SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

ELAVIL/Amitriptyline Tablets 25 mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Amitriptyline HC1 BP 25.00 mg

3    PHARMACEUTICAL FORM

Film-coated Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Symptoms of depression (especially where sedation is required), also effective in nocturnal enuresis in children

4.2    Posology and method of administration

Adults Initial dose:

Usually 75 mg daily in divided doses (or a single dose at night). This may be increased if necessary to a total of 150-200 mg a day, with the additional doses being given in the late afternoon and/or at bedtime.

The sedative effect is usually rapidly apparent, while antidepressant activity may be seen within three or four days or may take up to 30 days to develop adequately.

Maintenance dose:

The usual maintenance dosage is 50-100 mg daily. 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 chances of relapse.

Elderly:

In general lower dosages are recommended for these patients as they are more prone to side effects, especially confusion, agitation and postural hypotension. An initial dosage of 10-25 mg three times daily is recommended, which should be increased slowly. A daily dosage of 50 mg may be satisfactory in elderly patients who may not tolerate higher dosages. The required dosage may be administered either as divided doses or a single dose preferably in the evening or at bedtime.

Children:

Not recommended for treatment of depression in children under 16 years of age due to lack of clinical experience.

Enuresis:

Children from 7-10 years may receive 10-20 mg a day, while those aged 11-16 years may need 25-50 mg a day. Treatment should not exceed three months.

Route of administration: Oral.

4.3 Contraindications

Patients who are taking monoamine oxidase inhibitors or who have received them within the last two weeks; prior sensitisation to Amitriptyline; during the recovery phase after myocardial infarction; arrhythmias, particularly heart block of any degree; mania; severe liver disease; porphyria; lactation; children under 7 years of age.

4.4 Special warnings and precautions for use

Amitriptyline should be used with caution in patients with a history of epilepsy, phaeochromocytoma, porphyria and in those with impaired liver function. Due to its atropine-like action, it should be used with caution in patients with a history of urinary retention, prostatic hypertrophy, narrow-angle glaucoma, or increased intraocular pressure. Even average doses may precipitate an attack of glaucoma in patients with narrow-angle glaucoma.

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

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 know 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.

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

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

If possible, amitriptyline should be discontinued several days before surgery. If emergency surgery is unavoidable, the anaesthetist should be informed that the patient is being treated with amitriptyline, since anaesthesia may increase the risk of hypotension and arrhythmias.

Abrupt withdrawal of Amitriptyline should be avoided.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The concurrent use of antidepressants having various mechanisms of action should be undertaken only with due recognition of their possible potentiation and with a thorough knowledge of their pharmacology.

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 an MAOI and starting Amitriptyline, which should be introduced cautiously and dosage increased gradually. Antidepressant SSRI’s such as Fluoxetine markedly inhibit Cyt P450 II D6, which is involved in the metabolism of a number of tricyclic antidepressants. Patients should be monitored for increased antidepressant plasma levels and toxicity when Fluoxetine is used concurrently. Adjustment of the antidepressant dosage may be necessary.

Amitriptyline may block the antihypertensive action of adrenergic neurone blocking agents (e.g. guanethidine, debrisoquine, bethanidine) and possibly clonidine. All antihypertensive therapy should be reviewed during treatment with tricyclic antidepressants.

Anti-arrhythmics such as amiodarone and disopyramide, which prolong the QT interval, increase the risk of ventricular arrhythmias.

Amitriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine, due to enhanced pressor response to these agents.

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

Excessive anticholinergic effects may occur when tricyclic antidepressants are combined with anticholinergic drugs. Paralytic ileus, urinary retention or acute glaucoma may be precipitated, especially in elderly patients.

The metabolism of tricyclic antidepressants, including Amitriptyline, is accelerated by anti-epileptics and the anticonvulsant effect of anti-epileptics such as Primodone is reduced.

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 concurrently.

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 1 g ethchlorvynol and 75 mg to 150 mg of Amitriptyline.

Pregnancy and lactation

The safety of Amitriptyline for use during pregnancy and lactation 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 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. Withdrawal symptoms, including respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants during the last trimester of pregnancy. Urinary retention in the neonate has also been associated with maternal use of Amitriptyline.

Amitriptyline is detectable in breast milk. It should be avoided while breastfeeding due to the potential for serious adverse reactions in the infant.

4.7 Effects on ability to drive and use machines

Amitriptyline may impair alertness and enhance the CNS depressant effect of alcohol. Activities made hazardous by diminished alertness should be avoided.

4.8 Undesirable effects

In general, Amitriptyline is well tolerated. The most common side effects of amitriptyline are a dry mouth, rashes, hypotension, confusion, hallucinations and jaundice.

The side effects stated below include those of the tricyclic group of antidepressants in general. Not all of them have been reported with Amitriptyline, but are included due to similar pharmacology 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.

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

Cardiovascular: Postural hypotension, hypertension, palpitations, tachycardia, myocardial infarction, heart block, syncope and stroke. Arrhythmias and severe hypotension are likely to occur with high doses or overdosage.

CNS and Neuromuscular: Disturbed concentration, disorientation, confusional states, insomnia, nightmares, delusions, hallucinations, hypomania, excitement, anxiety, restlessness, peripheral neuropathy, numbness, tingling and paraesthesia of the extremities, inco-ordination, ataxia, tremors, convulsions, altered ECG, extrapyramidal symptoms including dyskinesia and tinnitus.

