Saroten retard - instructions for use, dose, side effects, contraindications

Excipients - sugar spheres 123,074 mg, stearic acid 0,123 mg, shellac (uncoated shellac) 8,480 - 14,140 mg, talc 16,016 - 29,610 mg, povidone 0,724-1,086 mg.

Composition of an empty capsule - gelatin 65.0 mg, iron dye red oxide (E 172) 0.98 mg, titanium dioxide (E 171) 0.33 mg.

Description:

Hard, gelatin capsules, opaque; the case and a cover of a red-brown color. The size of capsules number 2.

Contents of capsules - pellets from almost white to yellowish color.

Pharmacotherapeutic group:antidepressant

ATX: & nbsp

N.06.A.A.09 Amitriptyline

Pharmacodynamics:

Amitriptyline in vivo approximately equally inhibits the re-uptake of norepinephrine and serotonin in the presynaptic nerve endings. The main metabolite of amitriptyline - nortriptyline - is relatively stronger oppresses the reuptake of norepinephrine than serotonin. It has m-cholinoblocking and H1-histaminoblocking activity.

Has a powerful antidepressant, as well as sedative and anxiolytic action.

Rapid sleep phase suppression (REM-phase) is considered as a predictor of antidepressant activity. Tricyclic antidepressants, as well as SSRIs and MAO inhibitors, suppress REM phase of sleep and increase the duration of deep slow wave sleep.

Pharmacokinetics:

Absorption

When using Saroten Retard capsules, the plasma concentrations of amitriptyline increase gradually, reaching a maximum after 7.1 ± 1.9 hours. In this case, the peak serum concentrations are lower than when using immediate-release amitriptyline dosage form.

The use of prolonged action capsules avoids high peak concentrations of amitriptyline, which are associated with an increased risk of cardiac complications.

Bioavailability of amitriptyline when ingested by Saroten Retard is about 48%.

Distribution

The apparent volume of distribution after intravenous administration of amitriptyline is 1221 ± 280 liters.

The degree of binding to plasma proteins is approximately 95%.

Amitriptyline and its main metabolite, nortriptyline, penetrate the placental barrier.

Biotransformation

The metabolism of amitriptyline is mainly due to demethylation (isoenzymes CYP2D19, 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-hydroxyamitriptyline and cis- and trans-10-hydroxynortryptiline have a similar activity profile to nortriptylin, although their effect is much weaker. Demethylnortriptyline and amitriptyline-1M-oxide are 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.

Excretion

The half-life of amitriptyline in the application of Saroten Retard is approximately 25 hours. The half-life of nortriptyline is about 27 hours. The average overall clearance of amitriptyline is 39.24 ± 10.18 l / h.

It is excreted mainly by the kidneys. In the application of Saroten Retard unchanged, approximately 2% of the accepted dose of amitriptyline is excreted.

Nursing mothers amitriptyline and nortriptyline in small amounts are excreted in breast milk. The concentration in breast milk is 2 times lower than in blood plasma.When breastfeeding amitriptyline, the child's body gets on average 2% of the dose taken by the mother, in terms of body weight (in mg / kg).

Equilibrium plasma concentrations of amitriptyline and nortriptyline in most patients are achieved within a week. When prolonged action capsules are used in the evening, the concentration of amitriptyline reaches its maximum values late at night and decreases throughout the day, whereas the concentration of nortriptyline remains stable during the day, thus the effects of nortriptyline dominate throughout the day.

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 impaired function liver

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

Patients with impaired renal function

Renal failure does not affect the kinetics of the drug.

Pharmacokinetic / pharmacodynamic relationships The total therapeutic plasma concentration of amitriptyline and nortriptyline in the treatment of depression is 100-250 ng / ml ("3TO-925 nmol / l.) Concentrations above 300-400 ng / ml are associated with an increased risk of cardiac conduction disorders and the occurrence of AV-blocks and lengthening QRS-complex.

Indications:

Depressive episode, especially with accompanying anxiety, agitation and sleep disturbance.

Depressive states in schizophrenia.

Contraindications:

Hypersensitivity to amitriptyline or any of the excipients, hereditary intolerance to fructose, impaired absorption of glucose and galactose, or insufficiency of sucrose and isomaltase.

