Summary of Product Characteristics (SmPC) - Dosulepin Hydrochloride 75 mg tablets
1 NAME OF THE MEDICINAL PRODUCT
Dosulepin Hydrochloride 75mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains 75 mg Dosulepin Hydrochloride. For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet
Red, circular, convex sugar-coated tablets plain on both sides.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Dosulepin is indicated in adults 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 section 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
Full dosing range is not possible with Dosulepin 75 mg tablets, other products are available and may be used for 25 or 50 mg dosing.
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 and adolescents: Not recommended.
Method of Administration
For oral administration.
4.3 Contraindications
Dosulepin is contraindicated following recent myocardial infarction, and in patients with any degree of heart block or other cardiac arrhythmias. It is also contraindicated in mania and severe liver disease and in patients with known hypersensitivity to Dosulepin or any of the ingredients (see section 6.1).
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 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 overdoses, 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 patients with a history of epilepsy,
Blood sugar concentrations may be altered and as such dosulepin should be used in caution in diabetic patients.
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 especially liable to experience adverse reactions to antidepressants, especially agitation, confusion and postural hypotension.
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 taken where there is a history of mania or psychoses. Dosulepin may aggravate psychotic symptoms. Patients posing a high suicidal risk require close supervision.
After initiating antidepressant therapy, it may be two to four weeks before there is an improvement in the 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 should be withdrawn gradually, as withdrawal reactions may occur.
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.
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.
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. Information on excipients
Contains Ponceau 4R (E124); which may cause allergic reactions in some people.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. is essentially ‘sodium-free’.
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).
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.
There is an increased risk of postural hypotension when tricyclic antidepressants are given with diuretics. The hypotensive activity of certain antihypertensive agents (eg betanidine, debrisoquine, guanethidine) may be reduced by dosulepin hydrochloride. It would be advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.
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.
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 antagonise the antidepressant effect but side effects may be increased due to increased plasma concentrations of tricyclics.
Dosulepin tablets contain sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
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 although this is at levels which are unlikely to cause problems.
4.7 Effects on ability to drive and use machines
Dosulepin 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, have occurred with other tricyclic antidepressants. Atropine-like side effects are common early in treatment but usually lessen as treatment continues.:
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, blood sugar concentration changes.
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, 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
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 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 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).
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, restlessness, ataxia, drowsiness, loss of consciousness, respiratory or metabolic acidosis, muscle twitching, convulsions, widely dilated pupils, hyperreflexia, sinus tachycardia, cardiac arrhythmias, hypotension, hypothermia, depression of respiration, visual hallucinations, delirium, urinary retention and paralytic ileus. In severe overdosage, convulsions, myoclonus, hypotension, respiratory or cardiac depression with life threatening cardiac arrhythmias which may even occur after apparent recovery.
- Patients ingesting >5 mg/kg should seek immediate medical attention.
- All children ingesting dosulepin should be assessed by a physician.
- Onset of toxicity occurs within 4-6 hours after tricyclic antidepressant overdose.
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 patients 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 1hr).
- 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 hydrochloride is a thio derivative of amitriptyline and is an antidepressant of the tricyclic family.
Dosulepin potentiates the effects of biogenic amines in the brain by inhibition of their reuptake at nerve terminals. Dosulepin is active in inhibiting the reuptake of noradrenaline, 5-hydroxytryptamine (5HT) and dopamine. Dosulepin also reduces and/or down regulates central noradrenaline receptor numbers and reduces noradrenaline-induced cyclic AMP formation in the brain.
It inhibits the uptake of 5HT into the platelets.
Dosulepin also has some central and peripheral anticholinergic and antihistaminic activity at standard dose levels.
5.2 Pharmacokinetic properties
The following pharmacokinetic parameters were obtained with Dosulepin Hydrochloride Capsules 25mg (n=22, total dose 75mg, 3 capsules): Cmax 37.6ng/ml, Tmax 2.18 hours, t½.z 20.4 hours, AUD (0-tlast) 547ng.h/ml and AUDC587ng.h/ml.
Dosulepin is extensively metabolised in the liver. Dosulepin and its metabolites are eliminated in urine 50% - 60% and faeces 15%-40%, most of which is first excreted in the bile. The main metabolites are the Ndemethylated derivative northiaden (desmethyl-dosulepin) and dosulepin Soxide. Northiaden S-oxide is also produced.
Some is also excreted in the faeces. Dosulepin has been found in breast milk.
5.3 Preclinical safety data
There are no pre-clinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium phosphate, maize starch, povidone, magnesium stearate
Coating materials:
Polyvinyl alcohol, triacetin, talc, titanium dioxide, sucrose, microcrystalline cellulose, Hypromellose, sodium saccharin, lake Ponceau 4R, lake sunset yellow, polyethylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
White opaque PVC-Al blister packs containing 28 tablets.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
RUDIPHARM LIMITED
Unit 6, Salbrook Road Industrial Estate
Salbrook Road, Redhill
Surrey, RH1 5GJ
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 49565/0059
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/11/2022
10 DATE OF REVISION OF THE TEXT
19/08/2026