Each coated tablet contains:

active ingredients: amitriptyline hydrochloride–25 mg;

inactive ingredients: tablet core-microcrystalline cellulose, lactose monohydrate, povidone, maize starch, sodium starch glycolate, magnesium stearate, talc purified; tablet coating–hypromellose, titanium dioxide, propylene glycol, talc purified, color yellow (riboflavin).

3-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-N,N-dimethylpropan-1-amine hydrochloride; 549-18-8.

Tricyclic antidepressants; N06AA09.

Tricyclic antidepressants such as amitriptyline were developed from phenothiazine compounds related to chlorpromazine and, as the name suggests, possess a 3-ring molecular structure. They inhibit the neuronal reuptake of noradrenaline in the CNS; some, in addition, inhibit the reuptake of serotonin (5-HT). Prevention of the reuptake of these monoamine neurotransmitters, which potentiates their action in the brain, appears to be associated with antidepressant activity. Tricyclic antidepressants also possess affinity for muscarinic and histamine H1 receptors to varying degrees. Amitriptyline is one of the more sedating tricyclics. Antidepressants with one, two, or four rings have also been developed, and these share only some of the properties of the tricyclics.
While the sedative action and other adverse effects of amitriptyline and other tricyclics are soon apparent, it may be several weeks before any antidepressant effect is seen. After a response has been obtained, maintenance therapy should be continued at the optimum dose for at least 4 to 6 months (12 months in the elderly) to avoid relapse on stopping therapy. Patients with a history of recurrent depression should continue to receive maintenance treatment for at least 5 years and possibly indefinitely. It is important to use doses that are sufficiently high for effective treatment, but not so high as to cause toxic effects.

Amitriptyline is readily absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 6 hours after oral doses.
Bioavailability of amitriptyline is 30-60%, bioavailability of amitriptyline metabolite – nortriptyline – 46-70%.
Amitriptyline is 98% bound to plasma proteins.
Amitriptyline undergoes extensive first-pass metabolism and is demethylated in the liver by the cytochrome P450 isoenzymes CYP3A4, CYP2C9, and CYP2D6 to its primary active metabolite, nortriptyline. Other paths of metabolism of amitriptyline include hydroxylation (possibly to active metabolites) by CYP2D6 and N-oxidation; nortriptyline follows similar paths. 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 an elimination half-life ranging from about 9 to 25 hours, which may be considerably extended in overdosage. Plasma concentrations of amitriptyline and nortriptyline vary very widely between individuals and no simple correlation with therapeutic response has been established.
Amitriptyline and nortriptyline cross the placenta and are distributed into breast milk.

Depressive illness

Nocturnal enuresis where organic pathology is excluded and at the failure of other treatment.

Adults
Depression: initial dosage: Usually 75mg a day in divided doses (or a single dose at night). If necessary, after 1-2 weeks, daily dose may be increased by 25- 50 mg to a total of 150-200 mg a day, the additional doses being given in the late afternoon and/or at bedtime.
Maintenance dose 50-100mg at night which should be continued for at least 4-6 months (for elderly patient 12 months) to several years to lessen chances of relapse.
Elderly: initial dosage: usually 30-75mg a day in divided doses (or a single dose at night).

Children
Children under 16 years not recommended for depression.
Nocturnal enuresis
Children 7–10 years 10–20 mg, 11–16 years 25–50 mg at night; max. period of treatment (including gradual withdrawal) 3 months – full physical examination before further course.

Dry mouth, sedation, blurred vision (disturbance of accommodation, increased intra-ocular pressure), constipation, vomiting, stomatitis, nausea, difficulty with micturition; cardiovascular side-effects (such as ECG changes, arrhythmias, postural hypotension, tachycardia, syncope, particularly with high doses); sweating, tremor, rashes and hypersensitivity reactions (including urticaria, photosensitivity), clouded sensorium, behavioural disturbances (particularly children), hypomania or mania, confusion or delirium (particularly elderly), headache, dizziness, changes in libido, impotence, increased appetite and weight gain (occasionally weight loss); endocrine side-effects such as testicular enlargement, gynaecomastia, galactorrhoea, hyperglycemia, glycosuria, impaired glucose tolerance, also convulsions, weakness, extrapyramidal disorders, movement disorders and dyskinesias, disorientation, dysarthria, paraesthesia, taste disturbances, tinnitus, fever, agranulocytosis, leucopenia, eosinophilia, purpura, thrombocytopenia, hyponatraemia, abnormal liver function tests (jaundice).

Withdrawal
If possible tricyclic and related antidepressants should be withdrawn slowly.