Recently suffered myocardial infarction, intracardiac conduction disturbance, coronary artery insufficiency, acute alcohol poisoning, barbiturates or opioids, closed-angle glaucoma, simultaneous administration with MAO inhibitors and within 2 weeks after their withdrawal.

Children and adolescence (up to 18 years).

Breastfeeding period.

Carefully:

Convulsive disorders; retention of urination; hyperplasia of the prostate; heavyliver or cardiovascular disease; hyperthyroidism; paranoid symptoms; bipolar affective disorder (after exiting the depressive phase); intraocular hypertension (in persons with anatomical predisposition - narrow angle of the anterior chamber); chronic alcoholism; oppression of bone marrow hematopoiesis; hypotension of the bladder; bronchial asthma; decreased motor function of the gastrointestinal tract (risk of paralytic intestinal obstruction); simultaneous administration with selective serotonin reuptake inhibitors (SSRIs); elderly age; pregnancy.

Pregnancy and lactation:

During pregnancy, Saroten Retard should be used only if the intended benefit to the mother exceeds the potential risk to the fetus.

The use of tricyclic antidepressants in high doses in the third trimester of pregnancy can adversely affect the psychophysical development of the newborn.

In the appointment of amitriptyline to pregnant women, newborns only had a lethargic dream, and with nortriptyline (amitriptyline metabolite), urine retention.

During the period of breastfeeding, you must either refuse to take the drug, or cancel breastfeeding.

Dosing and Administration:

When taking Saroten Retard capsules are recommended to be taken with water. Capsules, however, can be opened and their contents (pellets) can be taken orally with water. In this case, pellets can not be chewed.

Depressive episode. Depressive states in schizophrenia. It is prescribed once a day 3-4 hours before bedtime.

Adults:

Start treatment Saroten Retard should be taken with one 50 mg capsule in the evening. If necessary, after a week, the daily dose can be gradually increased to 2 - 3 capsules in the evening (100-150 mg). After achieving a pronounced improvement, the daily dose can be reduced to the minimum effective, usually up to 1-2 capsules (50-100 mg / day).

The antidepressant effect usually develops in 2-4 weeks. Therapy of depression is symptomatic, therefore it is recommended to continue the use of antidepressants, including Saroten Retard, after achieving a pronounced effect for a sufficient period of time up to - 6 months to avoid relapse. Patients with recurrent depression (unipolar) may require long-term use of Saroten Retard, up to several years,in maintenance doses that have an anti-relapse effect.

Elderly patients (over 65 years of age)

One capsule 50 mg in the evening.

Decreased kidney function

Amitriptyline can be given in usual dosages to patients with renal insufficiency.

Decreased liver function

Caution should be exercised when using the drug in patients with reduced liver function, as far as possible, monitor the concentration of amitriptyline in serum.

Discontinuation of therapy

When discontinuing therapy, it is recommended to cancel the drug gradually over several weeks in order to avoid the development of "cancellation" reactions (see the "Side effect" section).

Side effects:

Amitriptyline may cause side effects similar to those caused by other tricyclic antidepressants. Some of the side effects listed below, for example, headache, tremor, attention disturbance, constipation and decreased libido can also be symptoms of depression and tend to decrease with an improvement in depressive state.

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

From the nervous system: very often - drowsiness, tremor, dizziness, headaches; often - a violation of concentration of attention, dysgeusia (a violation of taste sensations), paresthesia, ataxia, disorientation, agitation, extrapyramidal syndrome, frequent epileptic seizures; infrequently, convulsions.

From the side of mental activity: often confusion, decreased libido; infrequently - hypomania, mania, anxiety, insomnia, "nightmarish" dreams; rarely delirium (in elderly patients), hallucinations (in patients with schizophrenia), suicidal thoughts or behavior.

From the cardiovascular system: very often - palpitations, tachycardia, orthostatic hypotension; often - atrioventricular block, blockade of the bundle branch, changes in the electrocardiogram, including in the form of lengthening of the interval QT, lengthening complex QRS; infrequently - increased blood pressure; rarely - arrhythmia.

On the part of the organs of vision: very often - a violation of accommodation; often - mydriasis (dilated pupils); infrequent - increased intraocular pressure.

From the side of the hearing organ and labyrinthine disorders: infrequently, noise in the ears. From the blood and lymphatic system: rarely - oppression of bone marrow hematopoiesis, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia.

