Risperidone-TL - instructions for use, doses, side effects, contraindications

	1 mg	2 mg	3 mg	4 mg
Active substance
Risperidone	1.00 mg	2.00 mg	3.00 mg	4.00 mg
Excipients
Lactose Monohydrate	87.85 mg	86.85 mg	85.85 mg	84.85 mg
Microcrystalline cellulose	40.00 mg	40.00 mg	40.00 mg	40.00 mg
Corn starch	20.00 mg	20.00 mg	20.00 mg	20.00 mg
Magnesium stearate	0.75 mg	0.75 mg	0.75 mg	0.75 mg
Sodium lauryl sulfate	0.40 mg	0.40 mg	0.40 mg	0.40 mg
Film Sheath:
Opadrai II 85F48105 (white) [polyvinyl alcohol - 46.9%, macrogol 4000 - 23.6%, talc - 17.4%, titanium dioxide - 12.1%]	5.00 mg	-	-	-
Opaprai II 85F220031 (yellow) [polyvinyl alcohol - 40.0%, macrogol 4000 - 20.2%, titanium dioxide - 20.2%, talcum - 14.8%, iron dye oxide yellow 4.8%]	-	5.00 mg	-	-
Opaprai II 85F265031 (brown) [polyvinyl alcohol 40.0%, macrogol 4000-20.2%, talcum 14.8%, titanium dioxide 13.17%, iron dye oxide yellow 10.9%, iron dye oxide red - 0.93%)	-	-	5.00 mg	-
Opaprai II 85P265015 (brown) [polyvinyl alcohol - 40.0%, macrogol 4000 - 20.2%, titanium dioxide - 15.3%, talc - 14.8%, iron dye oxide yellow - 7.48%, iron dye oxide red - 2.22%]	-	-	-	5.00 mg

Description:

Tablets 1 mg. Round biconvex tablets, covered with a coat of white or almost white. The core of the tablet is white or almost white.

Tablets 2 mg. Round biconvex tablets covered with a coat of brownish-yellow color, two layers are visible on a cross section. The core of the tablet is white or almost white.

Tablets 3 mg. Round biconvex tablets covered with a light brown color, two layers are visible on the cross section. The core of the tablet is white or almost white.

Tablets 4 mg. Round biconvex tablets, covered with a light-brown shell with a pink shade of color, two layers are visible on the cross-section. The core of the tablet is white or almost white.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic).

ATX: & nbsp

Risperidone

Pharmacodynamics:Risperidone is a selective monoaminergic antagonist with a high affinity for serotonin 5-HT₂- and dopamine D₂receptors. Risperidone is also associated with α₁-adrenoceptors and, somewhat weaker, with H₁-histamine and α₁-adrenoceptors. Risperidone does not have tropism for cholinergic receptors. Risperidone reduces the productive symptoms of schizophrenia, causes less inhibition of motor activity and to a lesser degree induces catalepsy than classical antipsychotics. A balanced central antagonism to serotonin and dopamine probably reduces the propensity to extrapyramidal undesirable reactions and expands the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.

Pharmacokinetics:

Suction

Risperidone after oral intake is completely absorbed, reaching the maximum concentrations in the plasma after 1-2 hours. Absolute bioavailability of risperidone after ingestion is 70%. The relative bioavailability after oral administration of risperidone in the form of tablets is 94%. Food does not affect the absorption of the drug, so risperidone can be administered regardless of food intake. The equilibrium concentration of risperidone in the body in most patients is reached within 1 day. The equilibrium concentration of 9-hydroxyrisperidone is reached within 4-5 days.

Distribution

Risperidone is rapidly distributed in the body. The volume of distribution is 1-2 l / kg. In the plasma risperidone binds to albumin and α₁acid glycoprotein. Risperidone 90% bound by plasma proteins, 9-hydroxyrisperidone - by 77%.

Metabolism and excretion

Risperidone is metabolized by the CYP2D6 isoenzyme to the main metabolite of 9-hydroxyrisperidone, which has a pharmacological action similar to risperidone. Risperidone and 9-hydroxyrisperidone constitute the active antipsychotic fraction. The CYP2D6 isozyme is susceptible to genetic polymorphism. In patients with intensive metabolism by the isoenzyme CYP2D6 risperidone quickly turns into 9-hydroxyrisperidone, while in patients with weak metabolism this transformation occurs much more slowly. Although patients with intensive metabolism have a lower concentration of risperidone and a higher concentration of 9-hydroxyrisperidone than patients with poor metabolism,total pharmacokinetics of risperidone and 9-hydroxyrisperidone after receiving one or more doses in patients with similar intense and weak metabolism of CYP2D6.

