Amitriptyline 10 mg/ml, 2 ml, 10 pcs

1 ml of intramuscular administration solution contains:

active substance:

amitriptylin hydrochloride (in terms of amitriptyline) - 10 mg.

Pharmacodynamics

Amitriptilin is an antidepressant (tricyclic antidepressant). It also has some analgesic (central genesis), H2-histamine blocking and antiserotonin effect, helps eliminate night urinary incontinence and reduces appetite. It has a strong peripheral and central anticholinergic effect due to high affinity for m-choline receptors; a strong sedative effect associated with affinity for H1-histamine receptors, and alpha-adrenoblocking effect.

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

With prolonged use, it reduces the functional activity of beta-adrenergic and serotonin receptors of the brain, normalizes adrenergic and serotonergic transmission, restores the balance of these systems, disturbed by depressive conditions. In anxiety-depressive conditions, it reduces anxiety, agitation and depression. The mechanism of antiulcer action is due to the ability to block H2-histami-new receptors in parietal cells of the stomach, as well as to have sedative and m-choline-blocking effect (in case of stomach and duodenal ulcers relieves pain, accelerates ulcer healing).

The effectiveness of night urinary incontinence seems to be due to anticholinergic activity, leading to an increase in the ability of the bladder to stretch, direct beta-adrenergic stimulation, the activity of alpha-adrenergic agonists, accompanied by an increase in the tone of the sphincter, and the central blockade of serotonin capture. It has a central analgesic effect, which is believed to be associated with changes in the concentration of monoamines in the CNS, especially serotonin, and the effect on endogenous opioid systems. The mechanism of action in case of nervous bulimia is unclear (may be similar to that of depression). A distinct effect of the drug in bulimia in patients both without depression and in its presence has been shown, while a decrease in bulimia can be noted without concomitant weakening the depression itself. When performing general anesthesia, it reduces blood pressure (BP) and body temperature. Does not inhibit monoamine oxidase (MAO). The antidepressant effect develops within 2-3 weeks after the start of use.

Suction
Amitriptyline has high absorption. The maximum concentration in blood plasma (Cmax) is 0.04-0.16 μg/ml. Equilibrium concentration is achieved about 1-2 weeks after the start of course treatment. The concentration of amitriptylin in tissues is higher than in blood plasma. Bioavailability of amitriptyline in various ways of administration is 33-62%, its active metabolite nortriptyline is 46-70%. Distribution volume (Vd) - 5-10 l/kg. Effective therapeutic concentrations of amitriptylin 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 histohematological barriers, including the blood-brain barrier (including nortriptyline), penetrates through the placental barrier, is released into breast milk in concentrations similar to plasma ones.

Metabolism
Amitriptylin metabolism is carried out mainly through demethylation (isoenzymes CYP2D19, CYP3A) and hydroxylation (isoenzyme CYP2D6) with subsequent conjugation with glucuronic acid. Metabolism is characterized by significant genetic polymorphism. The main active metabolite is secondary amine - nortriptyline. Metabolites cis- and trans-10-hydroxyamitryptylene and cis- and trans-10-hydroxynortriptilin are characterized by a similar profile of activity to nortriptyline, although their action is much weaker.

Demetylnortriptyline and amitriptyline-N-oxide are present in blood plasma in negligible concentrations; the latter metabolite is practically devoid of pharmacological activity. Compared to amitriptylin, all metabolites have a much less pronounced m-choline-blocking effect.
The main factor determining renal clearance and, accordingly, plasma concentration is the hydroxylation rate. A small proportion of people have genetically conditioned delayed hydroxylation.

Withdignment
The half-life (T1/2) from blood plasma is 10-28 hours for amitriptyline, for nortriptyline - 16-80 hours. The average total clearance of amitriptylin 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 administered amitriptylin is excreted in the urine in the form of 10-hydroxy-amitriptyline and its conjugate with glucuronic acid, about 27% is excreted in the form of 10-hydroxy-nortriptylin and less than 5% of amitriptyline is excreted as a source substance and nortriptyline. Complete elimination of amitriptylin from the body takes place within 7 days.