Metabolic disorders and eating disorders: rarely - a decrease in appetite.

From the digestive system: very often - dry mouth, constipation, nausea; infrequently - diarrhea, vomiting, edema of the tongue, stomatitis; rarely - an increase in the salivary glands, paralytic intestinal obstruction.

From the hepatobiliary system: rarely - jaundice.

From the urinary system: infrequently urinary retention.

On the part of the reproductive system: often - erectile dysfunction, rarely - gynecomastia.

From the skin and subcutaneous tissue: very often hyperhidrosis; infrequently - swelling of the face; rarely - hair loss.

Allergic reactions: infrequently - skin rash, itching, hives; rarely - photosensitivity, angioedema.

On the part of the body as a whole: often fatigue, weight gain; rarely - hyperpyrexia, weight loss, impaired functional liver tests, increased alkaline phosphatase in the blood, increased levels of transaminases.

Symptoms of "cancellation"

With a sharp discontinuation of the drug after prolonged use, such undesirable reactions as nausea, vomiting, diarrhea, headache, malaise, insomnia, unusual dreams, agitation, irritability may occur; with a gradual cancellation after long-term use - irritability, sleep disturbances, unusual dreams. These symptoms do not indicate the development of drug dependence.

There have been reports of cases of suicidal thoughts and suicidal behavior during treatment or immediately after treatment with amitriptyline.

In epidemiological studies that were conducted mainly involving patients aged 50 years and older, an increased risk of bone fractures was observed with SSRIs and tricyclic antidepressants. The mechanism of this effect is unknown.

Overdose:

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, urine retention, dry mucous membranes, slowing of intestinal motility.Convulsions. Temperature increase. Sudden CNS depression. Reducing the level of consciousness down to coma. Suppression of respiration.

Symptoms from the heart: arrhythmias (ventricular tachyarrhythmia, cardiac arrhythmias by type torsade des 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. Expansion of the complex QRS usually correlates with the severity of toxic effects due to acute overdose. Heart failure, lowering blood pressure, cardiogenic shock. Metabolic acidosis, hypokalemia.

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

Treatment

Hospitalization (in the intensive care unit). Treatment is symptomatic and supportive. Probing and gastric lavage, even if after taking the drug inside a long time, with the prescription of activated charcoal.Careful observation, even if the case seems uncomplicated. Observation of the level of consciousness, pulse, arterial pressure and respiration. Frequent control of electrolytes in blood serum and blood gases. The control of airway passages, if necessary, should be performed using intubation. To prevent possible stopping of breathing, it is recommended to use an artificial respiration apparatus. Constant ECG monitoring and control of heart function for 3-5 days. When expanding the intervals QRS, Heart failure and ventricular rhythm disturbances are positive the effect can be achieved by shifting the pH to the alkaline side (by introducing bicarbonate or mild hyperventilation) and by rapid infusion of hypertonic sodium chloride solution (100-200 mmol Na+). It is possible to use appropriate antiarrhythmics, for example, lidocaine in ventricular arrhythmias at a dose of 50-100 mg IV (1-1.5 mg / kg), then 1-3 mg / min by IV infusion.

If necessary, cardioversion is performed, defibrillation. For the treatment of circulatory failure should use plasma substitutes, and in severe cases - infusion of dobutamine with an initial rate of 2-3 mcg / kg per min with an increase in dose depending on the response.With excitation and convulsions, diazepam can be used.

Interaction:

Pharmacodynamic interaction

MAO inhibitors

Simultaneous reception of amitriptyline and MAO inhibitors (nonselective, as well as selective inhibitors of MAO A (moclobemide) and MAO B (selegiline)) can cause the development of serotonin syndrome (possible agitation, confusion, tremor, myoclonus, hyperthermia). Amitriptyline can be appointed 14 days after discontinuation of treatment with irreversible nonselective MAO inhibitors and at least 1 day after discontinuation of therapy with the reversible MAO A inhibitor, moclobemide. Treatment with MAO inhibitors can be started 14 days after the end of amitriptyline intake.

Sympathomimetics

Amitriptyline can potentiate the effects of epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine and phenylpropanolamine on the cardiovascular system. Simultaneously with amitriptyline, do not use drugs that include sympathomimetics (local and systemic anesthetics, decongestant nasal sprays, etc.).

