Amitriptyline - instructions for use, dose, side effects, contraindications

Amitriptyline equally inhibits the re-uptake of norepinephrine and serotonin in the presynaptic nerve ending. The main metabolite of amitriptyline, nortriptyline, comparatively inhibits the reuptake of norepinephrine compared to serotonin. Has cholinolytic and H1-histamine activity. Has a powerful antidepressant, sedative and anxiolytic effect.

Pharmacokinetics:

Suction

Amitriptyline has a high absorption. Time to reach the maximum concentration (T_C_max) after oral administration - 4-8 hours, C_m_Oh is 0.04-0.16 μg / ml. The equilibrium concentration is reached approximately in 1-2 weeks after the beginning of course treatment. The concentrations of amitriptyline in tissues are higher than in plasma.Bioavailability of amitriptyline for various routes of administration is 33-62%, its active metabolite nortriptyline is 46-70%. Volume of distribution (Vd ) -5-10 l / kg. Effective therapeutic concentrations of amitriptyline in the blood - 50-250 ng / ml, for nortriptyline (its active metabolite) - 50-150 ng / ml. The connection with plasma proteins is 92-96%. Amitriptyline passes through the histohematological barriers, including the blood-brain barrier (including nortriptyline), penetrates the placental barrier, is excreted in breast milk in concentrations similar to plasma.

Metabolism

The metabolism of amitriptyline is mainly due to demethylation (isoenzymes CYP2D6, CYP3A) and hydroxylation (isoenzyme CYP2D6) followed by conjugation with glucuronic acid. Metabolism is characterized by significant genetic polymorphism. The main active metabolite is secondary amine - nortriptyline. Metabolites of cis- and trans-10-hydrosyamitriptyline and cis- and trans-10-hydroxynortriptyline are characterized by similar to nortriptyline activity profile, although their effect is much weaker. Demethylnortriptyline and amitriptyline-N- Oxide is present in blood plasma in negligible concentrations; the last metabolite is practically devoid of pharmacological activity. In comparison with amitriptyline, all metabolites have a much less pronounced m-cholinoblocking action. The main factor determining renal clearance, and, correspondingly, the concentration in the blood plasma, is the rate of hydroxylation. A small proportion of people have genetically determined delayed hydroxylation.

Excretion

Half-life (T_1/2) from the blood plasma - 10-28 h for amitriptyline, for nortriptyline - 16-80 h. The average total clearance of amitriptyline is 39.24 ± 10.18 l / h. Displayed amitriptyline mainly by the kidneys and through the intestines in the form of metabolites. About 50% of the administered amitriptyline is excreted in the urine as 10-hydroxy-amitriptyline and its conjugate with glucuronic acid, about 27% is excreted as 10-hydroxy-nortriptyline and less than 5% of amitriptyline is excreted as the starting material and nortriptyline. The complete excretion of amitriptyline from the body occurs within 7 days.

Elderly patients

In elderly patients there is an increase in the half-life and a decrease in the clearance of amitriptyline due to a decrease in metabolic rate.

Patients with hepatic impairment

Dysfunction of the liver can lead to a slowing of the metabolism of amitriptyline and increase its plasma concentrations.

Patients with impaired renal function

In patients with impaired renal function, excretion of metabolites of amitriptyline and nortriptyline is slow, although metabolism as such does not change. Because of the association with blood proteins amitriptyline not removed from the plasma by dialysis.

Indications:

Endogenous depression and other depressive disorders.

Contraindications:

Hypersensitivity, myocardial infarction (acute and subacute periods), arrhythmias, severe disturbances of atrioventricular and intraventricular conduction (blockade of the bundle of the bundle, atrioventricular block of the 2nd degree), heart failure, acute alcohol intoxication, acute intoxication with hypnotic, analgesic and psychoactive drugs, angle-closure glaucoma, retention of urine, including with prostatic hyperplasia, paralytic intestinal obstruction, stenosis of the pylorus, hypokalemia, joints The use of drugs that extend the interval QT, or causing hypokalemia, lactation, children under 18 years of age.

Contraindicated concurrent use with monoamine oxidase (MAO) inhibitors and their use within 14 days before and after treatment.

If you have any of these diseases, consult a doctor before taking the drug.

Carefully:

Convulsive disorders, chronic alcoholism, prostatic hyperplasia, severe liver and cardiovascular diseases, bronchial asthma, manic-depressive psychosis (MDP) and epilepsy (see section "Special instructions"), oppression of bone marrow hematopoiesis, hyperthyroidism, thyrotoxicosis, delay urination, bladder hypotension, stenocardia, increased intraocular pressure, decreased motor function of the gastrointestinal tract (risk of paralytic intestinal obstruction), schizophrenia (although the reception usually does not exacerbate the productive symptoms), elderly age, pregnancy, the period of breastfeeding.

