Amitriptyline ampoules 1% 2 ml №10

Pharmacology

Pharmacodynamics
Amitriptyline is an antidepressant (tricyclic antidepressant). It also has some analgesic (central genesis), H2-histamine-blocking and antiserotonin action, helps eliminate bed-wetting and reduces appetite. It has a strong peripheral and central anticholinergic action due to its high affinity for m-cholinergic receptors; strong sedative effect associated with affinity for H1-histamine receptors, and alpha-adreno-blocking action.

It has the properties of an antiarrhythmic drug (LS) of the subgroup Ia, like quinidine in therapeutic doses slows down ventricular conductivity (with an overdose it can cause severe intraventricular blockade). The mechanism of antidepressant action is associated with an increase in the concentration of norepinephrine in the synapses and / or serotonin in the central nervous system (CNS) (a decrease in their reverse absorption). The accumulation of these neurotransmitters occurs as a result of inhibition of their reuptake by the membranes of presynaptic neurons.

With prolonged use reduces the functional activity of beta-adrenergic and serotonin receptors in the brain, normalizes adrenergic and serotonergic transmission, restores the balance of these systems, disturbed in depressive states.In anxiety and depressive states, it reduces anxiety, agitation and depressive manifestations. The mechanism of anti-ulcer action is due to the ability to block H2-histamine-new receptors in the parietal cells of the stomach, as well as to have a sedative and m-anticholinergic action (in case of peptic ulcer and 12 duodenal ulcers, it reduces pain and accelerates ulcer healing).

Efficacy in nocturnal urinary incontinence is apparently due to anticholinergic activity leading to an increase in bladder's ability to stretch, direct beta-adrenergic stimulation, alpha adrenergic agonist activity, accompanied by an increase in sphincter tone, and a central blockade of serotonin uptake. It has a central analgesic effect, which is believed to be associated with changes in the concentration of monoamines in the central nervous system, especially serotonin, and the effect on endogenous opioid systems. The mechanism of action in bulimia nervosa is unclear (may be similar to that in depression). A distinct effect of the drug in case of bulimia in patients with and without depression is shown, and a decrease in bulimia may occur without a concomitant weakening of the depression itself. When performing general anesthesia, it lowers blood pressure (BP) and body temperature. Does not inhibit monoamine oxidase (MAO). Antidepressant effect develops within 2-3 weeks after the start of the application.

Suction
Amitriptyline has a high absorption. The maximum concentration in the blood plasma (Сmax) is 0.04-0.16 mcg / ml. Equilibrium concentration is reached approximately 1-2 weeks after the start of the course of treatment. The concentration of amitriptyline in tissues is higher than in plasma. The bioavailability of amitriptyline with various routes of administration is 33-62%, its active metabolite nortriptyline is 46-70%. The 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. Communication with plasma proteins - 92-96%. Amitriptyline passes through histohematological barriers, including the blood-brain barrier (including nortriptyline), penetrates the placental barrier, is secreted into breast milk at concentrations similar to those of the plasma.

Metabolism
Amitriptyline is metabolized mainly by demethylation (CYP2D19, CYP3A isoenzymes) and hydroxylation (CYP2D6 isoenzyme), followed by conjugation with glucuronic acid. Metabolism is characterized by significant genetic polymorphism. The main active metabolite is a secondary amine, nortriptyline. The cis- and trans-10-hydroxyamitriptyline and cis- and trans-10-hydroxynortriptyline metabolites are characterized by a similar activity profile to nortriptyline, although their effect is much less pronounced.

Demetilnortriptilin and amitriptyline-N-oxide are present in plasma in insignificant concentrations; the last metabolite is almost devoid of pharmacological activity.In comparison with amitriptyline, all metabolites have a significantly less pronounced m-anticholinergic action.
The main factor determining renal clearance and, accordingly, concentration in the blood plasma, is the rate of hydroxylation. A small proportion of people have genetically determined delayed hydroxylation.

Removal
The elimination half-life (T1 / 2) from blood plasma is 10-28 h for amitriptyline, for nortriptilin it is 16-80 h. The average total clearance of amitriptyline is 39.24 ± 10.18 l / h. Amitriptyline is excreted mainly by the kidneys and through the intestines in the form of metabolites. About 50% of the injected amitriptyline is excreted with urine as 10-hydroxy-amitriptyline and its glucuronic acid conjugate, about 27% is excreted as 10-hydroxy-nortriptyline, and less than 5% of amitriptyline is excreted as the starting material and nortriptyline. The complete elimination 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 the metabolic rate.