Another way of metabolizing risperidone is N-dealkylation. Research in vitro on microsomes of the human liver showed that risperidone at clinically relevant concentrations in general it does not inhibit the metabolism of drugs undergoing biotransformation isozymes of cytochrome P450 including CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A week after the start of the drug, 70% of the dose is excreted by the kidneys, 14% by the intestine. In the urine risperidone together with 9-hydroxyrisperidone constitute 35-45% of the dose. The rest is made up of inactive metabolites. After oral administration in patients with psychosis risperidone is excreted from the body with a half-life (T½) about 3 hours. T½ 9-hydroxyrisperidone and the active antipsychotic fraction is 24 hours.

Linearity

The concentration of risperidone in blood plasma is directly proportional to the dose taken in the therapeutic range of doses.

Pharmacokinetics in selected patient groups

Elderly patients and patients with hepatic and renal insufficiency

After a single dose of risperidone in elderly patients, the concentration of active antipsychotic fraction in plasma was an average of 43% higher, T½ - 38% longer, and the clearance decreased by 30%. In patients with renal insufficiency, an increase in plasma concentration and a decrease in the clearance of the active antipsychotic fraction was observed on average by 60%. In patients with hepatic insufficiency, the concentration of risperidone in the plasma did not change, but the average concentration of the free fraction of risperidone increased by 35%.

Children

The pharmacokinetics of risperidone, 9-hydroxyrisperidone and the active antipsychotic fraction in children are comparable to that of adult patients.

Sex, race, smoking

Population pharmacokinetic analysis did not reveal the obvious effect of sex, race or smoking on the pharmacokinetics of risperidone and the active pharmacokinetic fraction.

Indications:

treatment of schizophrenia in adults and children from age 13;
treatment of manic episodes associated with bipolar disorder, moderate to severe in adults and children 10 years of age;
short-term (up to 6 weeks) treatment of persistent aggression in patients with dementia due to Alzheimer's disease, moderate to severe,not amenable to non-pharmacological methods of correction and in case of risk of causing harm to the patient himself or others;
short-term (up to 6 weeks) symptomatic treatment of persistent aggression in the structure of behavioral disorder in children from the age of 13 with mental retardation diagnosed in accordance with DSM-IV, in which, due to the severity of aggression or other destructive behavior, medical treatment is required. Pharmacotherapy should be part of a wider treatment program, including psychological and educational activities. Risperidone should be appointed by a specialist in the field of pediatric neurology and child psychiatry or a physician familiar with the treatment of behavioral disorders in children and adolescents.

Contraindications:

increased sensitivity to risperidone and components of the drug;
lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
phenylketonuria;
children under 13 years of age in the treatment of schizophrenia;
children under 13 years of age (or body weight less than 50 kg) in the treatment of persistent aggression in the structure of conduct disorder;
children under 10 years old in the treatment of manic episodes associated with bipolar disorder.

Carefully:

diseases of the cardiovascular system (chronic heart failure, myocardial infarction, myocardial conduction disturbances);
dehydration and hypovolemia;
disorders of cerebral circulation;
Parkinson's disease;
convulsions (including in the anamnesis);
severe renal or hepatic impairment (see section "Method of administration and dose");
drug abuse or drug dependence (see section "Mode of administration and dose");
conditions predisposing to the development of tachycardia such as "pirouette" (bradycardia, electrolyte imbalance, concomitant medication prolonging the QT interval);
brain tumor, intestinal obstruction, cases of acute drug overdose, Reye's syndrome (antiemetic effect of risperidone may mask the symptoms of these conditions);
risk factors for thromboembolism of venous vessels;
disease of diffuse Levi bodies;
elderly patients with cerebrovascular dementia;
pregnancy;
simultaneous reception with furosemide in elderly patients with dementia.

Pregnancy and lactation:

Pregnancy

Controlled studies of the use of risperidone in pregnant women have not been conducted. According to observations, with the use of risperidone during the III trimester of pregnancy, neonatal patients developed reversible extrapyramidal symptoms and / or withdrawal syndrome, which varied in severity and duration. There have been reports of agitation, hypertension, hypotension, tremor, drowsiness, breathing disorder and eating disorders. Therefore, newborns should be carefully monitored. In animal studies risperidone did not have a teratogenic effect, but other types of toxic effects on the reproductive system were observed. The potential risk to people is unknown. The use of risperidone during pregnancy is only possible if the expected benefit to the mother exceeds the potential risk to the fetus. If it is necessary to stop therapy during pregnancy, the drug should be withdrawn gradually.

Breastfeeding period

In animal studies, it was shown that risperidone and 9-hydroxyrisperidone penetrate into breast milk. It was also demonstrated that risperidone and 9-hydroxyrisperidone in small amounts penetrate into the human breast milk. Data on adverse reactions in infants who are breastfed are absent. Therefore, the question of breastfeeding should be addressed in the light of the possible risk to the child.