If you have any of these diseases, consult a doctor before taking the drug.

Pregnancy and lactation:

Use during pregnancy is not recommended.

If the drug is used by pregnant women, it is necessary to warn of a high risk of this method for the fetus, especially in the third trimester of pregnancy. The use of high doses of tricyclic antidepressants in the third trimester of pregnancy can lead to neurological disorders in the newborn. Drowsiness cases were registered in newborns whose mothers used nortriptyline (amitriptyline metabolite) during pregnancy, and cases of urinary retention were noted. Amitriptyline penetrates into breast milk. The concentration ratio of breast milk / plasma is 0.4-1.5 in a breastfed infant. When using amitriptyline, breastfeeding should be discontinued.

If this is not done, you should monitor the condition of the child, especially during the first four weeks after birth.

A child who is breastfed may experience undesirable reactions (see section "Side effect").

Dosing and Administration:

Assign intramuscularly and intravenously.

Doses of the drug are selected individually depending on the age and condition of the patient.

With depression, resistant to therapy: intramuscularly and intravenously (inject slowly!) Is administered at a dose of 10-20-30 mg to 4 times a day, increasing the dose should be carried out gradually, the maximum daily dose of 150 mg; after 1-2 weeks go to the drug inside.

The elderly are given lower doses and increase them more slowly.

If the patient's condition does not improve within 3-4 weeks of treatment, then further therapy is impractical.

Cancel

The drug should be canceled gradually to avoid the development of withdrawal symptoms. Symptoms of "cancellation": after prolonged use with a sharp discontinuation of reception can occur such undesirable reactions as nausea, vomiting, diarrhea, headache, malaise, insomnia, unusual dreams, unusual arousal, irritability; after prolonged use with a gradual withdrawal - irritability, sleep disturbances, unusual dreams. These symptoms do not indicate the development of addiction to the drug.

Side effects:

WHO classification of unwanted adverse reactions according to the frequency of development

Very frequent - 1/10 appointments (≥10 %)

Frequent - 1/100 appointments (≥1%, but <10%)

Infrequent - 1/1000 appointments (≥0.1%, but <1%)

Rare - 1/10000 appointments (≥ 0.01%, but <0.1%)

Very rare - less than 1 / 10,000 appointments (<0.01%)

Violations from the blood and lymphatic system: rarely - oppression of bone marrow hematopoiesis, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia.

Disorders from the metabolism and nutrition: very often - weight gain; rarely - weight loss, loss of appetite.

Disorders of the psyche: often confusion, decreased libido; infrequently - hypomania, mania, anxiety, insomnia, "nightmarish" dreams; rarely delirium (in elderly patients), hallucinations (in patients with schizophrenia).

Impaired nervous system: very often - drowsiness, tremors, dizziness, headaches; often - violation of concentration, dysgeusia, paresthesia, ataxia; infrequently, convulsions.

Disorders from the side of the organ of vision: very often - a violation of accommodation; often - mydriasis; infrequent - increased intraocular pressure.

Hearing disorders and labyrinthine disturbances: infrequently, noise in the ears.

Heart Disease: very often - increased heart rate, tachycardia, orthostatic hypotension; often - atrioventricular block (AV-blockade), bundle branch blockade, intracardiac conduction disturbances, recorded only on the ECG, but not manifesting clinically (an increase QT interval, increase QRS complex); infrequently - arterial hypertension; rarely - arrhythmia.

Disorders from the gastrointestinal tract: very often - dry mouth, constipation, nausea; infrequently - diarrhea, vomiting, swelling of the tongue; rarely - an increase in the salivary glands, paralytic intestinal obstruction.

Disorders from the liver and bile ducts: rarely - jaundice, a violation of the liver functional status, increased activity of alkaline phosphatase (SCH) of blood and transaminases.

Disturbances from the skin and subcutaneous tissues: very often hyperhidrosis; infrequently - skin rash, hives, swelling of the face; rarely - alopecia, photosensitivity reactions.

Disorders from the kidneys and urinary tract: infrequently urinary retention.

Violations of the genitals and breast: often - erectile dysfunction; rarely - gynecomastia.

General disorders and disorders at the site of administration: often fatigue; rarely pyrexia.

Symptoms of withdrawal: after prolonged use with a sudden discontinuation of use may cause such adverse reactions as nausea, vomiting, diarrhea, headache, malaise, insomnia, unusual dreams, unusual arousal, irritability; after prolonged use with a gradual withdrawal - irritability, sleep disturbances, unusual dreams. These symptoms do not indicate the development of addiction to the drug.

Some of the unwanted reactions, for example, headache, tremor, impaired concentration, constipation and decreased libido, can be a manifestation of depression and disappear as resolution of depression.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose:

The reactions to overdose in different patients vary significantly.