Patients with impaired liver function
Impaired liver function can lead to a slowdown in the metabolism of amitriptyline and an increase in its plasma concentrations.

Indications

Endogenous depression and other depressive disorders.

Contraindications

• Hypersensitivity
• use together with MAO inhibitors and 2 weeks before the start of treatment,
• myocardial infarction (acute and subacute periods),
• arrhythmias,
• severe violations of atrioventricular and intraventricular conduction (blockade of the bundle of the bundle of His, atrioventricular block II of Art. II),
• heart failure,
• acute alcohol intoxication, acute intoxication with hypnotic, analgesic and psychoactive drugs,
• angle-closure glaucoma,
• urinary retention, including prostatic hyperplasia,
• paralytic intestinal obstruction,
• pyloric stenosis,
• hypokalemia,
• concomitant use of drugs that prolong the QT interval, or cause hypokalemia,
• lactation period
• children's age up to 18 years.

Pregnanacy and breastfeeding

If the drug is used by pregnant women, it is necessary to warn about the high risk of such admission to the fetus, especially in the I and III 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. There have been cases of drowsiness in newborns whose mothers used nortriptyline (amitriptyline metabolite) during pregnancy, there have been cases of urinary retention.

Amitriptyline passes into breast milk.The ratio of concentrations of breast milk / plasma is 0.4-1.5 in a child who is breastfed.
When using amitriptyline, breastfeeding should be discontinued.
If this is not done, the condition of the baby should be monitored, especially during the first four weeks after birth.
An infant who is breastfed may experience undesirable reactions.

Special notes

Before treatment, control of blood pressure is necessary (in patients with low or labile blood pressure, it may decrease even more); during treatment - control of peripheral blood (in some cases agranulocytosis may develop, and therefore it is recommended to monitor the blood picture, especially when the body temperature rises, the development of flu-like symptoms and tonsillitis); .

Treatment with amitriptyline in old age should be carried out under close supervision, with the use of minimum doses of the drug and their gradual increase, in order to avoid the development of delirious disorders, hypomania and other complications. In the elderly and patients with diseases of the functions of the cardiovascular system, control over the number of heartbeats (HR), blood pressure, ECG is shown. Clinically insignificant changes are possible on the ECG (smoothing of the T wave, depression of the ST segment, expansion of the QRS complex).
The use of the drug in high doses increases the likelihood of heart rhythm disturbances and severe arterial hypotension.The development of such conditions is also possible with the use of conventional doses in patients with heart disease.

The use of the drug is possible only in the hospital, under the supervision of a physician, in compliance with bed rest in the first days of therapy.
Care must be taken when abruptly moving to a vertical position from a "lying" or "sitting" position.
During the period of treatment should be excluded alcohol.
Assign no earlier than 14 days after the abolition of MAO inhibitors, starting with small doses.
With a sudden cessation of treatment after prolonged treatment may develop a syndrome of "cancellation."
Withdrawal symptoms: headache, nausea, vomiting, diarrhea, malaise, sleep disturbances, unusual dreams, agitation, motor restlessness, irritability, and general ill health.

Amitriptyline in doses above 150 mg / day reduces the threshold for seizure activity (consider the risk of epileptic seizures in susceptible patients, as well as in the presence of other factors predisposing to the onset of convulsive syndrome, such as brain damage of any etiology, simultaneous use of antipsychotic drugs (neuroleptics), in the period of refusal from alcohol or withdrawal of drugs with anticonvulsant properties, such as benzodiazepines).
The simultaneous use of amitriptyline, neuroleptics and hypnotic drugs (droperidol) should be avoided.If necessary, the simultaneous reception should be extremely careful.

If amitriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be exacerbated — in this case, it is advisable to prescribe amitriptyline in combination with neuroleptics.
Severe depression is characterized by the risk of suicidal acts, which can persist until a significant remission is achieved. In this regard, at the beginning of treatment, a combination with drugs from the group of benzodiazepines or antipsychotic drugs and constant medical supervision (to delegate storage and distribution of drugs) can be shown.
In patients with cyclic affective disorders during the depressive phase during therapy, manic or hypomania states may develop (a dose reduction or withdrawal of the drug and the prescription of an antipsychotic drug are necessary). After stopping these conditions, if there are indications, treatment in low doses can be resumed.

