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

Excipients: magnesium stearate 0.25 mg, povidone 0.83 mg, talc 2.25 mg, microcrystalline cellulose 9.5 mg, potato starch 28.2 mg, lactose monohydrate 27.0 mg;

shell: propylene glycol 0.2 mg, titanium dioxide 0.8 mg, hypromellose 1.2 mg, talc 0.8 mg.

One tablet, film-coated. 25 mg contains:

active substance: amitriptyline hydrochloride 28.3 mg in terms of amitriptyline 25 mg;

Excipients: magnesium stearate 0.5 mg, povidone 0.6 mg, talc 4.5 mg, microcrystalline cellulose 18.0 mg, potato starch 38.0 mg, lactose monohydrate 40.2 mg;

shell: propylene glycol 0.3 mg, titanium dioxide 0.9 mg, hypromellose 1.4 mg, talc 0.9 mg.

Description:The tablets covered with a film cover of white color, round, biconcave

Pharmacotherapeutic group:Antidepressant

ATX: & nbsp

N.06.A.A.09 Amitriptyline

Pharmacodynamics:

Amitriptyline is a tricyclic antidepressant from a group of nonselective monoamine reuptake inhibitors. Has a strong thymoanaleptic and sedative effect.

Pharmacodynamics

The mechanism of antidepressant action of amitriptyline is associated with an increase in the content of noradrenaline and serotonin in the synaptic cleft in the central nervous system (CNS).Accumulation of these neurotransmitters occurs as a result of inhibition of their inverse capture by the membranes of presynaptic neurons.

Amitriptyline is a blocker Ml- and M2-muscarinic cholinergic receptors, H1-histamine receptors and α₁adrenoreceptors. In accordance with the so-called monoamine hypothesis, there is a correlation between the emotional tone and the function of the neurotransmitters in the synapses of the brain.

A clear correlation between the concentration of amitriptyline in plasma and the clinical effect is not shown, but the optimal clinical effect appears to be achieved at concentrations in the range of 100-260 μg / l.

Clinical weakening of depression is reached later, than the equilibrium concentration in a blood plasma is reached, in 2-6 weeks of treatment.

Besides, amitriptyline has a quinidine-like effect on the innervation of the heart.

Pharmacokinetics:

Suction

After oral administration amitriptyline quickly and completely absorbed from the gastrointestinal tract. The maximum concentration in blood plasma (C_max) is achieved within 2-6 hours after administration.

Distribution

The concentration of amitriptyline in the blood plasma of different patients varies significantly. The bioavailability of amitriptyline is approximately 50%. Amitriptyline to a large extent (95%) binds to blood plasma proteins. Time to reach the maximum concentration (T_C_max) after ingestion - 4 hours, and the equilibrium concentration - about a week after the start of treatment. The volume of distribution is approximately 1085 l / kg. AND amitriptyline, and nortriptyline penetrate the placenta and are excreted with the thoracic milk.

Metabolism

Amitriptyline is metabolized in the liver and, to a large extent (about 50%), is metabolized on first passage through the liver. Wherein amitriptyline undergoes N-detylation with cytochrome P450 to form an active metabolite - nortriptyline. AND amitriptyline, and nortriptyline also undergo in the liver hydroxylation. N-hydroxy and 10-hydroxymetabolite amitriptyline and 10-hydroxynortriptyline are also active. AND amitriptyline, and nortriptyline are conjugated to glucuronic acid, and these conjugates are inactive. 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. In patients with impaired liver function, the half-life of amitriptyline and nortriptyline in blood plasma is increased.

Excretion

Half-life (T_1/2) from the blood plasma - 9-46 hours for amitriptyline and 18-95 hours for nortriptyline.

Displayed amitriptyline mainly by the kidneys and through the intestines in the form of metabolites. Only a small part of the accepted dose of amitriptyline is excreted through the kidneys unchanged. In patients with impaired renal function, the excretion of metabolites of amitriptyline and nortriptyline is slowed, 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 to the components of the drug;

- use in conjunction with MAO inhibitors and 2 weeks before the start of treatment;

- myocardial infarction (including recently transferred);

acute alcohol intoxication;

- Acute delirium;

- acute intoxication with sleeping pills, analgesic and psychotropic drugs;

- an angle-closure glaucoma;

- arrhythmia;

- violations of atrioventricular and intraventricular conduction;

- lactation period;

- lactose intolerance, lactase deficiency and glucose-galactose malabsorption;

- hyperplasia of the prostate with a delay of urine,

- hypokalemia, bradycardia, congenital syndrome of elongated QT, and also simultaneous application with drugs leading to QT interval elongation;

- Pyloric stenosis, paralytic obstruction of the intestine;

- Children under 18 years.

