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Amitriptyline 25mg Tablets Bp

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Amitriptyline 25mg Tablets BP.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg of Amitriptyline Hydrochloride For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM

Coated tablet.

Appearance: Pale yellow, circular, biconvex, sugar coated tablet.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications:

•    Amitriptyline is an anti-depressant drug of the tricyclic group.

•    It is indicated by symptoms of a depressive illness especially when sedation is required.

•    Amitriptyline is also effective in nocturnal enuresis where organic pathology is excluded

4.2    Posology and method of administration Adults:

Initially 75 mg per day in divided doses, or as a single dose at night, increasing to 150 mg per day according to clinical response, with the additional doses being given in the late afternoon and/or bedtime.

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

Maintenance dose:

50 - 100 mg at night which should be continued for at least three months to lessen chances of relapse. When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms.

Elderly:

In general lower dosages are recommended for these patients as they are more prone to side effects, especially confusion, agitation, and postural hypotension. A dose of 10 - 25 mg three times a day initially or as a single dose at night.

The initial dose should be increased with caution under close supervision.

Half the normal maintenance dose may be sufficient to produce a satisfactory clinical response.

Children (for nocturnal enuresis only):

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

6-10 years:    25 mg 30 minutes before bedtime.

11-16 years:    25 - 50 mg 30 minutes before bedtime.

The maximum period of treatment should not exceed three months. A further course of treatment should not be started until a full physical examination, including an ECG, has been made.

4.3 Contraindications:

Hypersensitivity to tricyclic antidepressants or to any of the ingredients in the tablets such as Lactose and Sucrose that may be unsuitable for those people with Lactose insufficiency galacrosaemia or an impact on blood sugar levels due to sucrose content.

Co-administration with monoamine oxidase inhibitors or who have received them within the last two weeks; prior sensitisation to amitriptyline; during the recovery phase after myocardial infarction; congestive heart failure, coronary artery insufficiency; arrhythmias, particularly heart block of any degree; mania; severe liver disease; lactation; children under 7 years of age; porphyria.The concomitant use of tricyclic antidepressants with amiodarone or sibutramine.

Amitriptyline tablets also contain sunset yellow E110 and can cause allergy type reactions including asthma. Allergy is more common in those are allergic to aspirin. Breast feeding (See also “Use in pregnancy” and “Precautions”).

4.4 Special warnings and precautions for use

General: Amitriptyline should be used with caution in patients with a history of epilepsy or recent convulsions, porphyria, phaeochromocytoma, in patients with impaired liver function and, because of its atropine-like action, in patients with a history of urinary retention, blood dyscrasias, 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.

There has been a report of fatal dysrhythmia occurring as late as 56 hours after amitriptyline overdose.

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 (see section 4.5).

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

Hyperpyrexia has been reported when tricyclic anti-depressants are administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.

Elderly patients are particularly liable to experience adverse reactions: especially agitation, confusion and postural hypotension. The initial dose should be increased with great caution under close supervision.

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

Cardiovascular/endocrine disorders: 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 when amitriptyline is given concurrently (see section 4.5).

Central nervous system disorders: 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.

Use in children: Behavioural changes have been observed in children receiving tricyclics for the treatment of enuresis.

Unless essential it is inadvisable to combine amitriptyline and electroconvulsive therapy (ECT) [see section 4.5 “Interactions”]

Abrupt withdrawal of amitriptyline should be avoided (see section 4.8 “Undesirable Effects, Other reactions”)

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, Endocrine’^

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, Such patients require careful supervision 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 care givers 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

Altretamine: Concurrent administration of altretamine and tricyclic antidepressants may cause severe orthostatic hypotension.

Analgesics: caution should be exercised when nefopam is administered concurrently with tricyclic antidepressants. Tramodol may increase the potential for tricyclic antidepressants to cause convulsions. The concurrent administration of opioid analgesics with the tricyclic antidepressants may lead to increased sedation. Levacetylmethadol should not be used concomitantly with amitriptyline due to the increased risk of ventricular arrhythmias.

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

Antibacterial: The plasma concentration of some tricyclic antidepressants may be reduced by rifampicin (reduces antidepressant effect). Concomitant use with linezolid may result in CNS excitation and hypertension.

Antihypertensives: Amitriptyline may block the antihypertensive action of guanethidine, debrisoquine, bethanidine, and possibly clonidine. There is an increased risk of postural hypotension if diuretics are given concomitantly with tricyclic antidepressants. It would be advisable to review all antihypertensive therapy during treatment with tricyclic antidepressants.

Anticholinergic agents/sympathomimetic drugs: 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.

Excessive anticholinergic effects may occur when tricyclic antidepressants are combined with anticholinergic drugs. Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with drugs having an anticholinergic action. Urinary retention or acute glaucoma may be precipitated especially in elderly patients.

Antifungal: 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.