Fertility

Like other drugs - dopamine antagonists D₂-receptors, risperidone increases the level of prolactin. Hyperprolactinemia can inhibit the secretion of the hypothalamic gonadotropin-releasing hormone, which leads to a decrease in the secretion of the pituitary gonadotropin. This, in turn, can cause suppression of the reproductive function due to the violation of steroidogenesis in the sex glands in patients both male and female. In preclinical studies, no significant effects were observed.

Dosing and Administration:

Inside. Eating does not affect the absorption of the drug. When administering a dose of less than 1 mg, it is recommended to start therapy with another manufacturer's drug, possibly in the form of a solution for oral administration, which provides the necessary lower dosage.

Schizophrenia

Adults

Risperidone can be prescribed 1 or 2 times a day.The initial dose is 2 mg / day. On the 2nd day the dose should be increased to 4 mg / day. From this moment the dose can either be kept at the same level, or individually adjusted if necessary. Usually the optimal dose is 4-6 mg / day. In some cases, a slower dose increase and lower initial and maintenance doses may be justified. Doses above 10 mg / day did not show higher efficacy compared with smaller doses and could cause extrapyramidal symptoms. Due to the fact that safety of doses above 16 mg / day has not been studied, doses above this level can not be used.

Elderly patients

An initial dose of 0.5 mg 2 times a day is recommended. The dose can be individually increased from 0.5 mg 2 times a day to 1-2 mg 2 times a day.

Children over 13 years of age

The recommended initial dose is 0.5 mg once a day in the morning or in the evening. If necessary, the dose can be increased at least after 24 hours by 0.5-1.0 mg / day to the recommended dose of 3 mg / day with good tolerability. Despite the efficacy shown in the treatment of schizophrenia in adolescents at doses of 1-6 mg / day, no additional efficacy was observed with doses above 3 mg / day, and higher doses caused more adverse reactions.The use of doses above 6 mg / day has not been studied.

Patients who have sustained drowsiness, it is recommended to take half the daily dose 2 times a day.

Information on the use of the drug for the treatment of schizophrenia in children under 13 years of age is absent.

Manic episodes, associated with bipolar disorder
Adults

The recommended initial dose of the drug is 2 mg once a day. If necessary, this dose can be increased at least 24 hours per 1 mg / day. For most patients, the optimal dose is 1-6 mg / day. The use of doses above 6 mg / day in patients with manic episodes has not been studied.

As for any other symptomatic therapy, it is necessary to regularly evaluate and confirm the feasibility of continuing treatment with risperidone.

Elderly patients

The recommended initial dose is 0.5 mg 2 times a day. The dose can be individually increased by 0.5 mg twice a day (up to 1-2 mg twice a day). Care must be taken in connection with the limited experience of the drug in elderly patients.

Children over 10 years old

The recommended initial dose is 0.5 mg 2 times a day. If necessary, the dose can be increased at least after 24 hours by 0.5-1.0 mg / day to the recommended dose of 1.0-2.5 mg / day with good tolerability.Despite the efficacy shown in the treatment of manic episodes associated with bipolar disorder in children at doses of 0.5-6.0 mg / day, no additional efficacy was observed with doses above 2.5 mg / day, and higher doses caused more undesirable reactions. The use of doses above 6 mg / day has not been studied.

Patients who have sustained drowsiness, it is recommended to take half the daily dose 2 times a day.

Non-stopping aggression the patients with dementia, caused by Alzheimer's disease

The recommended initial dose is 0.25 mg twice a day. If necessary, the dose can be individually increased by 0.25 mg twice a day, not more often than after 1 day. For most patients, the optimal dose is 0.5 mg 2 times a day, but some patients receive 1 mg twice daily.

Risperidone should not be used for more than 6 weeks in patients with persistent aggression and in patients with dementia due to Alzheimer's disease. During treatment, the condition of patients should be evaluated on a regular basis, as well as the need for continued therapy.

Unrestrained aggression in the structure of conduct disorder
Children older than 13 years (or with a body weight of 50 kg or more)

In patients with a body weight of 50 kg or more, the recommended initial dose of the drug is 0.5 mg once a day. If necessary, the dose can be increased at least after 24 hours by 0.5 mg / day. For most patients, a dose of 1 mg / day is optimal, but for some patients 0.5 mg / day is preferable, while others require an increase in the dose to 1.5 mg / day.

In patients with a body weight of less than 50 kg, the recommended initial dose of the drug is 0.25 mg once a day. If necessary, the dose can be increased at least after 24 hours by 0.25 mg / day. For most patients, a dose of 0.5 mg / day is optimal, but for some patients 0.25 mg / day is preferable, while others require a dose increase of up to 0.75 mg / day.

As for any other symptomatic therapy, it is necessary to regularly evaluate and confirm the feasibility of continuing treatment with risperidone.