In adults, taking more than 500 mg causes mild to severe intoxication.

The lethal dose of amitriptyline is 1200 mg.

Symptoms

Symptoms can develop slowly and imperceptibly, or abruptly and suddenly. During the first hours there is drowsiness or agitation, agitation and hallucinations.

Anticholinergic symptoms: mydriasis, tachycardia, urinary retention, dry mucous membranes, fever, intestinal motility slowing.

Neuropsychiatric signs: convulsions, sudden suppression of the central nervous system (CNS), lowering the level of consciousness down to coma, suppression of breathing.

Symptoms from the heart: As the signs of an overdose increase, changes in the cardiovascular system increase. Arrhythmias (ventricular tachyarrhythmia, cardiac rhythm disturbances by type Torsade de Pointes, ventricular fibrillation). The ECG is characterized by an elongation of the interval PR, expansion of the complex QRS, interval lengthening QT, flattening or inversion of the T wave, segment depression ST and blockade of intracardiac conduction of various degrees, which can progress up to cardiac arrest, lowering of blood pressure, heart failure, intraventricular blockade, frequent heartbeat.

Expansion of the complex QRS usually correlates with the severity of toxic effects due to acute overdose.

Heart failure, decreased blood pressure, cardiogenic shock. Metabolic acidosis, hypokalemia.

After awakening, confusion, excitement, hallucinations, and ataxia are again possible.

Treatment: discontinuation of amitriptyline therapy, administration of physostigmine 1 -3 mg every 1-2 hours IM or IV, fluid infusion, symptomatic therapy, maintenance of blood pressure and water-electrolyte balance. Monitoring of cardiovascular activity (ECG) for 5 days is shown, since relapse can occur after 48 hours and later. Hemodialysis and forced diuresis, gastric lavage are ineffective.

Interaction:

Simultaneous reception of amitriptyline and MAO inhibitors can cause serotonin syndrome (agitation, confusion, tremor, myoclonus, hyperthermia are possible).

Amitriptyline can be prescribed 14 days after discontinuation of treatment with irreversible MAO inhibitors and at least 1 day after discontinuation of therapy with a reversible MAO inhibitor of type A - moclobemide. MAO inhibitors can be prescribed 14 days after the end of amitriptyline intake. Amitriptyline can enhance the effect of alcohol, barbiturates and other substances that depress the central nervous system.

Because tricyclic antidepressants, including amitriptyline, can To intensify the effect of anticholinergic drugs on the organs of vision, the central nervous system, the intestines and the bladder, one should avoid their simultaneous application because of the risk of developing paralytic intestinal obstruction, hyperpyrexia.

When taking tricyclic antidepressants in combination with anticholinergic drugs or antipsychotics, especially in hot weather, the development of hyperpyrexia is possible.

Amitriptyline may enhance the effects of epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine and phenylpropanolamine on the cardiovascular system; therefore, anesthetics, decongestants and other preparations containing these substances should not be used simultaneously with amitriptyline.

Can reduce the antihypertensive effect of guanethidine, betanidine, reserpine, clonidine and methyldopa. With the simultaneous administration of tricyclic antidepressants, it is necessary to correct antihypertensive therapy.

When combined with antihistamine drugs, the oppressive effect on the central nervous system may be increased; with drugs that cause extrapyramidal reactions - an increase in the severity and frequency of extrapyramidal effects.

Simultaneous reception of amitriptyline and drugs that extend QT interval, (antiarrhythmics (quinidine), antihistamines (astemizole and terfenadine), some neuroleptics (cisapride, halofantrine and sotalol, especially pimozide and sertindole)), increases the risk of ventricular arrhythmia. Antifungal drugs, for example, fluconazole, terbinafine - increase the level of concentration of tricyclic antidepressants in serum and, accordingly, their toxicity. Possible syncope and development of paroxysms of ventricular tachycardia (Torsade de Pointes).

Barbiturates and other inducers of enzymes, for example, rifampicin and carbamazepine and others can enhance the metabolism of tricyclic antidepressants, and as a result, reduce the concentration of tricyclic antidepressants in blood plasma and reduce their effectiveness.

When used simultaneously with cimetidine, methylphenidate and blockers calcium channels possibly slowing the metabolism of amitriptyline, increasing its concentration in the blood plasma and the development of toxic effects.

When co-administered with neuroleptics, it should be borne in mind that tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism, reducing the threshold of convulsive readiness.

With the simultaneous use of amitriptyline and indirect anticoagulants (coumarin derivatives or indadion), an increase in anticoagulant activity of the latter is possible.

Amitriptyline may increase depression caused by glucocorticoid drugs (GCS).

When combined with anticonvulsant drugs, it is possible to increase the inhibitory effect on the central nervous system, reduce the threshold of convulsive activity (when used in high doses), and reduce the effectiveness of the latter.