Elderly patients
In elderly patients, there is an increase in the half-life and a decrease in amitriptylin clearance due to a decrease in metabolism rate.

Patients with liver disorders
Liver dysfunction can slow down the metabolism of amitriptylin and increase its plasma concentrations.

Patients with kidney dysfunction
In patients with kidney dysfunction, the excretion of amitriptyline and nortriptyline metabolites is slow, although metabolism as such does not change. Due to the connection with blood proteins, amitriptyline is not removed from blood plasma by dialysis.

Endogenous depressions and other depressive disorders.

• Hypersensitivity,
• use in conjunction with MAO inhibitors and 2 weeks before treatment,
• myocardial infarction (acute and subacute periods),
• arrhythmia,
• severe violations of atrioventricular and intraventricular conduction (blockade of the legs of the Gis beam, atrioventricular blockade of Art. II),
• heart failure,
• acute alcohol intoxication, acute intoxication with sleeping pills, analgesic and psychoactive drugs,
• closed-angle glaucoma,
• urine retention, including prostate hyperplasia,
• paralytic intestinal obstruction,
• gatekeeper stenosis,
• hypokalemia,
• concomitant use of drugs that lengthen the QT interval or cause hypokalemia,
• lactation period,
• children under 18 years of age.

From the hematopoietic organs: rarely - inhibition of bone marrow function, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia; frequency unknown - purple.

From the metabolic side: very often - increase in body weight, increased appetite; rarely - decreased appetite; very rarely - syndrome of inadequate hypersecretion of antidiuretic hormone; frequency unknown - hypo- or hyperglycemia, hyponatremia (decreased vasopressin production), hypoproteinemia.

From the nervous system: very often - drowsiness, tremors, dizziness, headaches, confusion (in elderly patients, confusion can manifest itself by anxiety, excitement, elements of hallucinatory delusional disorders), disorientation; often - decreased concentration, taste disorders (dysgeusia), peripheral neuropathy (paresthesia), agitation, increase and strengthening of epileptic seizures, extrapyramid symptoms: ataxia, akathisia, parkinsonism, dystonic reactions, late dyskinesia, speech delay; infrequently - weakening cognitive behavior of ending hypomania, mania, anxiety, insomnia, "nightmarine" dreams; rarely - aggressive, temporal disease (vegetations), severe halicinalypheral diseases (vestitis; very rare treatment of patients with elderly people; depersonalization, increased depression, yawning, activation of symptoms of psychosis, myoclonus, dysarthria, changes in the electroencephalogram (EEG).

On the part of the senses: very often - reduced visual acuity, impaired accommodation; often - midriase; infrequently - by exertion of intraocular pressure, tinnitus, rarely - loss of ability to accommodation, aggravation of narrow-angle glaucoma in the elderly.
From the cardiovascular system: very often - heartbeat sensation, tachycardia, orthostatic hypotension; often - atrioventricular blockade (AV blockade), intraventricular conduction disorders registered only on the ECG, but not clinically (increase in PQ, QT intervals, expansion of QRS complex, signs of blockade of the legs of the Gis beam, non-specific changes in the ST interval or tooth T, including in patients without heart diseases); infrequently - arterial hypertension, arrhythmia, rarely - myocardial infarction.

From the digestive system: very often - dry mouth, constipation, nausea; often - gum atrophy, inflammation of the oral cavity, tooth decay, burning sensation in the mouth; infrequently - diarrhea, vomiting, tongue swelling; rarely - increase in the salivary glands, paralytic intestinal obstruction, hepatitis (including liver function disorders and cholestatic jaundice); frequency is unknown - heartburn, gastralgia, darkening of the tongue.

