Sarotenum Retard

General characteristics. Structure:

Active ingredient: 50 mg of amitriptyline in the form of 55,56 mg of Amitriptylini hydrochloridum.

Excipients: sugar spheres, stearic acid, shellac (not waxed shellac), talc, povidone.

Structure of the empty capsule: gelatin, dye ferrous oxide red (Е 172), titanium dioxide (Е 171).

Sarotenum Retard is tricyclic antidepressant with sedation and the prolonged action.

Pharmacological properties:

Pharmacodynamics. In vivo amitriptyline approximately equally inhibits the return capture of Norepinephrinum and serotonin in presynaptic nerve termination. The main metabolite of amitriptyline – нортриптилин – oppresses the return capture of noradrenaline, than serotonin rather stronger. The m-holinoblokiruyushchey and H1-gistaminoblokiruyushchey has activity. Renders powerful antidepressive, and also sedative and anxiolytic action.

Suppression of a phase of a REM sleep (REM phase) is considered as a predictor of antidepressive activity. Tricyclic antidepressants, just as SIOZS and MAO inhibitors, suppress a REM phase of a dream and increase duration of a deep medlennovolnovy sleep.

Pharmacokinetics. Absorption. At use of capsules of Sarotenum Retard plasma concentration of amitriptyline increase gradually, reaching a maximum in 7,1±1,9 hours. At the same time peak serumal concentration are lower, than at use of a dosage form of amitriptyline with immediate release. Use of capsules of the prolonged action allows to avoid high peak concentration of amitriptyline which are associated with the increased risk of cardial complications. Bioavailability of amitriptyline at intake of Sarotenum Retard – about 48%.

Distribution. The seeming distribution volume after intravenous administration of amitriptyline makes 1221±280 l. Extent of linkng with proteins of a blood plasma makes about 95%. Amitriptyline and its main metabolite нортриптилин get through a placental barrier.

Biotransformation. Metabolism of amitriptyline is carried out preferential due to demethylation (isoenzymes of CYP2D19, SYP3A) and a hydroxylation (CYP2D6 isoenzyme) with the subsequent conjugation with glucuronic acid. Metabolism is characterized by considerable genetic polymorphism. The main active metabolite is secondary amine – нортриптилин. Metabolites cis-and trance-10-hydroxyamitriptyline and cis-and trance-10-gidroksinortriptilin are characterized similar with nortriptiliny an activity profile though their action is expressed much more weakly. Demetilnortriptilin and amitriptyline-N-oxide are present at a blood plasma in insignificant concentration; the last metabolite is almost deprived of pharmacological activity. In comparison with amitriptyline all metabolites possess the action which was considerably less expressed to m-holinoblokiruyushchim.

Removal. An amitriptyline elimination half-life at use of Sarotenum Retard makes about 25 hours. An elimination half-life of a nortriptilin – about 27 hours. The average general clearance of amitriptyline makes 39,24±10,18 l/h.

It is removed preferential by kidneys. At use of Sarotenum Retard in not changed look is brought by about 2% of the accepted amitriptyline dose. Nursing mothers have amitriptyline and нортриптилин in small amounts are allocated with breast milk. At the same time concentration in breast milk is twice lower, than in a blood plasma. When breastfeeding against the background of amitriptyline reception, in an organism of the child 2% the accepted mother of a dose, in terms of body weight get on average (to mg/kg).

Equilibrium plasma concentration of amitriptyline and nortriptilin at most of patients are reached within a week. At use of capsules of the prolonged action in the evening concentration of amitriptyline reaches the maximum values late at night and decreases during the day whereas concentration of a nortriptilin remains stable within a day, thus, effects of a nortriptilin during the day dominate.

Elderly patients. At elderly patients increase in an elimination half-life and reduction of clearance of amitriptyline owing to reduction in the rate of metabolism is noted.

Patients with abnormal liver functions. Abnormal liver functions can lead to delay of metabolism of amitriptyline and increase in its plasma concentration.

Patients with renal failures. The renal failure does not exert impact on drug kinetics.

