Apo-Amitriptyline (Tablets) Instructions for Use

ATC Code

N06AA09 (Amitriptyline)

Active Substance

Amitriptyline

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

An antidepressant from the group of tricyclic compounds, a derivative of dibenzocycloheptadiene.

The mechanism of antidepressant action is associated with an increase in the concentration of norepinephrine in the synapses and/or serotonin in the CNS due to the inhibition of the neuronal reuptake of these neurotransmitters.

With prolonged use, it reduces the functional activity of beta-adrenergic receptors and serotonin receptors in the brain, normalizes adrenergic and serotonergic transmission, and restores the balance of these systems, which is disturbed in depressive states.

In anxiety-depressive states, it reduces anxiety, agitation, and depressive manifestations.

It also has some analgesic effect, which is believed to be associated with changes in monoamine concentrations in the CNS, especially serotonin, and an effect on endogenous opioid systems.

It has a pronounced peripheral and central anticholinergic action, due to high affinity for m-cholinergic receptors; a strong sedative effect, associated with affinity for histamine H₁ receptors, and an alpha-adrenergic blocking action.

The mechanism of therapeutic action in bulimia nervosa has not been established (possibly similar to that in depression). A distinct efficacy of amitriptyline in bulimia has been shown in patients both without depression and with its presence, with a reduction in bulimia possibly occurring without a concomitant weakening of the depression itself.

The efficacy in nocturnal enuresis is apparently due to anticholinergic activity, leading to an increased ability of the bladder to stretch, direct beta-adrenergic stimulation, alpha-adrenergic receptor agonist activity, accompanied by increased sphincter tone, and central blockade of serotonin reuptake.

It has an antiulcer effect, the mechanism of which is due to the ability to block histamine H₂ receptors in the parietal cells of the stomach, as well as to exert a sedative and m-cholinolytic action (in gastric and duodenal ulcers, it reduces pain and promotes accelerated ulcer healing).

During general anesthesia, it reduces blood pressure and body temperature. It does not inhibit MAO.

The antidepressant effect develops within 2-3 weeks after the start of use.

Pharmacokinetics

The bioavailability of amitriptyline is 30-60%. Plasma protein binding is 82-96%. V_d – 5-10 L/kg. It is metabolized to form the active metabolite nortriptyline.

T_1/2 – 31-46 hours. It is excreted mainly by the kidneys.

Indications

Depression (especially with anxiety, agitation, and sleep disorders, including in childhood, endogenous, involutional, reactive, neurotic, drug-induced, in organic brain lesions, alcohol withdrawal), schizophrenic psychoses, mixed emotional disorders, behavioral disorders (activity and attention), bulimia nervosa, tension headache, migraine, neuropathic pain, chronic pain in cancer patients, rheumatic pain, nocturnal enuresis (except in patients with bladder hypotension), gastric and duodenal ulcer.

ICD codes

Dosage Regimen

Tablets

For oral administration, the initial dose is 25-50 mg at night. Then, over 5-6 days, the dose is individually increased to 150-200 mg/day (the larger part of the dose is taken at night). If no improvement occurs during the second week, the daily dose is increased to 300 mg. When signs of depression disappear, the dose is reduced to 50-100 mg/day and therapy is continued for at least 3 months. In elderly patients with mild disorders, the dose is 30-100 mg/day, usually once a day at night; after achieving a therapeutic effect, they switch to the minimum effective doses of 25-50 mg/day.

For nocturnal enuresis in children aged 6-10 years – 10-20 mg/day at night, aged 11-16 years – 25-50 mg/day.

IM – the initial dose is 50-100 mg/day in 2-4 injections. If necessary, the dose can be gradually increased to 300 mg/day, in exceptional cases – up to 400 mg/day.

Adverse Reactions

From the nervous system drowsiness, asthenia, fainting, anxiety, disorientation, agitation, hallucinations (especially in elderly patients and patients with Parkinson’s disease), anxiety, motor restlessness, manic state, hypomanic state, aggressiveness, memory impairment, depersonalization, worsening of depression, decreased ability to concentrate, insomnia, nightmares, yawning, activation of psychotic symptoms, headache, myoclonus, dysarthria, tremor (especially of the hands, head, tongue), peripheral neuropathy (paresthesia), myasthenia, myoclonus, ataxia, extrapyramidal syndrome, increased frequency and severity of epileptic seizures, EEG changes.

From the cardiovascular system orthostatic hypotension, tachycardia, conduction disorders, dizziness, nonspecific ECG changes (ST segment or T wave), arrhythmia, blood pressure lability, impaired intraventricular conduction (widening of the QRS complex, PQ interval changes, bundle branch block).

From the digestive system nausea, heartburn, vomiting, epigastric pain, increased or decreased appetite (increase or decrease in body weight), stomatitis, taste disturbance, diarrhea, darkening of the tongue; rarely – impaired liver function, cholestatic jaundice, hepatitis.

From the endocrine system testicular edema, gynecomastia, breast enlargement, galactorrhea, changes in libido, decreased potency, hypo- or hyperglycemia, hyponatremia (decreased vasopressin production), syndrome of inappropriate ADH secretion.

From the hematopoietic system agranulocytosis, leukopenia, thrombocytopenia, purpura, eosinophilia.

Allergic reactions skin rash, skin itching, urticaria, photosensitivity, swelling of the face and tongue.