From the skin: very often - hyperhidrosis; infrequently - skin rash, itching of the skin, hives, angioneurotic edema; rarely - alopecia, photosensitization reactions, hair loss. From the urinary system: infrequently - urinary retention, frequency unknown - pollak
On the part of the reproductive system: very often - weakening or increasing sex drive; often - in men impaired erection disorders, impotence; rarely - in women of the galaxy, delay in orgasm, loss of ability to reach orgasm, in men increase in the size (swelling) of the testicles, delay in ejaculation, gynecomastia.
Laboratory indicators: often - ECG change: increase in PQ, QT intervals, expansion of the QRS complex, signs of blockage of the legs of the Gis beam, non-specific changes in the ST interval or tooth T; rarely - violation of liver functional state indicators, increase in the activity of alkaline blood phosphatase and transaminase.

Others: often - fatigue; rarely - pyrexia, frequency unknown - decrease in sweating, increase in lymph nodes.
Symptoms of cancellation: after prolonged use, unwanted reactions such as nausea, vomiting, diarrhea, headache, malaise, insomnia, unusual dreams, unusual excitement, irritability may occur; after prolonged use with gradual cancellation - irritability, sleep disorders, unusual dreams. There is no connection with taking the drug: lupus-like syndrome (migrating arthritis, the appearance of antinuclear antibodies and positive rheumatoid factor), aheusia.
Some of the undesirable reactions, such as headache, tremors, impaired concentration, constipation and decreased libido, can be manifestations of depression and disappear as depression is resolved.

When using ethanol and drugs that inhibit the CNS together (including other antidepressants, barbiturates, benzadiazepines and general anesthetics), a significant increase in the oppressive effect on the CNS, respiratory depression and hypotensive effect is possible. Increases sensitivity to drinks containing ethanol. Increases the anticholinergic effect of drugs with anticholinergic activity (e.g. phenothiazines, antiparkinsonic drugs, amantadine, atropine, biperidene, antihistamine drugs), which increases the risk of side effects (from the CNS, vision, intestines and bladder).

When used in conjunction with antihistamine drugs, clonidine - increased oppressive effect on the CNS; with atropine - increases the risk of paralytic intestinal obstruction; with drugs that cause extrapyramidal reactions - increase the severity and frequency of extrapyramidal effects. Simultaneous use of amitriptyline and indirect anticoagulants (coumarin or indadion derivatives) may increase the anticoagulant activity of the latter. Amitriptyline can increase depression caused by glucocorticosteroids (GCS).

When used in conjunction with anticonvulsant drugs, it is possible to increase the oppressive effect on the CNS, reduce the threshold of convulsive 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-adrenoblockers. Microsomal oxidation inhibitors (cimetidine) lengthen T1/2, increase the risk of developing toxic effects of amitriptyline (it may be necessary to reduce the dose by 20-30%), inductors of microsomal liver enzymes (barbiturates, carbamazepine, phenytoin, nicotin and oral contraceptives) reduce plasma concentration and reduce the effectiveness of amitriptylin. Fluoxetine and fluvoxamine increase the concentration of amitriptylin in plasma (it may be necessary to reduce the dose of amitriptylin by 50%).

When used in conjunction with choline blockers, phenothiazines and benzodiazepines, mutual strengthening of sedative and central choline blocking effects and increasing the risk of epileptic seizures (reducing the threshold of convulsive activity); phenothiazines can also increase the risk of neuroleptic malignant Simultaneous use of amitriptyline with clonidine, guanetidin, betainidine, reserpine and methyldop - a decrease in the hypotensive effect of the latter; with cocaine - the risk of heart arrhythmias. Estrogens-containing oral contraceptive drugs and estrogens can increase the bioavailability of amitriptyline; antiarrhythmic drugs (such as quinidine) increase the risk of rhythm disorders (may be slowing down the metabolism of amitriptylin).

Combined use with disulfiram and other acetaldehydrogenase inhibitors provokes delirium. Incompatible with MAO inhibitors (possible increase in the frequency of hyperpyrexia periods, severe seizures, hypertensive crises and patient death). Pimosis and plug can increase heart arrhythmia, which manifests itself in the lengthening of the Q-T interval on the ECG. Enhances the effect of epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine on CVS (including when these drugs are part of local anesthetics) and increases the risk of heart rhythm disorders, tachycardia, severe arterial hypertension.