Long-term use of risperidone in children and adolescents should be carried out under the constant supervision of a physician.

Special patient groups
Impaired renal and hepatic function

In patients with kidney disease, the ability to excrete the active antipsychotic fraction is reduced compared to other patients. In patients with liver disease, there is an increased concentration of free fraction of risperidone in the blood plasma.

The initial and maintenance dose in accordance with the indications should be reduced 2 times; the dose increase in patients with liver and kidney disease should be slower. Risperidone in this category of patients should be administered with caution.

Cancellation of the drug

Termination of risperidone should be carried out gradually. Acute withdrawal symptoms, including nausea, vomiting, increased sweating and insomnia, were very rare after a sharp discontinuation of high doses of antipsychotics, including risperidone. Possible relapse of psychotic symptoms and the appearance of involuntary movements (such as akathisia, dystonia and dyskinesia).

Transition from therapy with other antipsychotic drugs
At the beginning of treatment with risperidone, it is recommended to gradually abolish previous therapy if it is clinically justified.In this case, if patients are transferred from the therapy of depot forms of antipsychotics, then risperidone therapy should be started instead of the next scheduled injection. Periodically, the need to continue current therapy with antiparkinsonian drugs should be evaluated.

Side effects:

The most frequently observed adverse reactions (frequency of occurrence ≥5%) were: parkinsonism, sedation, drowsiness, headache and insomnia. Parkinsonism and akathisia are dose-dependent undesirable reactions. Undesirable reactions of risperidone in therapeutic doses are given with a frequency distribution and organ systems.

The frequency of unwanted reactions was classified as follows: very often (≥1/10 cases), often (≥1/100 and <1/10 cases), infrequently (≥1/1000 and <1/100 cases), rarely (≥1/10 000 and <1/1000 cases), very rarely (<1/10 000 cases) and the frequency is unknown (it is impossible to estimate the frequency based on the available data).

In each frequency group, unwanted reactions are presented in order of decreasing importance.

Impact on laboratory and instrumental research results: often - an increase in the concentration of prolactin¹ in the blood serum, increase in body weight; an increase in the activity of liver enzymes, a decrease in the number of leukocytes in the blood, an increase in body temperature, an increase in the number of eosinophils in the blood, a decrease in hemoglobin, a decrease in hematocrit, an increase in the activity of creatine phosphokinase, an increase the concentration of cholesterol in the blood plasma; rarely - a decrease in body temperature, an increase in the concentration of triglycerides in the blood plasma.

Heart Disease: often - tachycardia; infrequently - atrioventricular blockade, bundle bundle, Hypertension, atrial fibrillation, palpitations, palpitations, cardiac conduction abnormalities, QT interval prolongation on the ECG, bradycardia, ECG deviations; rarely - sinus arrhythmia, sinus bradycardia. Vascular disorders: often - arterial hypertension; infrequently - arterial hypotension, orthostatic hypotension, "tides" of blood to the skin of the face; rarely - pulmonary embolism, venous thrombosis.

Violations from the blood and lymphatic system: infrequently - neutropenia, a decrease in the number of leukocytes, anemia, thrombocytopenia, a decrease in hematocrit, a decrease in the number of eosinophils, a decrease in the level of hemoglobin; rarely - granulocytopenia, agranulocytosis⁴.

Impaired nervous system: very often - parkinsonism², headache, drowsiness, sedation; often - akathisia², dizziness², tremor², dystonia², lethargy, dyskinesia²; infrequent - lack of response to stimuli, loss of consciousness, decreased level of consciousness, fainting, impaired consciousness, stroke, transient ischemic attack, dysarthria, attention disturbance, hypersomnia, postural dizziness, imbalance, tardive dyskinesia, speech impairment, coordination disorder, hypoesthesia, disorders taste sensations, perversion of taste, convulsions, cerebral ischemia, impaired movement, psychomotor agitation, paresthesia; rarely - malignant neuroleptic syndrome, diabetic coma, cerebrovascular disorders, tremor of the head.

Disorders from the side of the organ of vision: often - blurred vision, conjunctivitis; infrequent - redness of the eyes, impaired vision, discharge from the eyes, swelling around the eyes, dry eyes,increased lacrimation, photophobia; rarely - reduced visual acuity, eye movement disorder, involuntary eyeball rotation, crust formation at the edge of the eyelid, glaucoma, intraoperative syndrome of flabby iris⁴ (ISDR), occlusion of the retinal artery.

Hearing disorders and labyrinthine disturbances: infrequently - vertigo, pain in the ear, tinnitus.

Disturbances from the respiratory system, organs of the thorax and mediastinum: often - shortness of breath, nosebleed, cough, nasal congestion, pain in the larynx and pharynx; infrequently - wheezing, aspiration pneumonia, congestion in the lungs, impaired breathing, wet wheezing, impaired airway, dysphonia; rarely - sleep apnea syndrome, hyperventilation.