Due to possible cardiotoxic effects, care must be taken when treating patients with thyrotoxicosis or patients receiving thyroid hormone preparations.
In combination with electroconvulsive therapy is prescribed only under the condition of careful medical supervision.
In predisposed patients and elderly patients, it can provoke the development of medicinal psychoses, mainly at night (after discontinuation of the drug, they disappear within a few days).
It can cause paralytic intestinal obstruction, mainly in patients with chronic constipation, the elderly or in patients forced to adhere to bed rest.

Care must be taken when prescribing the drug to patients with impaired liver function, should, if possible, monitor the concentration of amitriptyline in the blood plasma.
Patients with renal insufficiency, the drug can be prescribed in the usual dosages.
The drug is contraindicated in patients with prostatic hyperplasia, especially with urinary retention (see section "Contraindications").
In patients receiving three / tetracyclic antidepressants simultaneously with local and general anesthetics, the risk of arrhythmia and a drop in blood pressure may be increased.
Prior to general or local anesthesia, the anesthetist should be warned that the patient is taking amitriptyline.

Due to the anticholinergic action, there can be a decrease in tearing and a relative increase in the amount of mucus in the composition of the tear fluid, which can lead to corneal epithelium damage in patients using contact lenses.
Patients should inform their dentist about taking amitriptyline.
Dry mouth can lead to changes in the oral mucosa, inflammation, burning sensation and dental caries. It is recommended to be regularly examined by a dentist. The need for riboflavin may be increased.
Reception of amitriptyline can change the body's tolerance to insulin and glucose, which requires correction of anti-diabetic therapy in patients with diabetes mellitus. Depression can also affect glucose metabolism.
It is reported about cases of hyperpyrexia on the background of the use of tricyclic antidepressants when prescribed simultaneously with anticholinergic or neuroleptic drugs, especially in hot weather.

The study of reproduction in animals revealed an adverse effect on the fetus, and adequate and strictly controlled studies in pregnant women have not been carried out. In pregnant women, the drug should be used only if the intended benefit to the mother outweighs the potential risk to the fetus.
Penetrates into breast milk and may cause drowsiness in infants.
In order to avoid the development of the "cancellation" syndrome in newborns (manifested by shortness of breath, drowsiness, intestinal colic, increased nervous irritability, hypotension or hypertension, tremor or spastic phenomena), amitriptyline is gradually canceled at least 7 weeks before the expected birth.
Children are more sensitive to acute overdose,which should be considered dangerous and potentially lethal to them.

Suicide / suicidal thoughts or clinical worsening of the course of the disease
Depression is associated with an increased risk of suicides. This risk persists until significant remission is achieved and may occur spontaneously throughout the course of therapy. Since the antidepressant effect develops only a few weeks after the start of treatment, the patient’s condition should be carefully monitored until clinical improvement is achieved. Possible increase in suicidal risk in the early stages of recovery.
There is a need for constant medical monitoring of patients with suicidal thoughts and suicidal attempts in history, including on the background of therapy. Storage and distribution of medicines to such patients should be carried out by authorized agents.
Amitriptyline (like other antidepressants) can itself increase the incidence of suicides in people under 25 years of age. Therefore, when prescribing amitriptyline in patients younger than 25 years old, the risk of suicide should be correlated with the benefit of using an antidepressant. In short-term studies in people over 25 years of age, the risk of suicide does not increase, and in people over 65 years old it decreases somewhat.

Any depressive disorder in itself increases the risk of suicide, so during treatment with antidepressants all patients should be monitored with the aim of early detection of violations or behavioral changes, as well as suicidal tendencies.Influence on ability to drive vehicles and mechanisms
During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and psychomotor speed.

Composition

1 ml solution for intramuscular injection contains:
active substance: amitriptyline hydrochloride (in terms of amitriptyline) - 10 mg.

Dosage and administration

Intramuscularly in a dose of 10-20-30 mg up to 4 times a day, the dose should be increased gradually, the maximum daily dose of 150 mg; after 1-2 weeks, if possible, switch to the drug inside. The duration of treatment is not more than 6-8 months.
Older people are administered lower doses and increase them more slowly.
Amitriptyline can be given in normal doses in patients with renal insufficiency.
If the patient's condition does not improve within 3-4 weeks of treatment, then further therapy is not appropriate.