When used together with alpha-adrenostimulants for intranasal administration or for use in ophthalmology (with significant systemic absorption), the vasoconstrictive effect of the latter may increase. When taken together with thyroid hormones - mutual enhancement of therapeutic effect and toxic action (including heart arrhythmia and stimulating effect on the CNS). M-choline blockers and antipsychotic drugs (neuroleptics) increase the risk of hyperpyrexia (especially in hot weather). When administered together with other hematotoxic drugs, hematotoxicity may increase.

Intramuscularly at a dose of 10-20-30 mg up to 4 times a day, the dose increase should be carried out gradually, the maximum daily dose is 150 mg; in 1-2 weeks, if possible, they switch to orally. The duration of treatment is no more than 6-8 months.

Elderly people are given lower doses and increased more slowly.
Amitriptyline can be prescribed at normal doses to patients with renal failure.

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

Symptoms:
From the CNS side: drowsiness, stupor, coma, ataxia, hallucinations, anxiety, psychomotor arousal, reduced ability to concentrate, disorientation, confusion, dysarthria, hyperreflection, muscle rigidity, choreoatetosis, epileptic syndrome.

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

Others: respiratory depression, shortness of breath, cyanosis, vomiting, hyperthermia, mydriasis, increased sweating, oliguria or anuria.

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

Treatment: symptomatic and supportive therapy; with severe anticholinergic effects (reduction of blood pressure, arrhythmia, coma, myoclonal epileptic seizures) - administration of cholinesterase inhibitors (the use of physiostigmin is not recommended due to the increased risk of seizures); maintaining blood pressure and water-electrolyte balance. Control of CVS functions (including ECG) for 5 days (recurrence may occur in 48 hours or later), anticonvulsant therapy, artificial lung ventilation (IVL) and other resuscitation measures are shown.
Hemodialysis and forced diuresis are ineffective.

Before starting treatment, BP control is necessary (in patients with reduced or labile blood pressure, it may decrease even more); during treatment - peripheral blood control (in some cases, agranulocytosis may develop, so it is recommended to monitor the blood picture, especially when body temperature rises, influenza-like symptoms and tonsillitis), during prolonged therapy -

Treatment with amitriptylin in old age should be carefully controlled, with minimal doses of the drug and their gradual increase, in order to avoid the development of delirium disorders, hypomania and other complications. In the elderly and patients with diseases of cardiovascular function, heart rate control (heart rate), blood pressure, ECG is indicated. Clinically insignificant changes may appear on the ECG (smoothing of the T tooth, depression of the ST segment, expansion of the QRS complex).
When using the drug at high doses, the likelihood of heart rhythm disorders and severe arterial hypotension increases. 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 a hospital, under the supervision of a doctor, in compliance with bed rest in the first days of therapy.
Care is needed when moving sharply to an upright position from a "lying down" or "sitting" position.
Alcohol consumption should be excluded during treatment.
Prescribed no earlier than 14 days after the abolition of MAO inhibitors, starting with small doses.
In case of sudden termination of admission after long-term treatment, the development of "cancellation" syndrome may develop.
Symptoms of cancellation: headache, nausea, vomiting, diarrhea, malaise, sleep disorders, unusual dreams, agitation, motor anxiety, irritability and general poor health.

Amitriptyline at doses above 150 mg/day lowers the threshold of convulsive activity (the risk of epileptic seizures in predisposed patients should be taken into account, as well as in the presence of other factors predisposing to convulsive syndrome, such as brain damage of any etiology, simultaneous use of antipsychotic drugs (neuroleptics), during the period of refusal of alcohol or withdrawal of drugs with anticonvulsant properties, such as benzodiazepines).
Simultaneous use of amitriptylin, neuroleptics and sleeping pills (droperidol) should be avoided. Extreme caution should be exercised if necessary to take simultaneous administration.

When amitriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may increase - in this case, amitriptyline should be prescribed in combination with neuroleptics.
Pronounced depressions are characterized by a risk of suicidal actions, which can persist until significant remission is achieved. In this regard, at the beginning of treatment, a combination of medicines from the group of benzodiazepines or neuroleptic drugs and constant medical control (to insure trustees the storage and issuance of medicines) may be indicated.
Patients with cyclic affective disorders may develop manic or hypomanic conditions against the background of therapy (it is necessary to reduce the dose or cancel the drug and prescribe an antipsychotic drug). After stopping these conditions, if there are indications, low dose treatment may be resumed.

Due to possible cardiotoxic effects, caution is required when treating patients with thyrotoxicosis or patients receiving thyroid hormones.
In combination with electroconvulsive therapy, it is prescribed only with careful medical supervision.
Predisposed and elderly patients can provoke the development of medicinal psychosis, mainly at night (after the withdrawal of the drug they take place within a few days).
It can cause paralytic intestinal obstruction, mainly in patients with chronic constipation, the elderly or in patients forced to observe bed rest.

Care should be taken when prescribing the drug to patients with liver disorders, if possible, the concentration of amitriptylin in blood plasma should be monitored.
Patients with renal failure can be prescribed the drug in normal dosages.
The drug is contraindicated in patients with prostate hyperplasia, especially with urination delay (see section "Contraindications").
Patients receiving three/tetracyclic antidepressants simultaneously with local and general anesthetics may have an increased risk of arrhythmia and lower blood pressure.
Before general or local anesthesia, an anesthesiologist should be warned that the patient is taking amitriptyline.

Due to the anticholinergic effect, it is possible to reduce tear separation and a relative increase in the amount of mucus in the lacrimal fluid, which can lead to damage to the corneal epithelium in patients using contact lenses.
Patients should inform their dentist about taking amitriptylin.
Dry mouth can lead to changes in the mucous membrane of the oral cavity, inflammatory phenomena, burning sensation and tooth decay. It is recommended to undergo regular examination by the dentist. The need for riboflavin may be increased.
Taking amitriptylin can change the body's tolerance to insulin and glucose, which requires correction of antidiabetic therapy in patients with diabetes. The state of depression can also affect glucose metabolism.
Cases of hyperpyrexia against the background of tricyclic antidepressants when prescribed simultaneously with anticholinergic or neuroleptic drugs, especially in hot weather, are reported.

The study of reproduction on animals revealed an adverse effect on the fetus, and no adequate and strictly controlled studies were conducted in pregnant women. In pregnant women, the drug should be used only if the intended benefit to the mother exceeds the potential risk to the fetus.
Penetrates breast milk and can cause drowsiness in infants.
In order to avoid the development of "cancellation" syndrome in newborns (shows of breath, drowsiness, intestinal colic, increased nervous excitability, hypotension or hypertension, tremors or spastic phenomena), amitriptylin is gradually canceled at least 7 weeks before the expected birth.
Children are more sensitive to an acute overdose, which should be considered dangerous and potentially deadly for them.

Suicide/suicidal thoughts or clinical deterioration of the disease
Depression is accompanied by an increased risk of suicide. This risk persists until significant remission is achieved and can occur spontaneously during the course of therapy. Since the antidepressive effect develops only a few weeks after the start of treatment, the patient's condition should be carefully monitored until clinical improvement is achieved. Suicidal risk may increase early recovery.
Constant medical control is necessary for patients with suicidal thoughts and suicide attempts in the history, including against the background of therapy. Storage and issuance of medicines to such patients must be carried out by proxies.
Amitriptyline (like other antidepressants) can itself increase the incidence of suicide in persons under 25 years of age. Therefore, when prescribing amitriptylin to patients under 25 years of age, the risk of suicide and the benefits of using an antidepressant should be correlated. In short-term studies, the risk of suicide does not increase in people over 25 years of age, and in people over 65 years of age decreases slightly.

Any depressive disorder itself increases the risk of suicide, so during antidepressant treatment, all patients should be monitored for early detection of disorders or behavior changes, as well as suicidal tendencies. Impact on the ability to drive vehicles and mechanisms
During treatment, care should be taken when driving vehicles and engaging in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Solution for intramuscular administration