Simultaneous reception with drugs for the treatment of thyrotoxicosis increases the risk of agranulocytosis.

Because of the risk of developing arrhythmias, special care must be taken when prescribing amitriptyline to patients with thyroid hyperthyroidism or to patients receiving thyroid medications.

Fluoxetine and fluvoxamine may increase the concentration of amitriptyline in blood plasma (a dose reduction of amitriptyline may be required).

When combined with holinoblokatorami, phenothiazines and benzodiazepines, mutual enhancement of sedative and central cholinoblocking effects and an increased risk of epileptic seizures (lowering the threshold of convulsive activity) is possible.

Estrogen-containing oral contraceptive medications and estrogens can increase the bioavailability of amitriptyline. To restore efficacy or reduce toxicity, it may be necessary to reduce the dose or estrogen, or amitriptyline. However, it may be necessary to cancel the drug.

Co-administration with disulfiram and other acetal dehydrogenase inhibitors may increase the risk of developing psychotic conditions and confusion.

When amitriptyline is used together with phenytoin, the metabolism of the latter is inhibited, and the risk of its toxic effects increases (ataxia, hyperreflexia, nystagmus, tremor). When amitriptyline is started in patients receiving phenytoin, it is necessary to monitor the concentration of the latter in blood plasma because of the increased risk of inhibition of its metabolism. At the same time, the therapeutic effect of amitriptyline should be monitored. it may be necessary to increase its dose.

Drug preparations of St. John's wort reduce the maximum concentration of amitriptyline in the blood plasma by approximately 20% due to activation of the hepatic metabolism of amitriptyline by isoenzyme CYP3A4. That raises the risk of occurrence of a serotonin syndrome. This combination can be used with a dose adjustment of amitriptyline depending on the results of measuring its concentration in the blood plasma.

With the simultaneous use of valproic acid, the clearance of amitriptyline from the blood plasma decreases, which can lead to an increase in the concentration of amitriptyline and its metabolite, nortriptyline. When combined with amitriptyline and valproic acid, the concentrations of amitriptyline and nortriptyline in serum should be monitored. You may need to reduce the dose of amitriptyline.

With the simultaneous use of amitriptyline in a high dose and lithium drugs for more than six months, the development of seizures, cardiovascular complications is possible.It is also possible the appearance of signs of a neurotoxic effect in the form of a tremor, memory impairment, distraction, disorganization of thinking even at normal concentration of lithium in the blood and medium doses of amitriptyline.

Special instructions:

Tricyclic antidepressants should not be given to children and adolescents under the age of 18 because of insufficient data on the efficacy and safety of drugs in this group of patients.

Amitriptyline in doses above 150 mg / day reduces the threshold of convulsive activity, therefore, it is necessary to take into account the possibility of occurrence of convulsive disorders in patients with those with anamnesis, and with brain damage of any etiology, simultaneous use of neuroleptics, in the period of refusal from ethanol or withdrawal of drugs with anticonvulsant properties (benzodiazepines).

Any depressive disorder in itself increases the risk of suicide. Therefore, during treatment with antidepressants, all patients should be monitored for early detection of abnormalities or behavioral changes, as well as suicidal tendencies.

The use of anesthetics during the course of treatment with tri- and tetracyclic antidepressants may increase the risk of arrhythmia and lowering blood pressure. If possible, discontinue the use of amitriptyline several days before surgery. In case of emergency surgical intervention, the anesthetist should be warned about the patient's treatment with amitriptyline.

Dry mouth and tearing can be reduced with a relative increase in the amount of mucus in the tear fluid, which can lead to damage to the corneal epithelium in patients using contact lenses.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Solution for intravenous and intramuscular injection 10 mg / ml in ampoules of 2 ml.

Packaging:5 ampoules per contour cell packaging made of polyvinylchloride film and foil of aluminum printed lacquered, or flexible packaging on the basis of aluminum foil, or without foil.

For 1 or 2 contour packs with instructions for use, a knife or a scarifier ampoule in a pack of cardboard.

For 20, 50 or 100 contoured cell packs with foil with 10, 25 or 50 instructions for use, knives or scarifiers ampoule in boxes of cardboard or boxes of corrugated cardboard (for inpatient).

When packing ampoules with incisions, rings or break points, the ampoule or scarifier knives are not inserted.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N002756 / 02

Date of registration:25.06.2008 / 19.03.2014

Expiration Date:Unlimited

The owner of the registration certificate:MOSCOW ENDOCRINE FACTORY, FSUE MOSCOW ENDOCRINE FACTORY, FSUE Russia

Manufacturer: & nbsp

MOSCOW ENDOCRINE FACTORY, FSUE Russia

Information update date: & nbsp13.09.2017

Illustrated instructions

Instructions

Amitriptyline (Amitriptyline)