Side effects

On the part of the blood-forming organs: rarely - inhibition of bone marrow function, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia; frequency unknown - purpura.
On the part of the metabolism: very often - an increase in body weight, increased appetite; rarely, decreased appetite; very rarely - inadequate hypersecretion syndrome antidiuretic hormone; the frequency is unknown - hypo-or hyperglycemia, hyponatremia (decreased vasopressin production), hypoproteinemia.
On the part of the nervous system: very often - drowsiness, tremor, dizziness, headaches, confusion (in older patients, confusion may be manifested by anxiety, agitation, elements of hallucinatory delusional disorders), disorientation; often - decreased concentration, taste disturbance (dysgeusia), peripheral neuropathy (paresthesia), agitation, increased and increased epileptic seizures, extrapyramidal symptoms: ataxia, akathisia, parkinsonism, dystonic reactions, late dyskinesia, speech slowness; infrequently - weakening of cognitive abilities, hypomania, mania, anxiety, insomnia, “nightmarish” dreams; rarely, aggressiveness, delirium (in the elderly), hallucinations (in patients with schizophrenia), convulsions; very rarely - during the period of treatment with amitriptyline and shortly after its completion suicidal thoughts, suicidal behavior; frequency is unknown - fainting, depersonalization, increased depression, yawning, activation of symptoms of psychosis, myoclonus, dysarthria, changes in electroencephalogram (EEG).

On the part of the senses: very often - reduced visual acuity, disturbance of accommodation; often - mydriasis; infrequently - increased intraocular pressure, tinnitus, rarely - loss of ability to accommodate, aggravation of narrow-angle glaucoma in the elderly.
Since the cardiovascular system: very often - a sensation of heartbeat, tachycardia,orthostatic hypotension; often - atrioventricular block (AV block), a violation of intraventricular conduction, recorded only on the ECG, but not manifested clinically (increased PQ, QT intervals, extended QRS complex, signs of blockade of the bundle of His, non-specific changes in the ST interval or T wave, in t. h in patients without heart disease)); infrequently - arterial hypertension, arrhythmia, rarely - myocardial infarction.
On the part of the digestive system: very often - dry mouth, constipation, nausea; often - atrophy of the gums, inflammation of the oral cavity, dental caries, burning sensation in the mouth; infrequently - diarrhea, vomiting, swelling of the tongue; rarely, an increase in the salivary glands, paralytic intestinal obstruction, hepatitis (including impaired liver function and cholestatic jaundice); frequency is unknown - heartburn, gastralgia, darkening of the tongue.

For the skin: very often - hyperhidrosis; infrequently - skin rash, itchy skin, urticaria, angioedema; rarely - alopecia, photosensitivity reactions, hair loss. On the urinary system: rarely - urinary retention, the frequency is unknown - pollauria.
On the part of the reproductive system: very often - weakening or increasing sexual desire; often - in men, erectile dysfunction, impotence; rarely - in women, galactorrhea, delayed orgasm, loss of ability to achieve orgasm, in men, increase in size (edema) of the testicles, delayed ejaculation, gynecomastia.
Laboratory indicators: often - ECG changes: an increase in the intervals of PQ, QT, expansion of the QRS complex, signs of blockade of the bundle of His, non-specific changes in the ST interval or T wave; rarely - a violation of the functional status of the liver, increased activity of blood alkaline phosphatase and transaminases.

Other: often - fatigue; rarely - pyrexia, the frequency is unknown - decreased sweating, swollen lymph nodes.
Withdrawal symptoms: after prolonged use with an abrupt cessation of use, undesirable reactions such as nausea, vomiting, diarrhea, headache, indisposition, insomnia, unusual dreams, unusual agitation, irritability may occur; after prolonged use with gradual cancellation - irritability, sleep disturbances, unusual dreams. The connection with the intake of the drug has not been established: lupus-like syndrome (migratory arthritis, the appearance of antinuclear antibodies and a positive rheumatoid factor), ageusia.
Some of the undesirable reactions, such as headache, tremor, impaired concentration, constipation and decreased libido can be manifestations of depression and disappear as depression resolves.

Drug interaction

When combined use of ethanol and drugs that depress the central nervous system (including other antidepressants, barbiturates, benzadiazepines and general anesthetics), a significant increase in the inhibitory effect on the central nervous system, respiratory depression and hypotensive effect is possible.Increases sensitivity to ethanol-containing beverages. Increases the anticholinergic effect of drugs with anticholinergic activity (for example, phenothiazines, antiparkinsonian drugs, amantadine, atropine, biperidine, antihistamine drugs), which increases the risk of side effects (from the central nervous system, vision, intestines and bladder).