Carefully:

Diseases of the cardiovascular system (angina, arterial hypertension), blood diseases, increased intraocular pressure, angle-closure glaucoma, flat anterior chamber of the eye and acute angle of the eye chamber, urinary retention, prostatic hyperplasia, patients with convulsive conditions, bladder hypotension, hyperthyroidism, bipolar disorder, schizophrenia, epilepsy (amitriptyline reduces the convulsive threshold), impaired liver or kidney function, chronic alcoholism, simultaneous reception with antipsychotics and hypnotics, and old age.

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

Pregnancy and lactation:

Pregnancy

Studies in animals have demonstrated a side effect in doses several times higher than the standard dose for humans.

Clinical experience with amitriptyline during pregnancy is limited. The safety of amitriptyline during pregnancy is not established. Amitriptyline is not recommended for use during pregnancy, especially in the first and third trimesters, except if the intended benefit to the mother outweighs the potential risk to the fetus. 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. Cases of drowsiness in newborns whose mothers used nortriptyline (amitriptyline metabolite) during pregnancy are documented, cases of urine retention are noted.

Breast-feeding

When using amitriptyline, breastfeeding should be discontinued. Amitriptyline penetrates into breast milk.The concentration ratio of breast milk / plasma is 0.4-1.5 in a breastfed infant. Unwanted reactions may occur.

Dosing and Administration:

Assign inside, not liquid (immediately after eating).

Adults.

The initial daily dose is 25-50 mg, divided into two doses, or as a single dose at bedtime. If necessary, the daily dose can be gradually increased to 200 mg.

The general course of treatment is usually 6 months or more to prevent relapse.

Elderly

Elderly people are more sensitive to m-holinoblocking undesirable effects of amitriptyline. Therefore, for them the recommended initial dose is 25-30 mg / day, usually 1 time per day (at night). A further increase in the dose should be carried out gradually, every other day, reaching a dose of 50-100 mg / day, if necessary, until a response (effect) is achieved. It is necessary to conduct an additional examination before the appointment of a second course of treatment.

Impaired renal function

In the presence of violations of kidney function, the drug can be used in a usual dose.

Impaired liver function

In patients with hepatic insufficiency, the dose of amitriptyline should be reduced.

Duration of treatment

Antidepressant action usually occurs after 2-4 weeks.Treatment with antidepressants is symptomatic, and therefore should be long enough, usually for 6 months or more to prevent recurrence of depression.

Cancel

The drug should be abolished gradually to avoid the development of the "withdrawal" syndrome, such as headache, sleep disorders, irritability and general poor health. These symptoms are not a sign of dependence on the drug.

Side effects:

More than 50% of patients receiving Amitriptyline Nicomed may have one or more of the following adverse reactions. Amitriptyline may cause side effects similar to those caused by other tricyclic antidepressants.

Some of the undesirable reactions listed below, such as headache, tremor, decreased concentration, constipation and decreased libido, may also be symptoms of depression, and they usually disappear when depression is reduced.

The incidence of side effects is indicated as: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10 000, <1/1000); very rarely (<1/10000).

From the side of the cardiovascular system:

Very often: palpitations and tachycardia, orthostatic hypotension.Often: arrhythmia (including conduction abnormalities, prolongation of the QT interval), hypotension, AV blockade, blockage of conduction along the legs of the bundle. Infrequently: increased blood pressure. Rarely: myocardial infarction.

From the nervous system:

Very often: sedative effect (lethargy, propensity to sleep), tremor, dizziness, headache. Often: decreased concentration, impaired taste, paresthesia, extrapyramidal symptoms: ataxia, akathisia, parkinsonism, dystonic reactions, tardive dyskinesia, delayed speech. Infrequently: convulsions.

From the urinary system:

Often: retention of urination.

From the skin:

Very often: hyperhidrosis. Infrequent: rash, skin vasculitis, hives. Rarely: photosensitivity, alopecia.

From the sense organs:

Very often: a decrease in visual acuity, a violation of accommodation (during the treatment may require reading glasses). Often: mydriasis. Infrequent: tinnitus, increased intraocular pressure. Rarely: loss of ability to accommodation, aggravation of narrow-angle glaucoma.

Mental disturbance:

Very often: confusion (confusion in elderly patients is characterized byanxiety, sleep disturbance, difficulty remembering, psychomotor agitation, disordered thoughts, delirium), disorientation. Often: decreased concentration of attention. Infrequently: cognitive impairment, manic syndrome, hypomania, mania, a sense of fear, anxiety, insomnia, nightmares. Rarely: aggressiveness, delirium (in adults), hallucinations (in patients with schizophrenia). Very rarely: suicidal thoughts, suicidal behavior.