Effects due to anticholinergic activity dry mouth, tachycardia, accommodation disturbances, blurred vision, mydriasis, increased intraocular pressure (only in persons with a narrow anterior chamber angle), constipation, paralytic ileus, urinary retention, decreased sweating, confusion, delirium, or hallucinations.

Other: hair loss, tinnitus, edema, hyperpyrexia, lymph node enlargement, pollakiuria, hypoproteinemia.

Contraindications

Acute period and early recovery period after myocardial infarction, acute alcohol intoxication, acute intoxication with hypnotics, analgesics and psychotropic drugs, closed-angle glaucoma, severe AV and intraventricular conduction disorders (bundle branch block, second-degree AV block), lactation period, children under 6 years of age (for oral administration), children under 12 years of age (for IM and IV administration), simultaneous treatment with MAO inhibitors and the period 2 weeks before their use, hypersensitivity to amitriptyline.

Use in Pregnancy and Lactation

Amitriptyline should not be used during pregnancy, especially in the first and third trimesters, except in cases of extreme necessity. Adequate and strictly controlled clinical studies on the safety of amitriptyline use during pregnancy have not been conducted.

Amitriptyline should be gradually discontinued at least 7 weeks before the expected delivery to avoid the development of withdrawal syndrome in the newborn.

In experimental studies, Amitriptyline had a teratogenic effect.

Contraindicated during lactation. It is excreted in breast milk and may cause drowsiness in infants.

Use in Hepatic Impairment

Use with caution in liver function disorders.

Use in Renal Impairment

Use with caution in renal function disorders.

Pediatric Use

Contraindication: children under 6 years of age (for oral administration), children under 12 years of age (for IM and IV administration).

Geriatric Use

In elderly patients, it may provoke the development of drug-induced psychoses, mainly at night (which resolve within a few days after drug withdrawal), and may also cause paralytic intestinal obstruction.

Special Precautions

Use with caution in coronary artery disease, arrhythmia, heart block, heart failure, myocardial infarction, arterial hypertension, stroke, chronic alcoholism, thyrotoxicosis, during therapy with thyroid drugs, in liver and/or kidney function disorders.

During therapy with amitriptyline, caution is required when abruptly moving to an upright position from a lying or sitting position.

Abrupt discontinuation of use may lead to the development of withdrawal syndrome.

Amitriptyline in doses greater than 150 mg/day lowers the seizure threshold; the risk of epileptic seizures in predisposed patients, as well as in the presence of other factors that increase the risk of developing a convulsive syndrome (including brain damage of any etiology, simultaneous use of antipsychotic drugs, during withdrawal from ethanol or withdrawal of drugs with anticonvulsant activity), should be taken into account.

It should be considered that suicidal attempts are possible in patients with depression.

In combination with electroconvulsive therapy, it should be used only under conditions of careful medical supervision.

In predisposed patients and elderly patients, it may provoke the development of drug-induced psychoses, mainly at night (which resolve within a few days after drug withdrawal).

It may cause paralytic intestinal obstruction, mainly in patients with chronic constipation, the elderly, or patients forced to observe bed rest.

Before general or local anesthesia, the anesthesiologist should be informed that the patient is taking Amitriptyline.

With long-term use, an increase in the frequency of dental caries is observed. An increased need for riboflavin is possible.

Amitriptyline can be used no earlier than 14 days after the withdrawal of MAO inhibitors.

It should not be used simultaneously with adreno- and sympathomimetics, including epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine, phenylpropanolamine.

Use with caution simultaneously with other drugs that have an anticholinergic effect.

During the intake of amitriptyline, alcohol consumption is not allowed.

Effect on the ability to drive vehicles and operate machinery

During the treatment period, one should refrain from potentially hazardous activities that require increased attention and rapid psychomotor reactions.

Drug Interactions

With simultaneous use with drugs that have a depressant effect on the CNS, a significant enhancement of the depressant effect on the CNS, hypotensive action, and respiratory depression is possible.

With simultaneous use with drugs that have anticholinergic activity, an enhancement of anticholinergic effects is possible.

With simultaneous use, an enhancement of the effect of sympathomimetic agents on the cardiovascular system and an increased risk of developing cardiac rhythm disorders, tachycardia, and severe arterial hypertension are possible.

With simultaneous use with antipsychotic agents (neuroleptics), metabolism is mutually inhibited, with a decrease in the seizure threshold occurring.

With simultaneous use with antihypertensive agents (except for clonidine, guanethidine and their derivatives), an enhancement of the antihypertensive effect and an increased risk of developing orthostatic hypotension are possible.

With simultaneous use with MAO inhibitors, the development of a hypertensive crisis is possible; with clonidine, guanethidine – a decrease in the hypotensive effect of clonidine or guanethidine is possible; with barbiturates, carbamazepine – a decrease in the effect of amitriptyline due to an increase in its metabolism is possible.

A case of serotonin syndrome development with simultaneous use with sertraline has been described.

With simultaneous use with sucralfate, the absorption of amitriptyline decreases; with fluvoxamine – the concentration of amitriptyline in the blood plasma increases and the risk of toxic effects increases; with fluoxetine – the concentration of amitriptyline in the blood plasma increases and toxic reactions develop due to inhibition of the CYP2D6 isoenzyme under the influence of fluoxetine; with quinidine – a slowdown in the metabolism of amitriptyline is possible; with cimetidine – a slowdown in the metabolism of amitriptyline, an increase in its concentration in the blood plasma and the development of toxic effects are possible.

With simultaneous use with ethanol, the effect of ethanol is enhanced, especially during the first few days of therapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.