Amitriptyline Hydrochloride 25mg/5ml Oral Solution

Amitriptyline Hydrochloride 50mg/5ml Oral Solution

25mg/5ml - Each 5ml of solution contains 25mg amitriptyline hydrochloride.

50mg/5ml - Each 5ml of solution contains 50mg amitriptyline hydrochloride.

Excipients

Each 5ml of solution contains:

1mg propyl hydroxybenzoate (E216)

6mg methyl hydroxybenzoate (E218)

3.35g liquid maltitol

Approximately 10.5mg ethanol

For full list of excipients, see section 6.1.

Oral solution.

A clear colourless solution with an orange/tangerine odour.

Amitriptyline is indicated for the treatment of:

-Symptoms of depression (especially where sedation is required).

-Nocturnal enuresis where organic pathology is excluded.

For oral administration only

Therapy should be started with a low dosage and increased gradually, according to the clinical response and any evidence of intolerance.

Adults - initial dosage: Usually 75mg a day in divided doses (or a single dose at night). If necessary, this may be increased to a total of 150mg a day, the additional doses being given in the late afternoon and/or at bedtime. The sedative effect is usually rapidly apparent. The antidepressant activity may be seen within three or four days or may take up to 30 days to develop adequately.

Adults - maintenance dosage: Usually 50 - 100mg a day. For maintenance therapy, the total dosage may be given in a single dose preferably in the evening or at bedtime. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms. Maintenance therapy should be continued for three months or longer to lessen the chances of relapse.

Children: Due to lack of clinical experience amitriptyline is not recommended for the treatment of depression in children under 16 years of age.

Enuresis: Children aged 6 - 10 years may receive 10 - 20mg a day, while those aged 11 - 16 may need 25 - 50mg a day. Treatment should not exceed three months.

Co-administration with monoamine oxidase inhibitors, prior sensitisation to amitriptyline, during the recovery phase after myocardial infarction, arrhythmias particularly heartblock of any degree, mania, severe liver disease, porphyria, lactation, children under 6 years of age. See also sections 4.4 and 4.6.

Amitriptyline should be used with caution in patients with a history of epilepsy, in patients with impaired liver function and, because of its atropine-like action, in patients with a history of urinary retention, prostatic hypertrophy, narrow-angle glaucoma or increased intra-ocular pressure. In patients with narrow-angle glaucoma, even average doses may precipitate an attack of glaucoma.

Patients with cardiovascular disorders, hyperthyroid patients and those receiving thyroid medication or anticholinergic agents should be closely supervised and the dosage of all medications carefully adjusted.

Elderly patients are particularly liable to experience adverse reactions especially agitation, confusion and postural hypotension.

When amitriptyline is used for the depressive component of schizophrenia, psychotic symptoms may be aggravated. In manic depressives, a shift towards the manic phase may occur; paranoid delusions, with or without associated hostility, may be aggravated. In such cases, a major tranquilliser should be given concurrently or the dosage of amitriptyline reduced.

The risk of suicide remains during treatment of depressed patients and until significant remission occurs such patients require careful supervision.

Concurrent administration with ECT may increase the hazards of treatment and should be limited to patients for whom it is deemed essential.

If possible, discontinue amitriptyline several days before surgery. But if emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being treated with amitriptyline because anaesthesia may increase the risk of hypotension and arrhythmias. Behavioural changes have been observed in children receiving tricyclics for the treatment of enuresis.

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. (See section 4.8 Undesirable Effects).

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suiciderelated 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 amitriptyline is prescribed can also be associated with an increased risk of suicide related events. In addition, these conditions may be comorbid 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 metaanalysis 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.

Excipient Warnings

This product contains liquid maltitol. Patients with rare hereditary problems of fructose should not take this medicine. Daily quantities of 10g or more may have a mild laxative effect. Calorific value 2.3 kcal/g maltitol.

Methyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

This product contains small amounts of ethanol (alcohol), less than 100mg per dose.