Disorders from the gastrointestinal tract: often - vomiting, diarrhea, constipation, nausea, abdominal pain, indigestion, dryness of the oral mucosa, discomfort in the abdomen, hypersalivation, toothache; infrequently - dysphagia, gastritis, fecal incontinence, fecaloma, gastroenteritis, flatulence; rarely - intestinal obstruction, pancreatitis, edema of the lips, edema of the tongue, cheilitis, very rarely - ileus.

Disorders from the nights and urinary tract: often - enuresis; infrequent - urinary retention, dysuria, urinary incontinence, pollakiuria.

Disturbances from the skin and subcutaneous tissues: often - skin rash, erythema; infrequently - hives, eczema, skin lesions, skin disorders, skin itching, acne, dyskinesia, alopecia, seborrheic dermatitis, dry skin, hyperkeratosis; rarely - toxicoderma, dandruff; very rarely - Quincke's edema.

Disturbances from the musculoskeletal and connective tissue: often - arthralgia, back pain, pain in the extremities, musculoskeletal pain, muscle spasms; infrequently - an increase in the level of creatine phosphokinase, muscle weakness, myalgia, neck pain, swelling of the joints, impaired posture, stiffness in the joints, muscle pain in the chest; rarely rhabdomyolysis.

Disorders from the endocrine system: often - an increase in the level of prolactin¹; rarely - a violation of the production of antidiuretic hormone, glucosuria.

Disorders from the metabolism and nutrition: often - weight gain, increased appetite, decreased appetite; infrequently - weight loss, diabetes mellitus³, anorexia, polydipsia, hyperglycemia, increased cholesterol concentration; rarely - hypoglycemia, hyperinsulinemia⁴; very rarely diabetic ketoacidosis; frequency unknown - water intoxication⁴.

Infectious and parasitic diseases: often - pneumonia, influenza, bronchitis, upper respiratory tract infections, urinary tract infections, sinusitis, ear infections; infrequently - viral infections, tonsillitis, inflammation of subcutaneous fat, otitis media, eye infections, localized infections, acarobacteria, respiratory infections, cystitis, onychomycosis; rarely - lower respiratory infections, chronic otitis media, subcutaneous abscess.

General disorders and disorders at the site of administration: often - edema, pyrexia, fatigue, generalized edema, peripheral edema, asthenia, pain in the chest, pain; infrequent - swelling of the face, gait disturbance, poor health, sluggishness, flu-like condition, thirst, discomfort in the chest, chills; rarely - hypothermia, withdrawal syndrome, cold extremities.

Immune system disorders: infrequently - hypersensitivity; rarely an anaphylactic reaction⁴.

Disorders from the liver and bile ducts: infrequently - an increase in the level of transaminases, an increase in the level of gamma-glutamyltransferase, an increase in "hepatic" enzymes; rarely - jaundice.

Violations of the genitals and breast: infrequently - amenorrhea, sexual dysfunction, erectile dysfunction, ejaculation disorder, galactorrhea, gynecomastia, menstrual cycle disorder², vaginal discharge, discomfort and pain in the mammary gland; rarely - priapism⁴, delay in menstruation, engorgement of the mammary glands, enlargement of mammary glands, discharge from the mammary glands.

Pregnancy, postpartum and perinatal conditions: rarely - withdrawal syndrome in newborns⁴.

Disorders of the psyche: very often insomnia; often - depression, anxiety, agitation, sleep disturbances; infrequent - confusion, mania, decreased libido, lethargy, nervousness, nightmarish dreams; rarely - anorgasmia, flattening of affect.

¹Hyperprolactinemia in some cases can lead to gynecomastia, menstrual cycle disorders, amenorrhea and galactorrhea.

²ECTPs can manifest as: Parkinsonism (hypersalivation, musculoskeletal stiffness,Parkinsonism, drooling, rigidity as a "cogwheel", bradykinesia, hypokinesia, masculine face, muscle tension, akinesia, stiff neck muscles, muscle rigidity, parkinsonian gait, glabellar reflex disorders), akathisia (restlessness, hyperkinesia and restless legs syndrome), tremor, dyskinesia (muscle twitching, choreoathetosis, athetosis and myoclonus), dystonia. The term "dystonia" includes dystonia, muscle spasms, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, movement of the eyeball, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonos, oropharyngeal spasm, plevrototonus, tongue spasm, and trismus. Tremor includes tremor and Parkinson's tremor tremor. It should also be noted that there is a wider range of symptoms that do not always have extrapyramidal origin. Insomnia includes a sleep disorder, an intrasomnia disorder. Seizures include a large seizure. Disorder of the menstrual cycle includes irregular menstruation, oligomenorrhoea.Edema includes generalized edema, peripheral edema, mild edema.

