Amitriptyline 10mg Film-coated Tablets

Each tablet contains Amitriptyline HCl 10.00mg.

For a full list of excipients, see section 6.1.

Film-coated tablet

Blue coloured, round, biconvex, film-coated tablets plain on both sides.

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

-Nocturnal enuresis where organic pathology is excluded.

Orally

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

Adults:

Initial dose:

Usually 75mg daily in divided doses (or a single dose at night). This may be increased if necessary to a total of 150mg a day, with the additional doses being given in the late afternoon and/or 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 50-100mg 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 10-25mg three times daily is recommended, which should be increased slowly. A daily dosage of 50mg may be satisfactory in elderly patients who may not tolerate higher doses. The required dosage may be administered either as divided doses or as 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 6-10 years may receive 10-20mg a day, while those aged 11-16 years may need 25mg-50mg a day.

Treatment should not exceed three months.

Hypersensitivity to tricyclic antidepressants or to any of the ingredients in the tablets

Patients who are taking mono-amine 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; congestive heart failure, coronary artery insufficiency, mania; severe liver disease, porphyria, lactation; children under 7 years. Breast feeding (See also “Use in pregnancy” and “Precautions”).

Amitriptyline should be used with caution in patients with a history of epilepsy, and 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, blood dyscrasias, narrow-angle glaucoma, or increased intra-ocular 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.

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

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.

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, 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. 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 (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.

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 co-morbid 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 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.

Excipient Warnings

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

The concurrent use of anti-depressants 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 anti-depressants 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. Concomitant use of reboxetine should be with caution. The plasma concentrations of some tricyclics are increased by SSRIs. Fluoxetine markedly inhibits Cytochrome 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.

Alpha₂-adrenoceptor stimulants: Concomitant use of apraclonidine and brimonidine should be avoided.

Altretamine: Risk of severe postural hypotension.

Analgesics: There is a possibility of increased side effects with nefopam. The risk of CNS toxicity is increased with tramadol. There is a possibility of increased sedation with opioid analgesics.

Anaesthetics: Concomitant 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 (see section 4.4).

Anti-arrhythmics: there is an increased risk of ventricular arrhythmias with drugs which prolong the QT interval, including amiodarone (avoid concomitant use), disopyramide, procainamide, propafenone and quinidine.

Antibacterials: Plasma concentrations of some tricyclics are reduced by rifampicin (reduces antidepressant effect). Concomitant use with linezolid may result in CNS excitation and hypertension.

Amitriptyline may block the antihypertensive action of guanethidine, debrisoquine, bethanidine and possibly clonidine. There is an increased risk of hypertension on clonidine withdrawal. All antihypertensive therapy should be reviewed during treatment with tricyclic antidepressants.

Amitriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine, and phenylpropanolamine due to hypertension and arrhythmias. Local anaesthetics with adrenaline appear to be safe. Methylphenidate may inhibit the metabolism of tricyclics and therefore increase the antidepressant action of amitriptyline.

Amitriptyline may enhance the response to alcohol, barbiturates and other CNS depressants. Concomitant use of disulfiram may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.

Concomitant use of antiepileptics may lower the convulsive threshold. Barbiturates and carbamazepine may decrease, and methylphenidate may increase, the antidepressant action of amitriptyline.

Antifungals: Increased serum concentraions have occurred in patients also taking Fluconazole. Serious adverse effects have been reported due to increased amitriptyline plasma concentration.

Antihistamines: Increased anticholinergic and sedative effects. Concomitant use of terfenadine should be avoided due the increased risk of ventricular arrhythmias.

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 concomitantly.

Antipsychotics: Increased risk of ventricular arrhythmias. Avoid concomitant use with pimozide or thioridazine. Concomitant use with antipsychotics may increase plasma concentrations of tricyclic antidepressants and increase the anticholinergic side-effects of phenothiazines and possibly clozapine.

Beta-blockers: There is an increased risk of ventricular arrhythmias associated with concomitant use of sotalol.

