SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

AMITRIPTYLINE TABLETS BP 50mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50mg Amitriptyline Hydrochloride.

3    PHARMACEUTICAL FORM

Tan film-coated tablets.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

1)    Symptoms of depressive illness (especially where sedation is required).

2)    Relief of nocturnal enuresis in children.

4.2    Posology and Method of Administration

Posology

Adults: Initially 50-75mg daily in divided doses or as a single dose at night, increasing to 150-200mg daily according to clinical response.

Maintenance dose 50-100mg at night which should be continued for at least three months to lessen chances of relapse.

Adolescents and the elderly: A lower strength dosage form is recommended for this group of patients. Half the normal maintenance dose may be sufficient to produce a satisfactory clinical response.

Children: For nocturnal enuresis only. A lower strength dosage is recommended for this group of patients.

Method of Administration For oral administration.

4.3 Contraindications

hypersensitivity to tricyclic antidepressants or to any of the ingredients in the tablets;

•    history of myocardial infarction, arrhythmias, particularly heart block to any degree, congestive heart failure, coronary artery insufficiency;

•    mania;

•    severe liver disease;

•    children under 7 years;

•    breast feeding;

•    patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.

4.4 Special warnings and precautions for use

The elderly are particularly liable to experience adverse reactions, especially agitation, confusion and postural hypotension.

Behavioural changes may occur in children receiving amitriptyline for the treatment of nocturnal enuresis.

Avoid if possible in patients with narrow angle glaucoma, urinary retention, hepatic insufficiency, blood dyscrasias, symptoms suggestive of prostatic hypertrophy and a history of epilepsy. 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. The dosage of all medications will need to be carefully adjusted. When used for the depressive component of schizophrenia, amitriptyline should be used with caution as it 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.

Unless essential, it is inadvisable to combine amitriptyline and electroconvulsive therapy (ECT).

Cardiac arrhythmias and severe hypotension are likely to occur with high dosages or in patients with pre-existing heart disease.

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 (see section 4.5).

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.

Suicidal thoughts and behaviours may also develop during early treatment with antidepressants for other disorders, the same precautions observed when treating patients with depression should therefore be followed when treating patients with other 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.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Enhances the sedative effect.

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

Altretamine: Risk of severe postural hypotension.

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).

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.

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.

Anticholinergics: 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.

Antidepressants: Concomitant use with MAOIs results in CNS excitation and hypertension. Severe convulsions and fatalities have occurred. Therefore, amitriptyline should not be given with a MAOI, and a minimum of 14 days should elapse between discontinuing a MAOI and starting amitriptyline. After this time, amitriptyline should be used 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.

Antiepileptics: Concomitant use of antiepileptics may lower the convulsive threshold. The plasma concentrations of some tricyclics may be reduced (eg by barbiturates, carbamazepine) resulting in reduced antidepressant effect.

Antifungals: Increased serum concentrations 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.

Antihypertensives: In general, the hypotensive effect is enhanced, but the effect of adrenergic neurone blockers (eg guanethidine, debrisoquine, bethanidine) and clonidine may be antagonised. There is an increased risk of hypertension on clonidine withdrawal. It is advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

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.

Antivirals: 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.

Anxiolytics and hypnotics: 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 of amitriptyline.

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.

Disulfiram: Concomitant use may inhibit the metabolism of tricyclics. Delirium has been reported in patients taking amitriptyline with disulfiram.

Diuretics: increased risk of postural hypotension.

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

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

Oestrogens andprogestogens: 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.

Sympathomimetics: 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.

Ulcer-healing drugs: Plasma concentrations of amitriptyline are increased by cimetidine (inhibition of metabolism).

4.6 Pregnancy and Lactation

The safety of amitriptyline during pregnancy and lactation has not been established. Amitriptyline should not be used during the first and third trimester and the hazards to the foetus, child or mother must be evaluated when considering the possible benefits of amitriptyline therapy during pregnancy. Clinical experience of the use of amitriptyline in pregnancy is 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 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.

4.7 Effects on Ability to Drive and Use Machines

Amitriptyline may initially impair alertness. Patients should be warned of the performance of potentially hazardous tasks such as driving a car or operating machinery.

4.8 Undesirable effects

In general, amitriptyline is well tolerated. Not all of the side-effects listed below have been reported with amitriptyline but are included due to the similar pharmacology of other tricyclics. Antidepressant effects of amitriptyline may

not become apparent for the first 2-4 weeks of therapy so patients should be closely monitored during this period.

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

Blood and lymphatic system disorders: Bone marrow depression including agranulocytosis, eosinophilia, leucopenia, thrombocytopenia and purpura. Endocrine disorders: Gynaecomastia, breast enlargement, galactorrhoea, testicular swelling, libido fluctuations, interference with sexual function, syndrome of inappropriate ADH secretion.

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

Nervous system disorders: Dizziness, fatigue, headache, drowsiness, weakness, 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 effects, 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, hyperpyrexia, blurred vision, accommodation disturbance, increased intra-ocular pressure, mydriasis, constipation, paralytic ileus, urinary retention, urinary tract dilatation.

Cardiovascular disorders: Postural hypotension, hypertension, palpitations, tachycardia, myocardial infarction, heart block and stroke. Arrhythmias and severe hypotension are likely to occur with high doses or overdosage. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, epigastric distress, anorexia, dysgeusia, stomatitis, parotid swelling, black tongue.

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

Skin and subcutaneous tissue disorders: Increased perspiration and alopecia. Renal and urinary disorders: Urinary frequency.

Class effects

Epidemiological studies show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this increased risk is unknown.

Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Gradual withdrawal has been associated with transient symptoms such as dream and sleep disturbances, irritability and restlessness during the first two weeks of dosage reduction. These are not thought to be signs associated with addiction.

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 to 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.

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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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, atropinelike) 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, nonspecific 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.

For further information or treatment in children discuss with your local poisons information service: in the UK NPIS 0844 892 0111, in Ireland NPIC (01) 809 2566.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Amitriptyline hydrochloride is a tricyclic antidepressant.

5.2    Pharmacokinetic properties

Amitriptyline is readily absorbed from the GI tract, peak plasma levels occurring within ~ 6 hours of oral administration. Amitriptyline is extensively demethylated in the liver to its primary metabolite, nortriptyline. Paths of metabolism include hydroxylation, N-oxidation and conjugation with glucuronic acid. It is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.

5.3    Preclinical safety data

There are no pre-clinical 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

The tablets contain: lactose monohydrate, microcrystalline cellulose (E460), maize starch, colloidal anhydrous silica, magnesium stearate.

The coating contains: hypromellose (E464), macrogol, talc (E553b), titanium dioxide (E171), quinoline yellow (E104), iron oxide (E172).

6.2    Incompatibilities

None known.

6.3    Shelf life

A three year shelf-life is claimed and our marketed products includes a three year expiry date.

6.4    Special precautions for storage

Store below 25°C in a dry place. Protect from light.

6.5    Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs and cartons:

a)    Carton: Printed carton manufactured from white folding box board.

b)    Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-6g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE

N Devon EX32 8NS

8    MARKETING AUTHORISATION NUMBER(S)

PL 00142/0178

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17.April.1984 / 28.October.2002

10    DATE OF REVISION OF THE TEXT

20/05/2015