³In placebo-controlled studies, diabetes was observed in 0.18% of patients taking risperidone, compared with 0.11% of patients in the placebo group. The overall incidence of diabetes by all clinical trials was 0.43% of all patients taking risperidone.

⁴ Not observed in clinical studies of risperidone, but observed with the post-marketing application of risperidone.

Undesirable reactions with paliperidone

Paliperidone is an active metabolite of risperidone, therefore the profiles of undesirable reactions of risperidone and paliperidone are interrelated. In addition to the above, with the use of paliperidone, the following undesirable reaction was noted, which may occur with the use of risperidone, with cardiovascular system: syndrome of postural orthostatic tachycardia.

Class Effects

As with the use of other antipsychotics, very rare cases of QT tooth enlargement were noted in the post-registration period of follow-up.Other class-effects from the cardiovascular system, observed with the use of antipsychotics, prolonging the QT interval: ventricular arrhythmias, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and polymorphic ventricular tachycardia of the pirouette type.

Venous thromboembolism

Cases of venous thromboembolism, including pulmonary embolism and cases of deep vein thrombosis, were observed with the use of antipsychotics (the frequency is unknown).

Weight gain

In placebo-controlled trials in patients with schizophrenia, weight gain of at least 7 % After 6-8 weeks, 18% of patients receiving risperidone, and in 9% of patients taking placebo. In placebo-controlled clinical trials in patients with manic episodes, the number of cases of weight gain of 7% or more after 3 weeks of treatment was comparable to that in the group receiving risperidone (2.5%), and in the placebo group (2.4%), while in the active control group there was slightly more (3.5%).

In children with behavioral disorders during long-term clinical trials, the body weight increased by an average of 7.3 kg after 12 months of therapy.The expected increase in body weight in children 5-12 years old with normal development is 3-5 kg per year. From the age of 12-16, the increase in body weight should be 3-5 kg per year for girls and about 5 kg per year for boys.

Special patient groups
Older patients with dementia

In elderly patients with dementia, transient ischemic attacks and stroke were observed in clinical trials at a frequency of 1.4 and 1.5%, respectively. In addition, the following adverse reactions were noted in elderly patients with dementia with frequency ≥5% and at a frequency at least twice that in other patient populations: urinary tract infections, peripheral edema, lethargy, and cough.

Children

The following undesirable reactions were noted in children (from 5 to 17 years) with a frequency ≥5% and at a frequency of at least 2 times that in other patient populations in clinical trials: drowsiness, sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain , dizziness, cough, pyrexia, tremor, diarrhea, enuresis.

Overdose:

Symptoms: drowsiness, sedation, tachycardia, hypotension, extrapyramidal disorders, in rare cases - prolongation of the QT interval and convulsions. In case of an overdose in patients simultaneously taking risperidone and paroxetine, described the development of polymorphic ventricular tachycardia of the type "pirouette". In the case of acute overdose, it is necessary to take into account the possibility of an overdose from taking several medications.

Treatment: ensure airway patency for adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and taking activated charcoal and laxatives should be done only if risperidone was adopted no more than 1 hour ago. For timely diagnosis of a possible heart rhythm disturbance, it is necessary to start ECG monitoring as soon as possible. There is no specific antidote, and appropriate symptomatic therapy should be performed. With a reduction in blood pressure and vascular collapse, intravenous infusion solutions and / or sympathomimetic drugs are recommended.In case of development of severe extrapyramidal symptoms - anticholinergics. Careful medical supervision and monitoring of the ECG is performed until the symptoms of intoxication disappear completely.

Interaction:

Interactions, pharmacodynamics related druga
Drugs that increase the QT interval

As with other antipsychotics, caution should be exercised in conjunction with the appointment of risperidone with drugs that increase the QT interval, for example, with antiarrhythmics (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol and others), tricyclic antidepressants (amitriptyline and others), tetracyclic antidepressants (maprotiline , etc.), some antihistamines, other antipsychotics, some antimalarial drugs (quinine, mefloquine and others), drugs that cause electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or inhibiting the hepatic metabolism of risperidone. This list is not exhaustive.

Drugs of central action and alcohol
Risperidone should be used with caution in combination with other drugs and substances of central action, especially with alcohol, opiates, antihistamines and benzodiazepines, due to the increased risk of sedation.

Levodopa and dopamine receptor agonists
Risperidone may reduce the effectiveness of levodopa and other dopamine receptor agonists. If this combination is necessary, especially at the terminal stage of Parkinson's disease, the lowest effective dose of each drug should be given.

Hypotensive drugs
When using risperidone in conjunction with antihypertensive drugs in the postgistrictive period, clinically significant hypotension was observed.