Drugs that reduce sympathetic activity

Tricyclic antidepressants can reduce the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and methyldopa. Against the background of therapy with tricyclic antidepressants, it is recommended to correct antihypertensive therapy.

Anticholinergic drugs

Tricyclic antidepressants can enhance the effects of anticholinergic drugs on the organs of vision, the central nervous system, the intestines and the bladder; simultaneous use of these drugs should be avoided due to an increased risk of developing paralytic intestinal obstruction.

Drugs that extend the interval QT

Drugs that extend the interval QT, including antiarrhythmics such as quinidine, H1-histamine receptor blockers, as astemizole and terfenadine, some neuroleptics (in particular, pimozide and sertindole), cisapride, halofantrine and sotalol can increase the likelihood of developing ventricular rhythm disturbances with concomitant administration with tricyclic antidepressants.

Drugs that depress the central nervous system

At simultaneous application with blockers of H1-histamine receptors, clonidine, alcohol and barbiturates, the oppressive effect on the central nervous system can be increased. Amitriptyline can enhance the effects of other drugs that depress the central nervous system.

Glucocorticoid means

Amitriptyline may increase depression caused by glucocorticoid agents.

Antithyroid drugs

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

Inhibitors of acetaldehyde dehydrogenase

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

Indirect anticoagulants

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

St. John's wort perforated

Simultaneous use of amitriptyline and preparations containing St. John's Wort can lead to an increase in the metabolism of amitriptyline and a decrease in the maximum serum concentration of amitriptyline by 20%, due to the induction of its metabolism by isoenzyme CYP3A4 liver. Theoretically, an increased risk of developing a serotonin syndrome is possible.

Lithium

With the simultaneous use of lithium and tricyclic antidepressants, the risk of psychoticsymptoms and toxic complications from the central nervous system, even against the background of therapeutic concentration of lithium in blood plasma. Described cases of mania, myoclonus, tremor, tonic-clonic seizures, memory disorders, confusion, disorganized thinking, hallucinations, serotonin syndrome and neuroleptic malignant syndrome, begins a few days after the start of the combination therapy; in most cases, treatment was required either with tricyclic antidepressants or with lithium. Elderly patients are particularly prone to the occurrence of such reactions.

Pharmacokinetic interactions

Tricyclic antidepressants, including amitriptyline, are metabolized by isoenzyme CYP2D6. In the isoenzyme population CYP2D6 is characterized by polymorphism. Isozyme CYP2D6 can inhibit various drugs, for example, antipsychotics, SSRIs with the exception of citalopram (very weak isoenzyme inhibitor CYP2D6), β-adrenoblockers and antiarrhythmics of the latest generation. These drugs can cause a pronounced slowdown in the metabolism of tricyclic antidepressants and a significant increase in theirconcentration in the blood plasma.

Other isoenzymes are also involved in the metabolism of amitriptyline, such as CYP2C19 and CYP3A.

Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism, which can lead to a reduction in the threshold of convulsive readiness and the development of seizures. You may need to adjust the dosage of these drugs.

Fluoxetine and fluvoxamine increase the concentration of tricyclic antidepressants in blood plasma.

Barbiturates and other inducers of microsomal liver enzymes, for example, rifampicin and carbamazepine, can enhance the metabolism of tricyclic antidepressants, reduce their plasma concentrations and reduce the antidepressant effect.

Cimetidine and methylphenidate, as well as blockers of "slow" calcium channels, can slow the metabolism of amitriptyline, increase its plasma concentrations and, consequently, increase toxic effects.

Antifungal drugs, such as fluconazole and terbinafine, increase the plasma concentrations of tricyclic antidepressants and enhance the associated toxic effects.

Estrogens and their oral contraceptives can increase the bioavailability of amitriptyline. You may need to adjust the dosage of drugs or cancel one of them.

Alcohol increases plasma concentrations of free amitriptyline and nortriptyline.

Tricyclic antidepressants can increase the serum concentration of phenytoin and, accordingly, increase the risk of its toxic effects (ataxia, hyperreflexia, nystagmus, tremor).

Special instructions:

Saroten Retard is not recommended for the treatment of depression in children and adolescents due to lack of data on efficacy and safety.