On the part of the organs of hematopoiesis:

Rarely: suppression of bone marrow function, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia.

From the digestive system:

Very often: dry mouth, constipation, nausea. Often: recession of gums, inflammation of the mouth, tooth decay, burning sensation in the mouth. Infrequent: diarrhea, vomiting, swelling of the tongue. Rarely: paralytic intestinal obstruction, swelling of the parotid gland, cholestatic jaundice, impaired liver function, hepatitis.

General disorders:

Often: weakness. Infrequent: swelling of the face. Rarely: fever.

From the side of metabolism:

Very often: weight gain increases appetite. Rarely: decreased appetite.Very rarely: the syndrome of inadequate secretion of antidiuretic hormone.

From the side of the reproductive system:

Very often: weakening or increase of sexual desire. Often: men - impotence, erectile dysfunction. Rarely: in men - delayed ejaculation, gynecomastia; women - galactorrhea, delayed orgasm, loss of ability to achieve orgasm.

Laboratory indicators:

Often: ECG change, QT interval elongation, QRS complex expansion. Rarely: a deviation from the norm of liver tests, increased activity of alkaline phosphatase, transaminase.

Undo effects

A sudden cessation of treatment after prolonged use can cause nausea, headache and malaise. The gradual withdrawal of the drug was associated with transient symptoms such as irritability, agitation and disturbances in dreams and sleep during the first two weeks of dose reduction. Rarely, individual cases of mania or hypomania occurred within 2-7 days after discontinuation of long-term treatment with tricyclic antidepressants.

Overdose:

Symptoms

Symptoms of an overdose of amitriptyline may develop slowly or occur suddenly.In the first two hours there is drowsiness or psychomotor agitation, hallucinations and symptoms associated with the anticholinergic action of the drug: mydriasis, tachycardia, urinary retention, dry mucous membranes, weakened intestinal motility, convulsions, fever. In the future, a sharp suppression of the functions of the central nervous system, impaired consciousness, progressing to coma, and respiratory failure are possible.

Cardiac symptoms: arrhythmia (ventricular tachyarrhythmia, flutter and ventricular fibrillation). On the ECG, the characteristic changes are prolongation of the PR interval, expansion of the QRS complex, prolongation of the QT interval, flattening or inverting of the T wave, depression of the ST segment and a different degree of blockade of intracardiac conduction that can cause cardiac arrest. Can develop heart failure, arterial hypotension, cardiogenic shock, metabolic acidosis and hypokalemia, confusion, anxiety, hallucinations and ataxia.

Influence on the central nervous system (CNS): oppression of central nervous system functions, strong craving for sleep, convulsions, coma.

Influence on the respiratory system: respiratory failure. Influence on the psychic sphere: psychomotor agitation, hallucinations.

Influence on the vascular system: hypotension.

M-holinoblokiruyuschie effects: dry mouth, disruption of accommodation, delayed urination, muscle cramps.

Treatment:

Treatment is symptomatic and supportive. Termination of therapy with amitriptyline, gastric lavage, even if it took some time after taking the drug, taking activated charcoal. Even in apparently uncomplicated cases, you should carefully monitor the patient. It is necessary to control the level of consciousness, heart rate, blood pressure and respiratory rate. It is often necessary to check the level of electrolytes and gases in the blood. To prevent stopping breathing, it is necessary to provide airway patency and artificial ventilation. ECG monitoring should be continued for 3-5 days. With the expansion of the QRS complex, heart failure and ventricular arrhythmias, it may be effective to shift the pH of the blood to the alkaline side (administration of a sodium bicarbonate solution or hyperventilation) with the rapid administration of a hypertonic sodium chloride solution (100-200 mmol Na +).With ventricular arrhythmias, it is possible to use traditional antiarrhythmic drugs, for example, 50-100 mg of lidocaine (1-1.5 mg / kg) intravenously with further infusion at a rate of 1-3 mg / min.

If necessary, cardioversion and defibrillation are used. Circulatory insufficiency is corrected with the help of plasma-substituting solutions, and in severe cases, dobutamine infusion is performed (at first - 2-3 μg / kg / min with a further increase in dose depending on the effect). Excitation and convulsions can be stopped with diazepam.

In metabolic acidosis, standard therapy should be started. Dialysis is inefficient, because the concentration of amitriptyline in the blood is low. The reactions to overdose in different patients vary significantly.