Paliperidone
It is not recommended to apply simultaneously risperidone and paliperidone, because the paliperidone is an active metabolite of risperidone. The combined use of a combination of risperidone and paliperidone may result in an increase in the concentration of the active antipsychotic fraction.

Interactions, associated with the pharmacokinetics of the drug
Eating does not affect the absorption of risperidone.
Risperidone is mainly metabolized by the isoenzyme CYP206 and, to a lesser extent, by the CYP3A4 isoenzyme. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Drugs that affect the activity of the CYP206 isoenzyme, and preparations that significantly inhibit or induce the activity of the isoparamite CYP3A4 and / or P-gp, may influence the pharmacokinetics of the active antipsychotic fraction of risperidone.

Powerful inhibitors of the isoenzyme CYP206
With the simultaneous use of risperidone and potent inhibitors of the CYP206 isoenzyme, the plasma concentration of risperidone and, to a lesser extent, the active antipsychotic fraction may increase.

Higher doses of a potent inhibitor of the CYP206 isoenzyme may increase the concentration of the active antipsychotic fraction of risperidone (for example, paroxetine, see below). It is expected that other inhibitors of the CYP206 isoenzyme, such as quinidine, may have a similar effect on the concentration of risperidone in blood plasma. When initiating or canceling therapy with a combination of risperidone and paroxetine, quinidine or another potent inhibitor of the CYP206 isoenzyme, especially at higher doses, the dosage of risperidone should be adjusted.

Inhibitors of the isoenzyme CYP3A4 and / or P-gp
The combined use of risperidone and potent inhibitors of the CYP3A4 and / or P-gp isoenzyme can significantly increase the concentration of the active antipsychotic fraction of risperidone in plasma. When initiating or canceling therapy with a combination of risperidone and itraconazole or another potent inhibitor of the isoenzyme CYP3A4 and / or P-gp, the dosage of risperidone should be adjusted.

Inductors of the isoenzyme CYP3A4 and / or P-gp
The combined use of risperidone with a potent inducer of the CYP3A4 and / or P-gp isoenzyme may reduce the concentration of the active antipsychotic fraction of risperidone in plasma. When initiating or canceling therapy with a combination of risperidone and carbamazepine or another potent inducer of the isoenzyme CYP3A4 and / or P-gp, the dosage of risperidone should be adjusted. The action of inducers of the CYP3A4 isoenzyme manifests itself over time, so it may take up to 2 weeks before the maximum effect is achieved after the onset of admission. Accordingly, if the inducer of the CYP3A4 isoenzyme is withdrawn, it may take up to 2 weeks before the effect disappears.

Preparations that bind strongly to plasma proteins
With the combined use of risperidone with drugs that have a high binding to plasma proteins, there is no clinically significant displacement of the drug from plasma proteins. When applying concomitant treatment, you should refer to the instructions for the use of the appropriate medication and, if necessary, adjust the dose of the drugs taken.

Children
Studies of drug interactions were conducted only in adult patients. Relevance of the results of these studies in children is unknown. The combined use of psychostimulants (eg, methylphenidate) and risperidone in children does not alter the pharmacokinetic parameters and efficacy of risperidone.

The effect of other drugs on the pharmacokinetics of risperidone
Antibacterial drugs

Erythromycin, a moderate inhibitor of the isoenzyme CYP3A4 and P-gp, does not affect the pharmacokinetics of risperidone and the active antipsychotic fraction.
Rifampicin, a powerful inducer of the isoenzyme CYP3A4 and P-gp, causes a decrease in the concentration of the active antipsychotic fraction in the plasma.

Anticholinesterase drugs

Donepezil and galantamine, which are substrates of the isoenzymes CYP206 and CYP3A4, do not have a clinically significant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

Antiepileptic drugs

Carbamazepine, a powerful inducer of the isoenzyme CYP3A4 and P-gp, reduces the concentration of the active antipsychotic fraction of risperidone in plasma. Similar effects were observed with the use of phenytoin and phenobarbital, which are also inducers of the isoenzyme CYP3A4 and P-gp.
Topiramate moderately reduces the bioavailability of risperidone, but not the active antipsychotic fraction. This interaction is not considered clinically significant.

Antifungal drugs

Itraconazole, a potent inhibitor of the isoenzyme CYP3A4 and P-gp, at a dose of 200 mg / day increases the concentration of the active antipsychotic fraction in the plasma by approximately 70% with risperidone at a dose of 2 to 8 mg / day.
Ketoconazole, a potent inhibitor of the isoenzyme CYP3A4 and P-gp, at a dose of 200 mg / day increases the concentration of risperidone in plasma and reduces the concentration of 9-hydroxyrisperidone in plasma.

Neuroleptics

Phenothiazines may increase the concentration of risperidone in plasma, but not the active antipsychotic fraction.