Calcium-channel blockers: Diltiazem and verapamil may possibly increase the plasma concentration of amitriptyline.

Diuretics: increased risk of postural hypotension.

Dopaminergics: Concomitant use with entacapone should be avoided. CNS toxicity has been reported with selegiline.

Muscle relaxants: Concomitant use of baclofen enhances its muscle relaxant effect.

Nitrates: Reduced effect of sublingual nitrates (owing to dry mouth).

Oestrogens and progestogens: Oral contraceptives antagonise the antidepressant effect but side-effects may be increased due to increased plasma concentrations of tricyclics.

Sibutramine: Concomitant use is not recommended due to the increased risk of CNS toxicity.

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.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants.

Concomitant use enhances the sedative effect.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 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 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. 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.

Breast feeding mothers: Amitriptyline is detectable in breast milk at high doses. 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 or operating machinery) should be avoided.

In general amitriptyline is well tolerated. 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.

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

Nervous system disorders; Dizziness,Weakness, fatigue, headache, drowsiness 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, coma, convulsions, altered EEG, extra-pyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria and 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: Blurred vision, accommodation disturbance, increased intra-ocular pressure, mydriasis, constipation, paralytic ileus, urinary retention, urinary tract dilation, hyperpyrexia and dry mouth.

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

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

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

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

Endocrine disorders; Gynecomastia, breast enlargement, galactorrhoea, testicular swelling, changes in libido, impotence,interference with sexual function, syndrome of inappropriate ADH secretion.

Skin and subcutaneous tissue disorders: increased perspiration, alopecia

Renal and urinary disorders: urinary frequency

Metabolism and nutrition disorders: Increased appetite and weight gain may be a drug reaction or due to relief of depression, elevation or lowering of blood sugar levels, weight loss,

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.

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 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 have 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. The recommended dosage must not be exceeded.

There is no specific antidote for tricyclic antidepressant poisoning. Patients should be hospitalised and treatment should be symptomatic and based on cardiac (including ECG monitoring) and respiratory support.

Symptoms

Toxicity is due to a combination of anticholinergic (antimuscarinic, atropine-like) effects at autonomic nerve endings and in the brain, cardiac sodium channel blockade and a1 adrenergic receptor blockade. In addition, tricyclic antidepressants block pre-synaptic uptake of amines and the cardiac delayed rectifier potassium channel (Ikr).

Features commonly include: sinus tachycardia, hot dry skin, dry mouth and tongue, dilated pupils, urinary retention and ileus, progressing to ataxia, nystagmus, divergent squint 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 (including brain-stem reflexes) may be abolished. Convulsions occur in >5% of cases and may herald haemodynamic compromise.

ECG features include prolongation of the PR, QRS and QT intervals, non-specific ST segment and T wave changes and atrioventricular block.

Metabolic acidosis may be present. Hypotension may occur and may be severe.

Hypothermia and rhabdomyolysis may occur in patients who have been unconscious. Occasionally skin blisters may occur.

During recovery confusion, agitation and visual hallucinations may occur.

Features of serotonin toxicity may occur. These include CNS effects (including agitation or coma), autonomic instability (including hyperpyrexia), and neuromuscular excitability (including clonus and raised serum creatine kinase)

This syndrome is more likely to occur if the patient has been exposed to two or more drugs that increase the effect of serotonin in serotonergic synapses (by increasing release, reducing reuptake or metabolism, or stimulating serotonin receptors), either as an acute overdose or if taken regularly, for example - SSRIs, MAOIs, tricyclic antidepressants, venlafaxine, tramadol, triptans, linezolid and St John's Wort; stimulant drugs of abuse (e.g. MDMA (ecstasy), amphetamines, cocaine, cathinone derivatives (mephedrone, etc)).

The cardiovascular and CNS effects in overdose will be potentiated by simultaneous ingestion of alcohol, cardiovascular agents and other psychotropic drugs

Management

Do not give flumazenil to reverse benzodiazepine toxicity in mixed overdoses.