In adults, moderate or severe intoxication develops with amitriptyline at a dose of more than 500 mg, with a dose of about 1000 mg, a lethal outcome is possible.

Interaction:

Amitriptyline potentiates CNS depression by the following drugs: neuroleptics, sedatives and hypnotics, anticonvulsants, central and narcotic analgesics, general anesthetics, and alcohol.Tricyclic antidepressants, including amitriptyline, are metabolized by isoenzyme CYP2D6 hepatic cytochrome P450. This isoenzyme in man has several isoforms.

Isozyme CYP2D6 can be inhibited by various psychotropic drugs, for example, antipsychotics, serotonin reuptake inhibitors (except citalopram, a very weak inhibitor), P-blockers and antiarrhythmic drugs of the latest generationprocainamide, phenytoin, propafenone, esmolol amiodarone).

These drugs can inhibit the metabolism of tricyclic antidepressants and significantly increase their concentration in blood plasma. In addition, the metabolism of amitriptyline involves isoenzymes CYP2C19 and CYP3A.

Contraindicated combinations:

Contraindicated the use of amitriptyline in conjunction with MAO inhibitors because of the risk of developing serotonin syndrome, including myoclonus, spasms excitement, delirium and coma.

The use of amitriptyline can be started 2 weeks after the cancellation of the irreversible, non-selective MAO inhibitor and the day after the reversal of the reversible inhibitor of moclobemide.

The use of MAO inhibitors can begin 2 weeks after the withdrawal of amitriptyline. In either case, both the MAO inhibitor, and amitriptyline should be started with small doses, gradually increasing them depending on the effect.

Not recommended combinations

Sympathomimetics: amitriptyline strengthens the effect on the cardiovascular system of epinephrine, ephedrine, isoprenaline, norepinephrine, dopamine and phenylephrine, used, for example, for local or general anesthesia or in the form of drops in the nose.

Adrenoblockers: while using amitriptyline with clonidine and methyldopa, weakening of the hypotensive effect of the latter is possible.

M-holinoblokatory: amitriptyline may enhance the effect of such drugs (eg, phenothiazine derivatives, antiparkinsonian agents, blockers H₁-gistaminovyh receptors, atropine, biperidena) on the organs of vision, central nervous system, intestine and bladder. You should avoid the simultaneous use of these drugs because of the risk of developing, including, intestinal obstruction and a strong increase in body temperature.

Drugs capable of lengthening the interval QT, including antiarrhythmic drugs (for example, quinidine), blockers H₁-gistamine receptors (eg, terfenadine), some antipsychotics (especially pimozide and sertindole), anesthetics (isoflurane, droperidol), chloral hydrate and sotalol. These drugs, when used together with amitriptyline, may increase the risk of ventricular arrhythmia.

Antifungal drugs, eg, fluconazole and terbinafine, increase the concentration of amitriptyline in the blood serum and increase the associated toxicity. Cases of fainting and fibrillation and fluttering of the ventricles are possible.

Lithium salts (lithium carbonate)

Lithium salts interact with amitriptyline by an unknown mechanism; this interaction can enhance the toxicity of lithium: tremor, tonic-clonic convulsions, difficulty memorizing, mismatched (thinking, hallucinations, malignant neuroleptic syndrome.

Combinations that require caution

Medications that depress the central nervous system: amitriptyline can enhance the inhibition of CNS functions caused by other psycho-depressants, for example, alcohol, hypnotics, sedatives and strong analgesics.

Barbiturates and other inducers of microsomal liver enzymes - inducers of enzymes, for example, rifampicin and carbamazepine, can enhance the metabolism of amitriptyline and reduce its concentration in the blood plasma with a corresponding weakening of antidepressant action.

Cimetidine, methylphenidate and blockers of "slow" calcium channels increase the concentration of amitriptyline in the blood plasma, which can be accompanied by increased toxicity.

Amitriptyline and neuroleptics can mutually inhibit each other's metabolism. This can lead to a decrease in the convulsive threshold and the development of seizures. When combined, a dose adjustment of these drugs may be required.

Avoid simultaneous use of amitriptyline, neuroleptics and hypnotics (droperidol). When joint admission should exercise extreme caution.

Sucralfate decreases the absorption of amitriptyline and can weaken the antidepressant effect.

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 blood serum should be monitored. You may need to reduce the dose of amitriptyline.

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, since an increase in its dose may be required.

Drug preparations of St. John's wort reduce AUC0-12 hours and the maximum concentration of amitriptyline in the blood plasma by about 20% due to the activation of the hepatic metabolism of amitriptyline by isoenzyme CYP3 A4.