Pharmacokinetic / фармакодинамические relationship. Total therapeutic plasma concentration of amitriptyline and a nortriptilin at treatment of a depression makes 100–250 ng/ml (≅ 370–925 nmol/l). Concentration higher than 300-400 ng/ml are associated with increase in risk of disturbances of cordial conductivity and emergence of AV blockade and lengthening of a QRS complex.

Indications to use:

• Depressive episode, especially with the accompanying alarm, agitation and a sleep disorder.
• Depressions at schizophrenia.

Route of administration and doses:

At reception of Sarotenum Retard is recommended to wash down capsules with water. Capsules, however, can be open and their contents (pellets) can be accepted inside with water. Pellets at the same time cannot be chewed.

Depressive episode. Depressions at schizophrenia. It is appointed in 3–4 hours prior to a dream once a day. Adults: it is necessary to begin treatment with Sarotenum Retard with one capsule of 50 mg in the evening. If necessary in a week the daily dose can be gradually increased to 2–3 capsules in the evening (100–150 mg). After achievement of the expressed improvement the daily dose can be lowered to minimum effective, usually to 1–2 capsules (50–100 mg/days). The antidepressive effect usually develops in 2–4 weeks. Therapy of depressions has symptomatic character therefore it is recommended to continue use of antidepressants including Sarotenum Retard, after achievement of the expressed effect during a sufficient span – up to 6 months in order to avoid a recurrence. At patients with a recurrent depression (unipolar) long reception of Sarotenum of Retard can be required, up to several years, in the maintenance doses having antirecurrent effect.

Elderly patients (65 years are more senior). On one capsule of 50 mg in the evening.

Reduced function of kidneys. Amitriptyline can be appointed in usual dosages to patients with a renal failure.

Reduced function of a liver. It is necessary to be careful at use of drug for patients with reduced function of a liver, it is necessary to carry out whenever possible monitoring of concentration of amitriptyline in blood serum.

Therapy termination. At the therapy termination drug withdrawal is recommended to be carried out gradually within several weeks in order to avoid development of reactions of "cancellation" (see the section "Side effect").

Features of use:

Sarotenum Retard is not recommended for treatment of a depression at children and teenagers due to the lack of data on efficiency and safety. Use of Sarotenum Retard at patients of all age groups is connected with risk of emergence of side effects from cardiovascular system. At use of high doses development of disturbances of a rhythm and a heavy lowering of arterial pressure is possible. At the patients having heart diseases, these phenomena can arise at purpose of a usual dose.

The depression is connected with the increased risk of emergence of suicide thoughts, drawings to itself injuries and a suicide. This risk remains before permanent remission. As improvement can not occur within the first several weeks of treatment or more, it is necessary to watch patients carefully before improvement.

The general clinical practice shows that the risk of a suicide can increase at early stages of recovery. Higher risk of emergence of suicide thoughts or attempts is characteristic of patients at whom in the anamnesis the suicide behavior, or with the expressed suicide ideas prior to therapy therefore during treatment these patients have to be under careful observation was noted. Placebo meta-analysis - controlled clinical trials of antidepressants with participation of adult patients with mental disorders revealed increase in risk of suicide behavior at patients more young than 25 years at use of antidepressants in comparison with placebo.

Patients demand careful observation, in particular, patients from group of high risk, especially in an initiation of treatment or after change of a dose.

Patients (and the persons which are carrying out care of them) need to be warned about need of control of any signs of clinical deterioration, suicide behavior or thoughts, unusual behavior and need of the immediate request for medical care at emergence of these symptoms.

With extra care patients need to appoint amitriptyline with a hyperthyroidism or to the patients receiving the drugs controlling function of a thyroid gland in connection with possible development of disturbances of a cordial rhythm.

At patients with a diabetes mellitus treatment by amitriptyline can change effect of insulin and concentration of glucose in blood that can demand dose adjustment of insulin and/or peroral hypoglycemic drugs.

