tricyclic antidepressants potentiate the central nervous depressant action of alcohol.
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.
Serotonin syndrome
Concomitant administration of dosulepin and buprenorphine may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).
If concomitant treatment with buprenorphine containing medicinal products is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.
Dosulepin Capsules contain lactose and sodium
The capsules contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
Dosulepin hydrochloride should not be administered concurrently with monoamine oxidase inhibitors, nor within 14 days of cessation of such treatment.Concomitant administration of dosulepin and selective serotonin re-uptake inhibitors (SSRIs) should be avoided. Increases in plasma tricyclic antidepressant levels have been reported with some SSRIs and dosulepin. Antimuscarinic side effects may be enhanced by concurrent use with antimuscarinic drugs.
Antidepressants may antagonise the activity of antiepileptics by lowering the convulsive threshold.
Dosulepin should be used cautiously when co-administered with buprenorphine as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
Dosulepin hydrochloride may alter the pharmacological effect of some concurrently administered drugs including CNSdepressants such asalcohol and narcotic analgesics, the effects of these will be potentiated as will be the effects of adrenaline and noradrenaline (some local anaesthetics contain these sympathomimetics). If surgery is necessary, the anaesthetist should be informed that the patient is being so treated.
Concurrent administration with SSRIs should be avoided since increases in plasma tricyclic antidepressant levels havebeen reported following the coadministration of some SSRIs.
Oral contraceptives may antagonise the antidepressant effect but side effects may be increased due to increased plasmaconcentrations of tricyclics.
There is an increased risk of postural hypotension on concurrent use with diuretics. The hypotensive effect of certain antihypertensive agents (e.g. betanidine, debrisoquine, guanethidine) may be reduced by dosulepin. It is advisable to review all antihypertensive therapy if administered concurrently with tricyclic antidepressants.
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.
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. Oral contraceptives may increase the serum concentration of dosulepin and thus affect its antidepressant action.
4.6 Fertility, pregnancy and lactation
Pregnancy
Treatment with dosulepin hydrochloride should be avoided during pregnancy unless there are compelling reasons. There is inadequate evidence as to the safety of the drug during human pregnancy, therefore it should only be administered if considered essential.
Breast-feeding
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 hydrochloride may cause drowsiness in some patients, if this occurs it is advisable not to drive or operate machinery.
4.8 Undesirable effects
The following adverse effects, although not necessarily all reported with dosulepin hydrochloride have occurred with tricyclic antidepressants. Atropine-like side effects including disturbances of accommodation, dry mouth, tachycardia, hesitancy of micturition and constipation are common early in treatment, but usually lessen.
Other serious adverse effects are:
Blood and lymphatic system disorders:
Rare: bone marrow depression, leucopenia, eosinophilia, thrombocytopenia and agranulocytosis,
Hepatobiliary disorders:
Hepatitis (rare), Increased liver function test values, cholestatic jaundice. Psychiatric disorders:
Confusion, hypomania, nervousness
Psychotic manifestations including mania and paranoid delusions may be exacerbated during treatment with tricyclic antidepressants. 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, blood sugar concentration changes. Nervous system disorders:
Drowsiness, tremor, dyskinesia, movement disorders, convulsions (rare), epileptiform seizures, occasional extrapyramidal symptoms including speech difficulties
Eye disorders:
Disturbances of accommodation, raised 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 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 if treatment is ceased abruptly, these include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration (see 4.4). Similar symptoms have been reported in neonates whose mothers received tricyclic antidepressants during the third trimester.
In high dosage or in deliberate overdosage, cardiac arrhythmias and severe hypotension are likely to occur. These effects may also occur in patients with pre-existing 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).
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 tricyclic antidepressants. The mechanism leading to this risk is unknown.
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 the 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
- Patients ingesting >5mg/kg should seek immediate medical attention.
- All children ingesting dosulepin should be assessed by a physician.
- Onset of toxicity occurs within 4-6 hours
Symptoms of overdose
Signs of overdosage are dryness of the mouth, ataxia, drowsiness, loss of consciousness, muscle twitching, widely dilated pupils, hyperreflexia, sinus tachycardia, hypothermia, visual hallucinations, delirium, urinary retention, paralytic ileus, excitement, restlessness and respiratory or metabolic alkalosis. In severe overdosage, convulsions, myoclonus, hypotension, respiratory and cardiac depression may develop with life threatening cardiac arrhythmias which may even occur after apparent recovery.
Management
- A clear airway and adequate ventilation should be ensured. Hypoxia and acid-base imbalances should be corrected by assisted ventilation and iv 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
6hrs 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 hr).
- Convulsions should be controlled with iv diazepam or lorazepam.
5 PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
ATC Code: N06A A16 (Non-selective monoamine reuptake inhibitors)
Dosulepin is a tricyclic antidepressant with similar actions to those of amitriptyline. It prevents the re-uptake (and hence the inactivation) of noradrenaline and serotonin at nerve terminals. The mode of action in the treatment of depression is not fully understood. In addition, dosulepin inhibits the neuronal uptake of dopamine.
As a result of its effects on monoamine levels, dosulepin appears to produce adaptive changes in the brain by reducing or down-regulating both noradrenaline-induced cyclic-AMP formation and noradrenaline receptor numbers.
5.2 Pharmacokinetic properties
Dosulepin is readily absorbed from the gastrointestinal tract. The half-life for dosulepin and its metabolites is reported to be about 50 hours. It is metabolised in the liver to its primary active metabolite, desmethyldosulepin. It is excreted in the urine, mainly in the form of metabolites. Some is also excreted in the faeces. Dosulepin has been found in breast milk.
5.3 Preclinical safety data
Pre-clinical information has not been included because the safety profile of dosulepin has been established after many years of clinical use. Please refer to Section 4.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate
Magnesium stearate
Size 4 capsule shells
Erythrosin E127
Quinoline Yellow E104
Titanium Dioxide E171
Red Iron Oxide E172
Yellow Iron Oxide E172
Black Iron Oxide E172
Gelatin
Printing ink-Opacode Black S-1-17823 Shellac glaze 45 % in ethanol
Black iron oxide E172
N-butyl alcohol
Isopropyl alcohol
Propylene glycol E1520 and
Ammonium hydroxide E527
6.2 Incompatibilities
No other major incompatibilities are known
6.3 Shelf life
4 years
6.4 Special precautions for storage
Blister packs: Do not store above 25ºC. Store in the original package.
6.5 Nature and contents of container
Blister packs: PVC/Child resistant push through foil blisters (250µm PVC/20µm Al with 15µm PVC film), or PVdC coated PVC/ Child resistant push through foil blisters (60gm/m PVdC on 250µm PVC/20µm Al with 15µm PVC film).
Packs of the appropriate size to accommodate 14 and 28 capsules.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Genethics Europe Limited
41 - 43 Klimentos
Klimentos Tower
Nicosia 1061
Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 42976/0044
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/06/2003 / 26/01/2009
10 DATE OF REVISION OF THE TEXT
10/12/2024