This combination can be used with a dose adjustment of amitriptyline depending on the results of measuring its concentration in the blood plasma.

Special instructions:

Before the start of treatment, it is necessary to control blood pressure (BP) (in patients with low or labile blood pressure, it can decrease even more).

Care must be taken when jumping to a vertical position from the "lying" or "sitting" position. Epidemiological studies, which were mainly conducted in patients aged 50 years and older, indicate an increased risk of bone fractures with the use of selective inhibitors of the capture of serotonin and tricyclic antidepressants. The mechanism of action that increases this risk is unknown.

During the treatment in some cases, agranulocytosis or hypokalemia may develop, in connection with this, control of peripheral blood is recommended, especially with an increase in body temperature, the development of influenza-like symptoms and tonsillitis; with long-term therapy - monitoring the functions of the cardiovascular system (SSS) and liver. In elderly patients and patients with SSS diseases, it is necessary to control the heart rate, blood pressure, electrocardiogram (ECG). On the ECG, there may be clinically insignificant changes (T wave smoothing, S-T segment depression, QRS complex expansion).

Caution should be exercised when using amitriptyline in patients receiving inhibitors or inducers of cytochrome P450 AP4.

In the period of treatment in some cases may develop mydriasis, tachycardia, urinary retention, dry mucous membranes, decreased motor function of the intestine. Cramps, fever. In the future, a sharp suppression of the functions of the central nervous system, impaired consciousness, progressing to coma, and respiratory failure.

During the treatment period, alcoholic drinks should be excluded.

Cancel amitriptyline should be gradual, as with the sudden discontinuation of treatment after long-term treatment, especially in high doses, the development of the syndrome of "withdrawal" is possible.

Due to the m-holinoblokiruyuschey action of amitriptyline, an attack of increased intraocular pressure, as well as a possible decrease in tear and a relative increase in the amount of mucus in the composition of tear fluid, which can lead to damage to the epithelium of the cornea in patients using contact lenses.

A case of a lethal arrhythmia occurred 56 hours after an overdose of amitriptyline.

In suicidal patients, suicidal risk persists during treatment until a significant improvement in depressive symptoms occurs.Since the effect of amitriptyline occurs in 2-4 weeks, suicidal patients require careful monitoring until the condition improves. For patients who have previously had suicidal phenomena or had pronounced suicidal thoughts, or who attempted to commit suicide before or during treatment, continuous medical supervision is required. Storage and dispensing of medicinal products must be carried out by authorized persons. Amitriptyline (like other antidepressants) can itself increase the incidence of suicides in people under 24 years of age, so when assigning amitriptyline in young people (younger than 24 years), you should correlate the risk of suicide and the benefits of their use.

In patients with manic-depressive syndrome, treatment with amitriptyline may provoke a manic phase. When manic symptoms appear amitriptyline should be canceled.

In patients receiving three / tetracyclic antidepressants, local and general anesthetics, the risk of arrhythmia and a drop in blood pressure may be increased. If possible, amitriptyline should be discontinued before surgery.In case of emergency operations, the anesthetist should be informed of the use of amitriptyline. Amitriptyline Nycomed can affect the effect of insulin and the change in glucose concentration after a meal. This may require correction of hypoglycemic therapy in patients with diabetes mellitus. The state of depression can also affect glucose metabolism. The simultaneous use of other m-holinoblokatorov can enhance the m-holinoblokiruyuschee effect of amitriptyline.

Patients should inform their dentist about taking amitriptyline. Dryness in the mouth can lead to a change in the mucous membrane of the mouth, inflammation, burning sensation and tooth decay. It is recommended to have a regular check-up at the dentist.

Effect on the ability to drive transp. cf. and fur:During the treatment period, amitriptyline is not recommended for the management of vehicles and moving mechanisms.

Form release / dosage:

Tablets, film-coated 10 mg and 25 mg.

Packaging:

For 50 tablets in a vial of dark glass, sealed with a screw cap made of polypropylene, under which is installed a gasket with a ring for tearing, providing control of the first opening.

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

At a temperature of 15 to 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N012536 / 01

Date of registration:13.10.2011 / 01.12.2014

Expiration Date:Unlimited

The owner of the registration certificate:Takeda Pharma A / STakeda Pharma A / S Denmark

Manufacturer: & nbsp

Takeda Pharma A / S Denmark

Representation: & nbspTAKEDA TAKEDA Japan

Information update date: & nbsp13.09.2017

Illustrated instructions

Instructions

Amitriptyline Nycomed (Amitriptyline Nycomed)