Elderly patients are especially subject to risk of orthostatic hypotension. Use of amitriptyline at bipolar disorder can provoke development of a maniacal phase; in this case Sarotenum Retard needs to be cancelled.

If amitriptyline is applied to treatment of a depressive component of schizophrenia, aggravation of psychotic symptoms is possible. In this case amitriptyline should be applied in a combination with an anti-psychotic.

At patients with such rare states as narrowing of an anterior chamber of an eye or closed-angle glaucoma, bad attacks of glaucoma in connection with a mydriasis are possible. At the patients applying contact lenses, decrease in formation of a tear and accumulation of a mucous secret owing to m-holinoblokiruyushchego of effect of tricyclic antidepressants can lead to damage of an epithelium of a cornea.

Dryness in a mouth can lead to emergence of changes of a mucous membrane, inflammatory reactions, a burning sensation and caries. Regular visit of the stomatologist is recommended. Sarotenum Retard has to be used with extra care at patients with convulsive frustration as amitriptyline reduces a threshold of convulsive readiness that can lead to decrease in efficiency of treatment by anti-epileptic drugs. This group of patients has the increased risk of development of convulsive attacks against the background of amitriptyline use.

Use of anesthetics during treatment by three/tetracyclic antidepressants can increase risk of developing of arrhythmia and lowering of arterial pressure. It is necessary to stop whenever possible reception of amitriptyline some days before surgical intervention; if the immediate surgery is required, the anesthesiologist has to be informed on what therapy is received by the patient.

At use of tricyclic antidepressants in combination with anticholinergic drugs or anti-psychotics, especially in hot weather, development of a hyper pyrexia is possible.

Amitriptyline has to be applied with care at the patients receiving SIOZS. The structure of the pellets which are in the capsule includes sucrose. Patients with the rare hereditary diseases connected with intolerance of fructose, disturbance of absorption of glucose and a galactose or insufficiency of invertase and isomaltase should not receive this drug.

Against the background of amitriptyline use alcohol intake is contraindicated.

Use at pregnancy and during breastfeeding. During pregnancy Sarotenum Retard should be applied, only if the estimated advantage for mother exceeds potential risk for a fruit. Use of tricyclic antidepressants in high doses in the third trimester of pregnancy can negatively affect psychophysical development of the newborn.

At purpose of amitriptyline to pregnant women at newborns only the lethargical sleep was noted, and at purpose of a nortriptilin (an amitriptyline metabolite) – an ischuria.

During feeding by a breast it is necessary or to refuse administration of drug, or to cancel breastfeeding.

Influence on ability to manage vehicles and mechanisms. In view of sedative action of Sarotenum Retard during its use is recommended to avoid control of vehicles and potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions. Patients to whom Sarotenum Retard is appointed have to be in advance warned by the doctor about this aspect of effect of drug.

Side effects:

Amitriptyline can cause side effects, similar to what is caused by other tricyclic antidepressants. Some of the listed below side effects, for example, the headache, a tremor, disturbance of attention, a lock and decrease in a libido can also be symptoms of a depression and, as a rule, decrease at improvement of a depression. Frequency of emergence of side effects is specified as: very often (≥1/10); often (from ≥1/100 to <1/10); infrequently (from ≥1/1000 to <1/100); seldom (from ≥1/10000 to <1/1000); very seldom (<1/10000).

From a nervous system: very often – drowsiness, a tremor, dizziness, headaches; often – disturbance of concentration of attention, a dysgeusia (disturbance of flavoring feelings), paresthesias, an ataxy, a disorientation, agitation, an extrapyramidal syndrome, increase of epileptic seizures; infrequently – spasms.

From mental activity: often – confusion of consciousness, decrease in a libido; infrequently – a hypomania, a mania, alarm, sleeplessness, "dreadful" dreams; seldom – a delirium (at elderly patients), hallucinations (at patients with schizophrenia), suicide thoughts or behavior.