The concurrent use of antidepressants having varying modes of action should be made only with due recognition of their possible potentiation and with a thorough knowledge of their respective pharmacologies. Monoamine oxidase inhibitors can potentiate the effects of tricyclic antidepressants such as amitriptyline and hyperpyretic crises, severe convulsions and fatalities have occurred. A minimum of 14 days should elapse between discontinuing a MAOI and starting amitriptyline which should be introduced cautiously and dosage increased gradually. Amitriptyline may block the antihypertensive action of guanethidine, debrisoquine, betanidine and possibly clonidine. It would be advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

Amitriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine.

Amitriptyline may enhance the response to alcohol, barbiturates and other CNS depressants. In turn, barbiturates may decrease and methylphenidate may increase, the antidepressant action of amitriptyline. Delirium has been reported in patients taking amitriptyline with disulfiram.

Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with drugs having an anticholinergic action.

Based on the known metabolism of amitriptyline, the protease inhibitor, ritonavir, may increase the serum levels of amitriptyline. Therefore, careful monitoring of therapeutic and adverse effects is recommended when these drugs are administered concommitantly.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants. Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients treated with 1g ethchlorvynol and 75mg to 150mg amitriptyline.

St John's Wort may decrease plasma levels of amitriptyline.

Amitriptyline may increase levels of thioridazine leading to cardiac side effects.

The safety of amitriptyline for use during pregnancy has not been established. Amitriptyline is not recommended during pregnancy, especially during the first and third trimesters unless there are compelling reasons, and in these patients the benefits should be weighed against the possible hazards to the foetus, child or mother. Clinical experience of the use of amitriptyline in pregnancy has been limited. Animal studies have shown harmful effects at exceptionally high doses.

Breast feeding mothers: Amitriptyline is detectable in breast milk. Because of the potential for serious adverse reactions in infants from amitriptyline, a decision should be made whether to discontinue breast feeding or discontinue the drug.

Amitriptyline may impair alertness in some patients and activities made hazardous by diminished alertness (e.g. driving a car) should be avoided.

In general, amitriptyline is well tolerated. The side effects given below are essentially a combined list of all those of the tricyclic group of antidepressants. Some of them have not been reported with amitriptyline, but are included because of the similar pharmacologies of the group members. As the antidepressant effects of amitriptyline may not become apparent for the first 2-4 weeks of therapy, patients should be closely monitored during this period.

Blood and lymphatic system disorders: Bone marrow depression including agranulocytosis, leucopenia, eosinophilia, purpura, thrombocytopenia.

Immune system disorders: Skin rash, urticaria, photosensitisation, oedema of face and tongue.

Endocrine disorders: Testicular swelling, gynaecomastia, breast enlargement, galactorrhoea, increased or decreased libido, impotence, interference with sexual function, syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Metabolism and nutrition disorders: Elevation or lowering of blood sugar levels, weight loss, increased appetite and weight gain (may be a drug reaction or due to relief of the depression).

Nervous system disorders: Dizziness, weakness, drowsiness, fatigue, headache, confusional states, disturbed concentration, disorientation, delusions, hallucinations, hypomania, excitement, anxiety, restlessness, insomnia, nightmares, numbness, tingling and paraesthesia of the extremities, peripheral neuropathy, inco-ordination, ataxia, tremors, coma, convulsions, alteration of the ECG, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria, tinnitus. Cases of suicidal ideation and suicidal behaviours have been reported during amitriptyline therapy or early after treatment discontinuation (see section 4.4). Anticholinergic effects include: dry mouth, blurred vision, disturbance of accommodation, increased intra-ocular pressure, constipation, paralytic ileus, hyperpyrexia, urinary retention, urinary tract dilatation.

Eye disorders: mydriasis.

Cardiovascular disorders: Hypotension, syncope, postural hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke, non-specific ECG changes and changes in AV-conduction. Arrhythmias and severe hypotension are likely to occur with high dosage or overdose.

Gastro-intestinal disorders: Nausea, epigastric distress, vomiting, anorexia, stomatitis, unpleasant taste, diarrhoea, parotid swelling, black tongue.

Hepato-biliary disorders: Rarely hepatitis (including altered liver function and jaundice).

Skin and subcutaneous tissue disorders: Increased perspiration, alopecia.

Renal and urinary disorders: Urinary frequency.

Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Reports have associated gradual withdrawal with transient symptoms including irritability, restlessness, as well as dream and sleep disturbances during the first two weeks or dosage reduction. These symptoms are not indicative of addictions.

Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants in the last trimester of pregnancy.

Mania or hypomania has been reported rarely within 2-7 days of stopping chronic therapy with tricyclic antidepressants.

Side effects in enuresis: Dosages used in enuresis are low compared with those used in depression and side effects are therefore less frequent. The most common are drowsiness and anticholinergic effects. The only other side effects, reported infrequently at these dosages, have been mild sweating and itching. The recommended dosage must not be exceeded.

Class effects

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

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose will be potentiated by simultaneous ingestion of alcohol and other psychotropic drugs.

Overdose effects are mainly due to anticholinergic (atropine-like) effects at autonomic nerve endings and in the brain. There is also a quinidine-like effect on the myocardium.

Peripheral symptoms

Commonly include sinus tachycardia, hot dry skin, dry mouth and tongue, dilated pupils and urinary retention.

The most important ECG feature of toxicity is prolongation of the QRS interval, which indicates a high risk of ventricular tachycardia. In very severe poisoning the ECG may be bizarre. Rarely, prolongation of the PR interval or heart block may occur. QT interval prolongation and torsade de pointes has also been reported.

Central symptoms

Commonly include ataxia, nystagmus and drowsiness, which may lead to deep coma and respiratory depression. Increased tone and hyperreflexia may be present with extensor plantar reflexes. In deep coma all reflexes may be abolished. A divergent squint may be present.

Hypotension and hypothermia may occur. Fits occur in >5% of cases.

During recovery confusion, agitation and visual hallucinations may occur.

Management

An ECG should be taken and in particular the QRS interval should be assessed since prolongation signifies an increased risk of arrhythmia and convulsions. Give activated charcoal by mouth or naso-gastric tube if more than 4 mg/kg has been ingested within one hour, provided the airway can be protected. A second dose of charcoal should be considered after two hours in patients with central features of toxicity who are able to swallow.

Tachyarrhythmias are best treated by correction of hypoxia and acidosis. Even in the absence of acidosis 50 millimoles of sodium bicarbonate should be given by intravenous infusion to adults with arrhythmias or clinically significant QRS prolongation on the ECG.

Control convulsions with intravenous diazepam or lorazepam. Give oxygen and correct acid base and metabolic disturbances. Phenytoin is contraindicated in tricyclic overdosage, because, like tricyclic antidepressants, it blocks sodium channels and may increase the risk of cardiac arrhythmias. Glucagon has been used to correct myocardial depression and hypotension.

ATC Code: N06A A

Amitriptyline is a tricyclic antidepressant which mode of action in depression is not fully understood. It has anticholinergic and sedative properties.

It prevents the re-uptake of noradrenaline and serotonin at nerve terminals.

Amitriptyline is readily absorbed from the gastro intestinal tract. Peak plasma concentrations occur within about 6 hours of oral administration. Since amitriptyline slows gastro intestinal transit time, absorption may be delayed, particularly in overdosage. Amitriptyline is demethylated in the liver to the primary active metabolite, nortriptyline. The metabolism pathway includes N-oxidation and conjugation with glucuronic acid. It is distributed extensively into plasma and tissue protein. It has a half life from 9 to 25 hours. It will cross the placental barrier and is excreted in breast milk. It is excreted in urine in the form of metabolites.

None known

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Propylene glycol

Ascorbic acid

Orange flavour 10950-56 (contains ethanol).

Orange/tangerine flavour 10888-56 (contains ethanol).

Sucralose powder

Liquid maltitol

Purified water.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened: 24 months

After first opening: 1 month

Do not store above 25°C.

Store in the original bottle and outer carton in order to protect from light.

150 ml amber soda glass (type III) bottle fitted with a 28 mm white child resistant tamper evident cap, with expanded polyethylene (EPE) liner, and outer cardboard carton.

No special requirements.

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

25mg/5ml - PL 29831/0356

50mg/5ml - PL 29831/0439

UK: 27/08/2010

September 2010