Antipsychotics: There is an increased risk of ventricular arrhythmias if thioridazine or pimozide are taken concomitantly with tricyclic antidepressants. Concurrent administration with phenothiazines may lead to increased plasma concentrations of tricyclic antidepressants and increased antimuscarinic side effects of phenothiazines and possibly clozapine.

Antiepileptic: Tricyclic antidepressants may precipitate seizures in susceptible patients and the dosage of antiepileptic may need to be adjusted. The plasma concentration of some tricyclic antidepressants may be reduced by antiepileptic (e.g. by barbiturates, carbamazepine).

Antiviral: 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.

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

Central nervous system depressants: Amitriptyline may enhance the depressant action of alcohol, barbiturates, and other CNS depressants. In turn, barbiturates may decrease, and methylphenidate may increase, the antidepressant action of amitriptyline. Caution is advised if patients receive large doses of ethchlorvynol concurrently as transient delirium has been reported in patients receiving 1 g ethchlorvynol and 75 - 150 mg of amitriptyline.

Cimetidine: Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants when taken concurrently resulting in increased plasma concentration of amitriptyline..

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

Disulfiram: Concomitant use enhances the sedative effect. Delirium has been reported in patients taking amitriptyline with disulfiram. Concomitant use may inhibit the metabolism of tricyclics. Increased plasma concentrations and increased disulfiram reaction has been reported in patients taking amitriptyline, alcohol and disulfiram concomitantly.

Diuretics: increased risk of postural hypotension.

Dopaminergics: The concomitant use of entacapone with tricyclic antidepressants is not recommended. Severe CNS toxicity has been reported in patients with the combination of tricyclic antidepressants and selegiline.

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

Muscle relaxants: The use of baclofen and tricyclic antidepressants may result in the potentiation of the effect of baclofen resulting in pronounced muscular hypotenia.

Nitrates: The effectiveness of sublingual and buccal tablets preparations may be reduced by drugs that cause dry mouth since dissolution may be delayed.

Other antidepressant drugs: 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 cases of 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. CNS excitation and hypertension have occurred with MAOIs.

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.

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

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

Thyroid preparations e.g. levothyroxine: the action of tricyclic antidepressants such as amitriptyline may be accelerated by the concurrent use of thyroid hormone medication (see section 4.4).

Concurrent administration of amitriptyline with electroconvulsive therapy should be limited to patients for whom it is considered essential, as the hazards of each treatment may be increased.

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

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

4.6 Fertility, pregnancy and lactation

There is no, or inadequate evidence of safety of the drug in human pregnancy; although it has been in wide use for many years without apparent ill-consequence. Withdrawal symptoms, including respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants during the last trimester of pregnancy. Do not use during the first and third trimester or in nursing mothers unless there are compelling reasons, and in these patients the benefits should be weighed against the possible hazards to the foetus, child or mother. There is evidence of harmful effects in pregnancy in animals, when given in exceptionally high doses. Urinary retention in the neonate has also been associated with maternal use of amitriptyline.

Breast feeding mothers: Amitriptyline is detectable in breast milk. Because of the potential 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 not to drive or operate machinery until it has been established that their alertness is not impaired.

4.8 Undesirable effects

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.

Cardiac disorders: Syncope, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke, non-specific ECG changes and changes in AV conduction. Cardiac arrhythmias and severe hypotension are likely to occur with high dosage or over dosage. They may also occur in patients with pre-existing heart disease taking normal dosage.

Vascular disorders: Hypotension, postural hypotension, hypertension

Nervous system disorders: Dizziness, weakness, fatigue, headache, disturbed concentration, drowsiness, numbness, tingling, and paraesthesiae of the extremities, peripheral neuropathy, in coordination, ataxia, tremors, coma, convulsions, alteration of the EEG, extra pyramidal symptoms, including abnormal involuntary movements and tardive dyskinesia, dysarthria, Mania or hypomania has been reported rarely within 2-7 days of stopping chronic therapy with tricyclic antidepressants.

Psychiatric disorders: Confusional states, disorientation, delusions, hallucinations, hypomania, excitement, anxiety, restlessness, drowsiness, insomnia, nightmares.

Ear and labyrinth disorders: 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: Dry mouth, blurred vision, mydriasis, disturbance of accommodation, increased intra-ocular pressure, constipation, paralytic ileus, hyperpyrexia, urinary retention, urinary tract dilatation.

Immune system disorders: Allergic reactions oedema of face and tongue.

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

Gastro-intestinal: Nausea, epigastric distress, vomiting, anorexia, dysgeusia stomatitis, unpleasant taste, diarrhoea, parotid swelling, black tongue, constipation, paralytic ileus.

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

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

Skin and subcutaneous tissue disorders: Skin rash, urticaria, photosensitisation, 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,

Investigations: elevation or lowering of blood sugar levels, weight gain may be a drug reaction or due to relief of depression.

Confusion may occur at high doses or in elderly patients requiring reduction of dosage.

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

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

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.

Side effects - causal relationship unknown: The following additional side-effects have been reported; however, a causal relationship to therapy with amitriptyline has not been established: lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor).

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.