From cardiovascular system: very often – a heart consciousness, tachycardia, orthostatic hypotension; often – an atrioventricular block, blockade of a leg of a ventriculonector, change on the electrocardiogram, including in the form of lengthening of an interval of QT, lengthening of the QRS complex; infrequently – increase in arterial pressure; seldom – arrhythmia.

From organs of sight: very often – accommodation disturbance; often – a mydriasis (expansion of pupils); infrequently – increase in intraocular pressure.

From an acoustic organ and labyrinth disturbances: infrequently – a sonitus.

From circulatory and lymphatic system: seldom – oppression of a marrowy hemopoiesis, an agranulocytosis, a leukopenia, thrombocytopenia, an eosinophilia. Metabolic disturbances and frustration of food: seldom – a loss of appetite.

From the alimentary system: very often – dryness in a mouth, a lock, nausea; infrequently – diarrhea, vomiting, a paraglossa, stomatitis; seldom – increase in sialadens, paralytic intestinal impassability.

From gepatobiliarny system: seldom – jaundice.

From an urinary system: infrequently – an ischuria.

From reproductive system: often – erectile dysfunction, it is rare – a gynecomastia.

From integuments and hypodermic cellulose: very often – a hyperhidrosis; infrequently – a face edema; seldom – a hair loss.

Allergic reactions: infrequently – skin rash, an itch, a small tortoiseshell; seldom – a photosensitization, a Quincke's disease.

From an organism in general: often – fatigue, increase in weight; seldom – a hyper pyrexia, weight reduction, disturbance of functional trials of a liver, increase in an alkaline phosphatase in blood, increase in level of transaminases. Symptoms of "cancellation": At the sharp termination of administration of drug after prolonged use there can be such undesirable reactions as nausea, vomiting, diarrhea, a headache, an indisposition, sleeplessness, unusual dreams, excitement, irritability; at gradual cancellation after prolonged use – irritability, sleep disorders, unusual dreams. These symptoms do not demonstrate development of medicinal dependence.

It was reported about cases of emergence of suicide thoughts and suicide behavior during treatment or right after the end of treatment by amitriptyline. In epidemiological researches which were conducted with participation generally of patients at the age of 50 years and is more senior, increase in risk of fractures of bones at use of SIOZS and tricyclic antidepressants was revealed. The mechanism of this effect is unknown.

Interaction with other medicines:

Pharmakodinamichesky interaction. MAO inhibitors. The concomitant use of amitriptyline and MAO inhibitors (non-selective, and also the MAO A selection inhibitors (моклобемид) and MAO B (селегилин)) can cause development of a serotoninovy syndrome (agitation, confusion of consciousness, a tremor, a myoclonus, a hyperthermia are possible). Amitriptyline can be appointed in 14 days after the treatment termination the MAO irreversible non-selective inhibitors and at least in 1 day after the therapy termination by the MAO A reversible inhibitor – moklobemidy. Treatment by MAO inhibitors can be begun in 14 days after the end of reception of amitriptyline.

Sympathomimetics. Amitriptyline can exponentiate effects of Epinephrinum, ephedrine, an izoprenalin, Norepinephrinum, Phenylephrinum and fenilpropanolamin on cardiovascular system. Along with amitriptyline it is not necessary to use drugs which part sympathomimetics are (local and system anesthetics, antiedematous nasal sprays, etc.).

The drugs reducing sympathetic activity. Tricyclic antidepressants can weaken anti-hypertensive effects of a guanetidin, betanidin, Reserpinum, clonidine and Methyldopums. Against the background of therapy tricyclic antidepressants recommend to correct anti-hypertensive therapy.

Anticholinergic drugs. Tricyclic antidepressants can strengthen effects of anticholinergic drugs on organs of sight, TsNS, intestines and a bladder; simultaneous use of these drugs should be avoided in connection with increase in risk of development of paralytic intestinal impassability.

The drugs extending QT interval. The medicines extending QT interval including such antiaritmik as quinidine, H1 blockers - histamine receptors as астемизол and терфенадин, some neuroleptics (in particular, Pimozidum and сертиндол), цизаприд, галофантрин and соталол can increase probability of development of ventricular disturbances of a rhythm at co-administration with tricyclic antidepressants.

