Thaden Tablets 75mg
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Thaden Tablets 75mg Dosulepin Tablets 75mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 75mg dosulepin hydrochloride
For excipients, see 6.1
3 PHARMACEUTICAL FORM
Coated tablet for oral administration
A round, red film coated, biconvex tablet embossed “PTN 75”
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Dosulepin hydrochloride 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 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
Adults: Initially 75mg/day in divided doses or as a single dose at night, increasing to 150mg/day. In certain circumstances, e.g. in hospital use, dosages up to 225mg daily have been used. Suggested regimes: 25 or 50mg three times a day or alternatively, 75 or 150mg as a single dose at night.
Should the regimes of 150mg as a single dose be adopted, it is better to give a smaller dose for the first few days.
Elderly: 50 - 75mg daily initially. As with any antidepressant, the initial dose should be increased with caution under close supervision. Half the normal dose may be sufficient to produce a satisfactory clinical response.
Children: Not recommended
4.3 Contraindications
• Recent myocardial infarction.
• Any degree of heart block or other cardiac arrhythmias.
• Mania.
• Severe liver disease.
• Hypersensitivity to dosulepin or to any of the excipients.
• Dosulepin hydrochloride is contraindicated during breast feeding
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 overdose, patients should seek IMMEDIATE MEDICAL ATTENTION (see section 4.9)
The elderly are especially liable to experience adverse reactions to antidepressants, especially agitation, confusion and postural hypotension. Patients posing a high suicidal risk require close supervision. Dosulepin hydrochloride should be given with caution to epileptic patients and those with a history of mania, history of urinary retention, or in patients with hepatic impairment, thyroid disease, phaeochromocytoma, porphyria, and used with caution in patients having concurrent electroconvulsive therapy.
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 is using dosulepin in the elderly and in patients with suspected cardiovascular disease (see section 4.3).
Avoid if possible in patients with narrow angle glaucoma, symptoms suggestive of prostatic hypertrophy and a history of epilepsy.
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.
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 the patient is being so treated.
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.
It is recommended that antidepressants should be withdrawn gradually.
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.
Contains E124 and E110; which may cause allergic reactions in some people.
4.5 Interaction with other medicinal products and other forms of interaction
Dosulepin hydrochloride should not be given concurrently with an MAO inhibitor nor within fourteen days of ceasing such treatment.
Dosulepin hydrochloride may alter the pharmacological effect of some concurrently administered drugs including CNS depressants such as alcohol 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).
Concurrent administration with SSRIs should be avoided since increases in plasma tricyclic antidepressant levels have been reported following the coadministration of some SSRIs.
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.
There is an increased risk of postural hypotension on concurrent use 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.
4.6 Pregnancy and lactation
Treatment with dosulepin hydrochloride should be avoided during pregnancy unless there are compelling reasons. There is inadequate evidence of safety of the drug during human pregnancy.
Dosulepin hydrochloride is contraindicated during breast feeding.
4.7 Effects on ability to drive and use machines
As dosulepin hydrochloride 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 hydrochloride 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
Immune system disorders:
Hypersensitivity reactions (see Skin and subcutaneous tissue 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.
Psychotic manifestations; including mania and paranoid delusions may be exacerbated during treatment with tricyclic antidepressants.
Cases of suicidal ideation and suicidal behaviour have been reported during dosulepin therapy or early after treatment discontinuation (see section 4.4).
Withdrawal symptoms may occur on abrupt cessation of tricyclic therapy and include insomnia, irritability and excessive perspiration. Similar symptoms in neonates whose mothers receive tricyclic antidepressants during the third trimester have also been reported.
Nervous system disorders:
Drowsiness, tremor, dyskinesia, movement disorders, convulsions (rare).
Eye disorders:
Disturbances of accommodation, raised intraocular pressure.
Cardiac disorders:
Tachycardia, ECG changes including conduction defects
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
Gastrointestinal disorders: Dry mouth, constipation.
Hepatobiliary disorders:
Increased liver function test values, cholestatic jaundice, hepatitis (rare)
Skin and subcutaneous tissue disorders:
Rash, urticaria, photosensitivity, purpura, increased sweating
Renal and urinary disorders:
Urinary hesitation
Reproductive system and breast disorders:
Sexual dysfunction, testicular enlargement, gynaecomastia, galactorrhoea
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
Main dangers are unconsciousness, convulsions, abnormal cardiac rhythms and depression of respiration. Drowsiness, metabolic acidosis, hyperreflexia, hypotension, hypothermia, delirium, confusion, agitation, dry mouth, blurring of vision, tremor, excitement and hallucinations can occur.
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 1hr).
Convulsions should be controlled with iv diazepam or lorazepam.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Antidepressants N06A
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, t'Az 20.4 hours, AUD (0-tlast) 547ng.h/ml and AUDC 587ng.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 N-demethylated derivative northiaden (desmethyl-dosulepin) and dosulepin S-oxide. Northiaden S-oxide is also produced.
5.3 Preclinical safety data
No data of relevance to the prescriber, which is additional to that included in other sections of the SPC
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tribasic calcium phosphate
Starch maize Povidone K25 Magnesium stearate Purified Talc
Tablet coating:
Red dye containing:-Hypromellose (E464) Macrogol 400 Ponceau 4R (E124) Titanium dioxide (E171) Indigo carmine (E132) Sunset yellow FCF (E110)
6.2 Incompatibilities
None
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C. Store in the original package
6.5 Nature and contents of container
PVC blister with aluminium/PVC child resistant (CR) foil containing 14 or 28 tablets
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Co-pharma Ltd Unit 4 Metro Centre Tolpits Lane Watford Hertfordshire
WD1 8SS
8 MARKETING AUTHORISATION NUMBER(S)
PL 13606/0098
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/04/2007
10 DATE OF REVISION OF THE TEXT
23/03/2012