Limited quantities of tricyclic antidepressants should be prescribed at any one time because their cardiovascular effects are dangerous in overdosage. In particular, overdosage with amitriptyline is associated with a relatively high rate of fatality.
Symptoms: inhibition or stimulation of the central nervous system. Expressed effects of anticholinergic drugs (tachycardia, dry mucous membranes, urinary retention) and cardiotoxicity actions (arrhythmias, hypotension, heart failure), convulsive disorders, hallucinations, delirium, coma, hyperthermia.
Treatment: Patients should be hospitalised and treatment should be symptomatic and based on cardiac (including ECG monitoring) and respiratory support for 3-5 days.
Gastric lavage and administration of activated charcoal should be used as soon as possible. Epinephrine should not be used. Control convulsions with intravenous diazepam. At the anticholinergic effects (arrhythmia, coma) should be used physostigmine (0.5-2 g) intravenously or intramuscularly .

Recent myocardial infarction,

arrhythmias (particularly heart block),

manic phase of depression,

severe liver disease,

hypersensitivity.

Cardiac disease (particularly with arrhythmias), history of epilepsy, pregnancy, breast-feeding, history of mania, hepatic impairment (avoid if severe), thyroid disease, phaeochromocytoma, psychoses (may aggravate psychotic symptoms), susceptibility to angle-closure glaucoma, history of urinary retention, concurrent electroconvulsive therapy; if possible avoid abrupt withdrawal; anaesthesia (increased risk of arrhythmias and hypotension); acute porphyria, diabetes.
Driving: drowsiness may affect performance of skilled tasks (e.g. driving); effects of alcohol enhanced
Elderly patients and adolescents can be particularly sensitive to the adverse effects of tricyclic antidepressants and a reduced dose, especially initially, should be used.
Patients with rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine, because 1 tablet of Amitriptyline content 20.43 mg lactose monohydrate.
Patients receiving anticholinergic agents should be closely supervised and the dosage of all medications carefully adjusted.
Amitriptyline should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine due to hypertension and arrhythmias.
A minimum of 14 days should elapse between discontinuing a MAOI and starting amitriptyline which should be introduced cautiously and dosage increased gradually.
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.

Alcohol: increased sedative effect when tricyclics given with alcohol.
Barbiturates and carbamazepine may decrease, and methylphenidate may increase, the antidepressant action of amitriptyline.

Anti-arrhythmics: there is an increased risk of ventricular arrhythmias with drugs which prolong the QT interval, antiarrhythmics (quinidine), antihistamines, astemizole and terfenadine, some antipsychotics (pimozide and sertindole), cisapride, halofantrine and sotalol.

Antidepressants: possible increased serotonergic effects when amitriptyline given with duloxetine; increased risk of hypertension and CNS excitation when tricyclics given with MAOIs, tricyclics should not be started until 2 weeks after stopping MAOIs (3 weeks if starting clomipramine or imipramine), also MAOIs should not be started for at least 1–2 weeks after stopping tricyclics; after stopping tricyclics do not start moclobemide for at least 1 week; plasma concentration of some tricyclics increased by the selective serotonin re-uptake inhibitors (SSRIs); plasma concentration of amitriptyline reduced by St John’s wort.

Antipsychotics: plasma concentration of tricyclics increased by antipsychotics—possibly increased risk of ventricular arrhythmias; possibly increased antimuscarinic side-effects when tricyclics given with clozapine; increased risk of antimuscarinic sideeffects when tricyclics given with phenothiazines; increased risk of ventricular arrhythmias when tricyclics given with pimozide—avoid concomitant use.

Barbiturates: tricyclics antagonises anticonvulsant effect of barbiturates (convulsive threshold lowered), also metabolism of tricyclics possibly accelerated (reduced plasma concentration).

Calcium-channel Blockers: plasma concentration of imipramine increased by diltiazem and verapamil; plasma concentration of tricyclics possibly increased by diltiazem and verapamil.
Amitriptyline may block the antihypertensive action of clonidine, guanethidine, debrisoquine, betanidine.

Clonidine: tricyclics antagonise hypotensive effect of clonidine, also increased risk of hypertension on clonidine withdrawal.

Sympathomimetics: increased risk of hypertension and arrhythmias when tricyclics given with adrenaline (epinephrine) (but local anaesthetics with adrenaline appear to be safe); metabolism of tricyclics possibly inhibited by methylphenidate; increased risk of hypertension and arrhythmias when tricyclics given with noradrenaline (norepinephrine).

Ulcer-healing Drugs: plasma concentration of tricyclics possibly increased by cimetidine; metabolism of amitriptyline inhibited by cimetidine (increased plasma concentration).

Breast feeding: in general, only small amounts of tricyclic antidepressants are distributed into breast milk. Nevertheless, all antidepressants, including tricyclics, are drugs whose effect on nursing infants is unknown but may be of concern. In addition, most manufacturers advise that tricyclics should be avoided by the mother during breast feeding.
Pregnancy: tricyclic antidepressants should be used during pregnancy only if there were compelling reasons.

Yellow coated tablets.

2 blister packets with 24 tablets in the cardboard box.

3 years.

Store at a room temperature (15-25⁰C), in a dry place, out of the reach of children. Protect from light.