Drugs, the oppressing TsNS. At simultaneous use with H1 blockers - histamine receptors, a clonidine, alcohol and barbiturates strengthening of the oppressing action on TsNS is possible. Amitriptyline can strengthen effects and other drugs, the oppressing TsNS.

Glucocorticoid means. Amitriptyline can strengthen the depression caused by glucocorticoid means.

Anti-thyroid means. The concomitant use with medicines for treatment of a thyrotoxicosis increases risk of development of an agranulocytosis.

Atsetaldegiddegidrogenaza inhibitors. Combined use with Disulfiramum and other inhibitors of an atsetaldegiddegidrogenaza can increase risk of development of psychotic states and confusion of consciousness.

Indirect anticoagulants. At simultaneous use of amitriptyline and indirect anticoagulants (derivative coumarin or an indadion) increase in anticoagulating activity of the last is possible.

The St. John's Wort which is made a hole. Simultaneous use of amitriptyline and the drugs containing a St. John's Wort can lead to strengthening of metabolism of amitriptyline and decrease in the maximum serumal concentration of amitriptyline by 20%, owing to induction of his metabolism by a liver CYP3A4 isoenzyme. Increase in risk of emergence of a serotoninovy syndrome is theoretically possible.

Lithium. At simultaneous use of lithium and tricyclic antidepressants the risk of emergence of psychotic symptoms and toxic complications from TsNS can increase even against the background of therapeutic concentration of lithium in a blood plasma. Cases of developing of a mania, a myoclonus, a tremor, toniko-clonic spasms, dysmnesias, the confusion of consciousness, disorganization of thinking, hallucinations, a serotoninovy syndrome and a malignant antipsychotic syndrome beginning in several days after the beginning of a combination therapy are described; in most cases cancellation of therapy by either tricyclic antidepressants, or lithium was required. Elderly patients are especially predisposed to emergence of such reactions.

Pharmacokinetic interactions. Tricyclic antidepressants, including amitriptyline, are metabolized by CYP2D6 isoenzyme. In population the isoenzyme of CYP2D6 is characterized by polymorphism. An isoenzyme of CYP2D6 various drugs can inhibit, for example, neuroleptics, SIOZS except for a tsitalopram (very weak inhibitor of an isoenzyme CYP2D6), β-adrenoblockers and antiaritmik of the last generation. These drugs can cause the expressed delay of metabolism of tricyclic antidepressants and significant increase in their concentration in a blood plasma.

Other isoenzymes, such as CYP2C19 and CYP3A are also involved in metabolism of amitriptyline. Tricyclic antidepressants and neuroleptics mutually inhibit metabolism of each other that can lead to reduction of the threshold of convulsive readiness and development of spasms. Correction of doses of these drugs can be required.

Fluoxetine and флувоксамин increase concentration of tricyclic antidepressants in a blood plasma. Barbiturates and other inductors of microsomal enzymes of a liver, for example, rifampicin and carbamazepine, can strengthen metabolism of tricyclic antidepressants, lead to decrease in their plasma concentration and reduction of antidepressive effect.

Cimetidinum and methylphenidate, and also blockers of "slow" calcium channels can slow down amitriptyline metabolism, increase its plasma concentration and, therefore, strengthen toxic effects.

Antifungal drugs, such as флуконазол and тербинафин, increase plasma concentration of tricyclic antidepressants and strengthen the related toxic effects.

Estrogen and peroral contraceptives containing them can increase bioavailability of amitriptyline. Correction of doses of drugs or cancellation of one of them can be required.

Alcohol increases plasma concentration of free amitriptyline and a nortriptilin.

Tricyclic antidepressants can increase serumal concentration of Phenytoinum and, respectively, increase risk of emergence of its toxic effects (an ataxy, a hyperreflexia, a nystagmus, a tremor).

Contraindications:

Hypersensitivity to amitriptyline or any of excipients, hereditary intolerance of fructose, disturbance of absorption of glucose and a galactose or insufficiency of invertase and isomaltase.