The use of Saroten Retard in patients of all age groups is associated with a risk of side effects from the cardiovascular system.

When high doses are used, it is possible to develop rhythm disturbances and a severe decrease in blood pressure. In patients suffering from heart disease, these phenomena can occur when the usual dose is prescribed.

Depression is associated with an increased risk of suicidal thoughts, self-injury and suicide.This risk persists until a stable remission occurs. Since the improvement may not occur during the first few weeks of treatment or more, patients should be carefully monitored before the onset of improvement. General clinical practice shows that the risk of suicide may increase in the early stages of recovery. A higher risk of suicidal thoughts or attempts is characteristic of patients who have a history of suicidal behavior, or with pronounced suicidal ideation prior to initiation of therapy, so these patients should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants involving adult patients with mental disorders revealed an increased risk of suicidal behavior in patients younger than 25 years with antidepressants compared with placebo.

Patients require careful monitoring, in particular, patients from the high-risk group, especially at the beginning of treatment or after a dose change.

Patients (and caregivers) should be warned about the need to monitor any signs of clinical impairment, suicidal behavior or thoughts,unusual behavior and the need to seek immediate medical attention when these symptoms occur.

With special care, it is necessary to appoint amitriptyline patients with hyperthyroidism or patients receiving drugs that control the function of the thyroid gland, in connection with the possible development of violations of the heart rhythm.

In patients with diabetes, treatment with amitriptyline may alter the action of insulin and the concentration of glucose in the blood, which may require correction of the dose of insulin and / or oral hypoglycemic drugs.

Elderly patients are particularly at risk of orthostatic hypotension.

The use of amitriptyline in bipolar disorder can provoke the development of the manic phase; In this case, Saroten Retard must be canceled.

If amitriptyline is used to treat a depressive component of schizophrenia, possibly exacerbating psychotic symptoms. In this case amitriptyline should be used in combination with antipsychotics.

In patients with such rare conditions as narrowing of the anterior chamber of the eye or angle-closure glaucoma, acute attacks of glaucoma are possible in connection with the dilatation of the pupil.

In patients using contact lenses, reducing the formation of tears and the accumulation of mucous secretions, as a consequence of m-holinoblokiruyuschey action of tricyclic antidepressants, can lead to damage to the epithelium of the cornea.

Dry mouth can lead to changes in mucous membrane, inflammatory reactions, burning sensation and caries. Regular visits to the dentist are recommended.

Saroten Retard should be used with extreme caution in patients with convulsive disorders, since amitriptyline reduces the threshold of convulsive readiness, which may lead to a decrease in the effectiveness of treatment with antiepileptic drugs. This group of patients has an increased risk of developing seizures with amitriptyline.

The use of anesthetics during treatment with tri / tetracyclic antidepressants may increase the risk of arrhythmia and lowering blood pressure. It should be possible to stop taking amitriptyline several days before surgery; If an emergency operation is required, the anesthetist should be informed of the therapy the patient is receiving.

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

Amitriptyline should be used with caution in patients receiving SSRIs.

The composition of pellets inside the capsule includes sucrose. Patients with rare hereditary diseases associated with intolerance to fructose, a violation of glucose absorption and galactose, or a deficiency of sucrose and isomaltase, should not receive this drug.

Against the background of the use of amitriptyline, alcohol intake is contraindicated.

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

In view of the sedative action of Saroten Retard, it is recommended to avoid driving and potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions during its application. Patients, who are appointed Saroten Retard, should be warned in advance by a doctor about this aspect of the drug's action.

Form release / dosage:

Capsules of prolonged action of 50 mg.

Packaging:For 30 capsules in a plastic container with protection from opening by children and control of the first autopsy.On the cover by embossing method, a scheme for opening the container is made. Container with instructions for use in a cardboard box.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

18 months.

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

Terms of leave from pharmacies:On prescription

Registration number:П N012120 / 01

Date of registration:08.04.2009

The owner of the registration certificate:H. Lundbeck A / SH. Lundbeck A / S Denmark

Manufacturer: & nbsp

H.LUNDBECK, A / S Denmark

Representation: & nbspLUNDBEK EXPORT A / C LUNDBEK EXPORT A / C Denmark

Information update date: & nbsp18.05.2012

Illustrated instructions

Instructions

Saroten retard (Saroten retard)