1. Ensure a clear airway and adequate ventilation. Check arterial blood gases and correct any hypoxia. If hypercapnia is present assisted ventilation is indicated.

2. The benefit of gastric decontamination is uncertain. Consider activated charcoal by mouth or naso-gastric tube if the patient presents within 1 hour of ingestion of more than 5mg/kg, provided the airway can be protected.

A second dose of charcoal should be considered after 1 -2 hours in patients with features of toxicity who are able to swallow, or who have been intubated.

3. After cardiac arrest, prolonged resuscitation may be successful and should be continued for at least 1 hour.

4. Observe for at least 6 hours after ingestion. Monitor BP, pulse and cardiac rhythm. Repeat ECGs should be performed. Patients who remain asymptomatic and have a normal ECG by 6 hours are unlikely to develop late complications.

5. Check urea and electrolytes and monitor urine output. Check serum creatine kinase in patients who have been unconscious.

6. If metabolic acidosis persists despite correction of hypoxia and adequate fluid resuscitation consider correction with intravenous sodium bicarbonate. Rapid correction is particularly important if there is prolongation of the QRS or QT intervals.

7. Control convulsions with intravenous diazepam or lorazpam. Give oxygen and correct acid base and metabolic disturbances. Phenytoin is contraindicated in tricyclic overdosage (because in common with TCAs it blocks sodium channels and may increase the risk of cardiac arrhythmias).

8. Correct hypotension by raising the foot of the bed. In severe cases administration of colloid to expand the intravascular volume is required (central venous pressure monitoring may be required). Alkalinisation with sodium bicarbonate may correct hypotension.

9. Agitated adults can be sedated with oral or IV diazepam. If ineffective consider oral or parenteral haloperidol.

10. Glucagon 10mg IV bolus may be given if patients are severely hypotensive.

11. If the patient is hypothermic, rewarm slowly using conventional means.

12. Monitor for rhabdomyolysis if the patient has been unconscious for a considerable time.

13. Forced diuresis, haemodialysis and haemoperfusion are of no value due to the large volume of distribution of tricyclic antidepressants.

14. Other measures as indicated by the patient's clinical condition.

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 medicament.

Pharmacotherapeutic Group: Tricyclic Antidepressants

ATC code: N06AA09

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 serotonin in the CNS by inhibiting their re-uptake by the pre-synaptic neuronal membrane.

Amitriptyline is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring within about 6 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 demethylated in the liver to its primary active metabolite, nortriptyline. The metabolism pathway includes N-oxidation and conjugation with glucuronic acid. Amitriptyline and nortriptyline are widely distributed throughout the body and are very highly bound to plasma and tissue protein. The estimated half-life of amitriptyline is 9-25 hours. It will cross the placental barrier and is excreted in breast milk. It is excreted in urine in the form of metabolites.

There are no preclinical data of relevance to the prescriber, other than that presented in other parts of the SPC.

Core Tablet

Lactose Monohydrate

Microcrystalline Cellulose (PH 102)

Maize Starch

Magnesium Stearate

Colloidal Anhydrous silica

Film Coat:

Hydroxy Propyl Methylcellulose

Ethyl Cellulose

Diethyl pthalate

Titanium Dioxide ( E171 )

Lake of Indigo Carmine (E 132)

Purified Talc

None known

3 years

Container pack: Do not store above 25°C.

Store in the original container. Keep the container tightly closed.

Blister pack: Do not store above 25°C. Store in the original package.

1. High density polystyrene container with polythene lid and polyurethene / polythene insert. Pack size 100 and 500 Tablets

2. Polypropylene container with polypropylene or polythene lids and polyurethene / polythene insert. Pack size 100 and 500 Tablets.

3. Blister pack of PVC/PVdC – Aluminium ,containing 28 tablets

Not all the pack sizes may be marketed

No special instructions

ACCORD HEALTHCARE LIMITED

SAGE HOUSE

319 PINNER ROAD

HARROW

MIDDLESEX

HA1 4HF

UNITED KINGDOM

PL 20075/0034

26^th April 2005

02-Mar-2012