Recently postponed myocardial infarction, disturbance of endocardiac conductivity, insufficiency of coronary circulation, acute alcoholic poisoning, barbiturates or opioids, closed-angle glaucoma, a concomitant use with MAO inhibitors and within 2 weeks after their cancellation.

Children's and teenage age (up to 18 years). Breastfeeding period.

With care. Convulsive frustration; urination delay; prostate hyperplasia; serious illness of a liver or cardiovascular system; hyperfunction of a thyroid gland; paranoid symptomatology; bipolar affective disorder (after an exit from a depressive phase); intraocular hypertensia (at persons with anatomic predisposition – a narrow corner of an anterior chamber); alcoholism; oppression of a marrowy hemopoiesis; bladder hypotonia; bronchial asthma; decrease in motor function of digestive tract (risk of emergence of paralytic intestinal impassability); a concomitant use with the selective serotonin reuptake inhibitors (SSRI); advanced age; pregnancy.

Overdose:

Symptoms. Symptoms can develop slowly and imperceptibly, or sharply and suddenly. Within the first hours drowsiness or excitement, agitation and hallucinations is observed.

Anticholinergic symptoms: mydriasis, tachycardia, ischuria, dryness of mucous membranes, delay of motility of intestines. Spasms. Temperature increase. Sudden oppression of TsNS. Decrease in level of consciousness up to a coma. Breath suppression.

Symptoms from heart: arrhythmias (a ventricular tachyarrhythmia, disturbances of a cordial rhythm as torsade des pointes, fibrillation of ventricles). On an ECG lengthening of an interval of PR, expansion of the QRS complex, lengthening of an interval of QT, flattening or inversion of a tooth T, a depression of a segment of ST and blockade of endocardiac conductivity of various degree which can progress up to a cardiac standstill is characteristic. Expansion of the QRS complex usually correlates with weight of toxic effects owing to acute overdose.

Heart failure, lowering of arterial pressure, cardiogenic shock. Metabolic acidosis, hypopotassemia.

After awakening confusion of consciousness, excitement, hallucinations, an ataxy is again possible.

Treatment. Hospitalization (in intensive care unit). Treatment has the symptomatic and supporting character. Sounding and a gastric lavage even if after administration of drug inside there passed the long time, with preliminary purpose of absorbent carbon. Careful observation even if the case seems uncomplicated. Observation of consciousness level, pulse, arterial pressure and breath. Frequent control of electrolytes in blood serum and blood gases. Control of passability of respiratory tracts if necessary has to be exercised with use of an intubation. For prevention of a possible apnoea it is recommended to use the medical ventilator. Continuous ECG monitoring and control of function of heart within 3 – 5 days. At expansion of intervals of QRS, heart failure and ventricular disturbances of a rhythm of positive effect it is possible to achieve at shift рН in the alkaline party (due to administration of bicarbonate or a moderate hyperventilation) and by bystry infusion of hypertonic salt solution of sodium chloride (100–200 mmol of Na +). Use of the corresponding antiaritmik, for example, of lidocaine is possible at ventricular arrhythmias in a dose of 50-100 mg in/in (1–1,5 mg/kg), then 1–3 mg/min. by method in/in infusion. If necessary cardioversion, a defibrillation is carried out. For treatment of a circulatory unefficiency it is necessary to use plasma substitutes, and in hard cases – infusions of Dobutaminum with an initial speed of 2-3 mkg/kg in doses, min. with increase, depending on the answer. At excitement and spasms diazepam use is possible.

Storage conditions:

Sarotenum capsules Retard have to be stored at a temperature not above 25 °C in the dry place. A period of validity - 18 months. Not to use on the termination of a period of validity. To store in places, inaccessible to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of the prolonged action of 50 mg. Packaging: on 30 capsules in a plastic container with protection against opening by children and control of the first opening. On a cover the method of a stamping applied the scheme of opening of a container. A container with the application instruction in a cardboard pack.