Anticholinergic: Blurred vision, accommodation disturbance, increased intra-ocular pressure, mydriasis, constipation, paralytic ileus, urinary retention, urinary tract dilatation, hyperpyrexia and dry mouth.

Allergic: Skin rash, urticaria, photosensitisation, oedema of face and tongue.

Haematological: Bone marrow depression including agranulocytosis, eosinophilia, leucopenia, thrombocytopenia, hyponatraemia and purpura.

Gastro-intestinal: Nausea, vomiting, diarrhoea, epigastric distress, anorexia, constipation, stomatitis, parotid swelling, black tongue, rarely hepatitis (including altered liver function and jaundice).

Endocrine: Gynaecomastia, breast enlargement, galactorrhoea, testicular swelling, changes in libido, interference with sexual function, elevation or lowering of blood sugar levels, syndrome of inappropriate ADH secretion.

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.

Other reactions: Weakness, fatigue, headache, fever, increased perspiration, urinary frequency, alopecia, and drowsiness. Increased appetite and weight gain (or occasionally loss) may be a drug reaction or due to relief of depression. Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise.

Gradual withdrawal of amitriptyline has been associated with transient symptoms such as irritability, restlessness, and dream and sleep disturbances during the first two weeks of dosage reduction. These are not thought to be signs associated with addiction.

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

Side effects in enuresis: As dosages used in enuresis are low compared with those used for depression, side effects are less frequent. The most common are drowsiness and anticholinergic effects. Infrequently, mild sweating and itching have been reported. Behavioural changes have been observed in children receiving tricyclics for treatment of enuresis.

4.9 Overdose

High dosage may cause transient visual hallucinations, temporary confusion and disturbed concentration. Overdosage may cause tachycardia, other arrhythmic abnormalities such as bundle branch block, ECG evidence of impaired conduction, congestive heart failure, severe hypotension, dilated pupils, drowsiness, hypothermia, convulsions, stupor and coma. Other symptoms may include agitation, hyperactive reflexes, muscle rigidity, vomiting, hyperpyrexia, or any of the other side effects listed previously.

Persons suspected of having taken an overdose should be admitted to hospital as soon as possible, where treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible by emesis. Gastric lavage should be performed upon arrival at hospital, and may be followed by activated charcoal during the first 24-48 hours at a dosage of 20-30 g every four to six hours. An ECG should be taken and cardiac function closely monitored if there is a sign of abnormality. An open airway and an adequate fluid intake should be maintained, and body temperature regulated.

Intravenous physostigmine salicylate, 1-3 mg, has been reported to reverse the symptoms of tricyclic antidepressant poisoning. Because it is rapidly metabolised, the dosage of physostigmine should be repeated as required, particularly if life-threatening signs such as arrhythmias, convulsions and deep coma recur or persist after the initial dose. Since physostigmine itself may be toxic, it is not recommended for routine use.

Standard measures should be used to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine or propranolol. Should cardiac failure occur, use of digitalis should be considered. Close monitoring of cardiac function should occur for at least five days.

Convulsions, if they occur, should be treated with paraldehyde, diazepam or an inhalation anesthetic. Barbiturates should not be used because Amitriptyline increases their CNS depressant action.

Dialysis is of no value due to the high degree of protein binding of Amitriptyline. Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental overdosage have occurred with this class of medicines.

5.1    Pharmacodynamic properties

Amitriptyline is a tricyclic antidepressant with marked anticholinergic and sedative properties. Its mode of action in depression is not fully understood, though it is thought to increase the synaptic concentration of noradrenaline and serotinin in the CNS by inhibiting their re-uptake by the presynaptic neuronal membrane.

5.2    Pharmacokinetic properties

Amitriptyline is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring within 4-8 hours of oral administration.

Since Amitriptyline slows gastro-intestinal transit time, absorption may be delayed, particularly in overdosage. Onset of antidepressant activity takes 2-3 weeks.

Amitriptyline is extensively metabolized in the liver by hydroxylation and by demethylation to its primary active metabolite, nortriptyline. Amitriptyline is excreted in the urine, mainly in the form of the metabolites, either in conjugated or non-conjugated form. Amitriptyline and nortriptyline are widely distributed throughout the body and very highly bound to plasma and tissue protein. The estimated half-life of Amitriptyline is 9 to 25 hours, which may be considerably extended in overdosage. Plasma concentrations of Amitriptyline and nortriptyline vary widely between individuals and no simple correlation with therapeutic response has been established.

Amitriptyline and nortriptyline cross the placental barrier and are excreted in breast milk.

5.3 Preclinical safety data

There are no relevant preclinical safety data to this application.

6 PHARMACEUTICAL PARTICULARS

List of excipients

Lactose; calcium hydrogen phosphate; maize starch; microcrystalline cellulose; colloidal anhydrous silica; stearic acid, magnesium stearate; quinoline yellow (E104); sunset yellow (E110)); Titanium Dioxide (E171); hydroxypropylmethylcellulose 5cps; ethylcellulose l0cps; diethylphthalate; Opaspray K-1F-3048.

6.2    Incompatibilities

None known.

6.3    Shelf life

36 months.

6.4    Special precautions for storage

Store in a dry place below 25 °C.

6.5    Nature and contents of container

High density polystyrene with polythene lids and/or polypropylene or polythene lids and polyurethane/polythene inserts, containing 100 or 500 tablets.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Chelonia Healthcare Limited

11 Boumpoulinas Street, 3^rd floor, 1060 Nicosia Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0006

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/12/1976

10    DATE OF REVISION OF THE TEXT

20/09/2010