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose:

There is no specific antidote for tricyclic antidepressant poisoning. All persons suspected of having taken an over dosage should be admitted to hospital as soon as possible. Treatment is symptomatic and supportive based on cardiac (including ECG monitoring) and respiratory.

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 presynaptic uptake of amines and the cardiac delayed rectifier potassium channel (Ikr).

Features commonly include: hot dry skin, dry mouth and tongue, 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 haemo-dynamic compromise. Hypothermia; tachycardia and other arrhythmic abnormalities such as bundle branch block; congestive heart failure; ECG evidence of impaired conduction; dilated pupils; disorders of ocular motility, severe hypotension; stupor, and polyadiculoneuropathy; constipation.

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

Standard measures should be employed to manage circulatory shock and metabolic acidosis. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine or propranolol. If cardiac failure occurs, use of digitalis should be considered. It is advisable to closely monitor cardiac function for at least five days.

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

High doses of amitriptyline may cause temporary confusion, disturbed concentration, or transient visual hallucinations.

Other symptoms which may occur include agitation, muscle rigidity, hyperactive reflexes, hyperpyrexia, vomiting or any of the effects listed in the section on undesirable effects above.

The stomach should be emptied as quickly as possible by emesis, followed by gastric lavage once in hospital.

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.

If convulsions occur, they should be treated with paraldehyde, diazepam or an inhalation anaesthetic. Barbiturates should not be used because amitriptyline increases their CNS-depressant action.

Management

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

1.    An open airway and an adequate fluid intake should be maintained; body temperature should be regulated. Check arterial blood gases and correct any hypoxia. If hypercapnia is present assisted ventilation is indicated.

2.    Following gastric lavage, oral administration of activated charcoal during the first 24 - 48 hours at a dosage of 20 - 30 g every four to six hours has been shown to reduce the delayed toxic effects due to enterohepatic circulation and slow absorption.

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 the cardiac function should be monitored closely if there is any sign of abnormality. Repeat ECG should be taken. 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.    Physostigmine salicylate, 1-3 mg, given intravenously has been reported to reverse the symptoms of tricyclic antidepressant poisoning. Because of the rapid metabolism of physostigmine, the dosage of physostigmine should be repeated as required, particularly if life-threatening signs such as convulsions, arrhythmias and deep coma recur or persist after the initial dose of physostig- mine. Because physostigmine may itself be toxic, it is not recommended for routine use.

7. 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.

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

9.    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.

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

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

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

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

14.    Forced diuresis, haemodialysis and haemoperfusion is of no value in amitriptyline over dosage because of the low plasma concentrations of amitriptyline.

15.    Other measures as indicated by the patient's clinical condition. Since over dosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Deaths by deliberate or accidental over dosage have occurred with tricyclic antidepressants.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC CODE: N06 AA09

Pharmacotherapeutic group: Antidepressants, tricyclic derivatives

Amitriptyline is a tricyclic antidepressant. It has marked antimuscarinic and sedative properties, and prevents the re-uptake (and hence the inactivation) of noradrenaline and serotonin at nerve terminals. Its mode of action in depression is not fully understood. Amitriptyline is used in the treatment of depression, particularly endogenous depression.

5.2. Pharmacokinetic Properties

Amitriptyline is readily absorbed from the gastro-intestinal tract, peak plasma concentration occurring within about 6 hours of oral administration. Amitriptyline is extensively demethylated in the liver to its primary active metabolite, nortriptyline. Paths of metabolism of both amitriptyline and nortriptyline include hydroxylation (possibly to active metabolites) and N-oxidation. Amitriptyline is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form. Amitriptyline and nortriptyline are widely distributed throughout the body and are extensively bound to plasma and tissue protein. Amitriptyline has been estimated to have a half life ranging from 9 to 25 hours, which may be considerably extended in overdosage.

5.3. Preclinical Safety Data

No information submitted.

6. PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Lactose monohydrate, povidone, magnesium stearate, stearic acid, maize starch.

Sugar-coat excipients: Polyvinylacetate phthalate, stearic acid, talc, calcium carbonate, acacia, titanium dioxide (E171), sucrose, povidone, quinoline yellow aluminium lake (E104), sunset yellow aluminium lake (E110), sodium benzoate (E211), shellac, yellow carnauba wax, white beeswax.

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf Life

3 years.

6.4.    Special Precautions for Storage

Do not store above 25°C. Store in the original container.

Keep the container tightly closed.

6.5 Nature and contents of container

Polypropylene tubes with low density polyethylene caps. Packing material: High density polyethylene film.

Pack size: 7, 14, 28, 56, 84, 50, 100, 250 and 500 tablets. Not all pack sizes may be marketed.

6.6. Instruction for Use/Handling

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Pharmvit Limited 177 Bilton Road Perivale Greenford Middlesex UB6 7HQ

8. MARKETING AUTHORISATION NUMBER

PL 04556/0039

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14th July 2005

10    DATE OF REVISION OF THE TEXT

17/10/2013