When combined with antihistamine drugs, clonidine - increased inhibitory effects on the central nervous system; with atropine - increases the risk of paralytic intestinal obstruction; with drugs causing extrapyramidal reactions, an increase in the severity and frequency of extrapyramidal effects. With the simultaneous use of amitriptyline and indirect anticoagulants (coumarin or indadione derivatives), the anticoagulant activity of the latter can be increased. Amitriptyline can strengthen the depression caused by glucocorticosteroids (GKS).

When combined with anticonvulsant drugs may increase the inhibitory effect on the central nervous system, reducing the threshold of seizure activity (when used in high doses) and reduce the effectiveness of the latter. Drugs for the treatment of thyrotoxicosis increase the risk of agranulocytosis. Reduces the effectiveness of phenytoin and alpha-blockers. Inhibitors of microsomal oxidation (cimetidine) lengthen T1 / 2, increase the risk of developing toxic effects of amitriptyline (a dose reduction of 20-30% may be required), inducers of microsomal liver enzymes (barbiturates, Carbamazepine, phenytoin, nicotine and oral contraceptives) decrease plasma concentration. reduce the effectiveness of amitriptyline.Fluoxetine and fluvoxamine increase plasma concentration of amitriptyline (it may be necessary to reduce the dose of amitriptyline by 50%).

When combined with anticholinergics, phenothiazines and benzodiazepines, mutual reinforcement of the sedative and central anticholinergic effects and increased risk of epileptic seizures (lowering the seizure threshold); Phenothiazines, in addition, may increase the risk of neuroleptic malignant syndrome. With the simultaneous use of amitriptilin with clonidine, guanethidine, betanidin, reserpine and methyldopa - reducing the hypotensive effect of the latter; with cocaine - the risk of heart arrhythmias. Estrogen-containing oral contraceptive drugs and estrogens can increase the bioavailability of amitriptyline; antiarrhythmic drugs (such as quinidine) increase the risk of developing rhythm disturbances (possibly slowing down amitriptyline metabolism).

Combined use with disulfiram and other acetaldehyde hydrogenase inhibitors provokes delirium. Incompatible with MAO inhibitors (possible increase in the frequency of periods of hyperpyrexia, severe seizures, hypertensive crises and death of the patient). Pimozide and probucol can enhance cardiac arrhythmias, which is manifested in the prolongation of the Q-T interval on the ECG. It enhances the effect on the CVS of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine (including when these drugs are part of local anesthetics) and increases the risk of developing heart rhythm disorders, tachycardia, and severe arterial hypertension.

When used jointly with alpha-adrenostimulants for intranasal administration or for use in ophthalmology (with significant systemic absorption), the vasoconstrictor effect of the latter can be enhanced. When taken together with thyroid hormones, mutual enhancement of the therapeutic effect and toxic action (including cardiac arrhythmias and a stimulating effect on the central nervous system). M-holinoblokatory and antipsychotic drugs (neuroleptics) increase the risk of hyperpyrexia (especially in hot weather). In a joint appointment with other hematotoxic drugs may increase hematotoxicity.

Overdose

Symptoms:
From the side of the central nervous system: drowsiness, stupor, coma, ataxia, hallucinations, anxiety, psychomotor agitation, decreased ability to concentrate, disorientation, confusion, dysarthria, hyperreflexia, muscle rigidity, choreoathetosis, epileptic syndrome.

From the side of the cardiovascular system: reduction of blood pressure (BP), tachycardia, arrhythmia, violation of intracardiac conduction, changes in electrocardiogram (ECG) characteristic of intoxication with tricyclic antidepressants (especially QRS), shock; in very rare cases, cardiac arrest.

Other: respiratory depression, dyspnea, cyanosis, vomiting, hyperthermia, mydriasis, increased sweating, oliguria or anuria.

Symptoms develop 4 hours after an overdose, reach a maximum after 24 hours and last 4-6 days.If overdose is suspected, especially in children, the patient should be hospitalized.

Treatment: symptomatic and supportive therapy; with severe anticholinergic effects (lowering blood pressure, arrhythmias, coma, myoclonic epileptic seizures) - administration of cholinesterase inhibitors (the use of physostigmine is not recommended due to the increased risk of seizures); maintaining blood pressure and water-electrolyte balance. Control of functions of the cardiovascular system (including ECG) for 5 days (relapse may occur after 48 hours and later), anticonvulsant therapy, artificial lung ventilation (ALV) and other resuscitation measures are shown.
Hemodialysis and forced diuresis are ineffective.

In the dark place at a temperature of no higher than 25 ºС. Keep out of reach of children.