Antiviral drugs

Protease inhibitors: official research data are not available.

Because the ritonavir is a potent inhibitor of the CYP3A4 isoenzyme and a weak inhibitor of the CYP2D6 isoenzyme, ritonavir and protease inhibitors, ritonavir-enhanced, may lead to an increase in the concentration of the active antipsychotic fraction of risperidone.

β-adrenoceptor blockers

Some β-adrenoceptor blockers may increase the concentration of risperidone in plasma, but not the active antipsychotic fraction.

Calcium channel blockers

Verapamil, Moderate SYR3A4 isoenzyme inhibitor and P-gp, increases the concentration of antipsychotic risperidone and active fractions in plasma.

Gastrointestinal drugs

Antagonists of H₂-receptors: cimetidine and ranitidine, Are weak inhibitors of the SYR206 and SYR3A4, increase the bioavailability of risperidone, but marginally affect the concentration of active antipsychotic fraction.

Serotonin reuptake inhibitors and tricyclic antidepressants

Fluoxetine, A potent inhibitor of isozyme SYR206, increases the concentration of risperidone in the plasma, but to a lesser degree affected by the concentration of the active antipsychotic fraction.
Paroxetine, a potent inhibitor of the isoenzyme CYP206, increases the concentration of risperidone in plasma, but at doses up to 20 mg / day to a lesser extent affects the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction of risperidone.
Tricyclic antidepressants may increase the concentration of risperidone in plasma, but do not affect the concentration of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
Sertraline is a weak inhibitor of the CYP206 isoenzyme, and fluvoxamine - a weak inhibitor of the isoenzyme CYP3A4. In doses up to 100 mg / day sertraline and fluvoxamine have no clinically significant effect on the concentration of the active antipsychotic fraction of risperidone. However, the use of sertraline or fluvoxamine in doses above 100 mg / day may result in an increase in the concentration of the active antipsychotic fraction of risperidone.

The effect of risperidone on the pharmacokinetics of other drugs

Antiepileptic drugs

Risperidone does not have a clinically significant effect on the pharmacokinetics valproic acid or topiramate.

Neuroleptics

Aripiprazole, a substrate of isoenzymes CYP206 and CYP3A4: risperidone does not affect the pharmacokinetics of aripiprazole and its active metabolite dehydroaripiprazole.

Cardiac glycosides

Risperidone does not have a clinically significant effect on the pharmacokinetics digoxin.

Lithium preparations

Risperidone does not have a clinically significant effect on the pharmacokinetics of lithium preparations.

Simultaneous application with furosemide

Information on increased mortality in elderly patients with dementia, concomitantly taking furosemide, see "Special instructions".

Special instructions:

Use in elderly patients with dementia
Increased mortality in elderly patients with dementia
Based on the results of a meta-analysis of clinical trials in elderly patients with dementia who have used atypical antipsychotics, an increase in mortality was found in comparison with the placebo group. Mortality in patients who received risperidone or placebo, were 4.0 and 3.1%, respectively. The average age of the deceased patients was 86 years (range 67-100 years). According to two extensive observational studies,in elderly patients with dementia in the treatment of typical antipsychotic drugs, there is a slight increase in the risk of death compared to that in patients not receiving treatment. At the moment, there is insufficient data to accurately assess this risk. The cause of this risk increase is also unknown. Also, the extent to which an increase in mortality may not be applicable to antipsychotics, nor to the characteristics of this group of patients, has been determined.

Co-administration with furosemide

With simultaneous administration of furosemide and risperidone in elderly patients with dementia, there was an increased mortality (7.3%, mean age 89 years, range 75-97 years) compared with the group taking only risperidone (3.1%, average age 84 years, range 70-96 years), and the group that accepted only furosemide (4.1%, average age 80 years, range 67-90 years). An increase in mortality with furosemide combined with risperidone was noted in 2 of 4 clinical studies. Simultaneous use of risperidone with other diuretics (mainly with thiazide diuretics in small doses) was not accompanied by an increase in mortality.

There are no pathophysiological mechanisms that explain this observation. Nevertheless, special care should be taken when using the drug in such cases. Before use, the risk / benefit ratio should be carefully assessed. There was no increase in mortality in patients taking other diuretics concurrently with risperidone. Regardless of therapy, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

Cerebrovascular adverse events

In placebo-controlled clinical trials in patients with dementia, taking some atypical antipsychotics, an increased risk of cerebrovascular adverse events was approximately 3-fold. Combined data from 6 placebo-controlled trials, including mainly elderly patients with dementia (age over 65 years), show that cerebrovascular unwanted reactions (serious and non-serious) occurred in 3.3% (33 out of 1009) of the patients taking risperidone, and 1.2% (8 of 712) of patients taking placebo.The risk ratio was 2.96 (1.34, 7.50) at a confidence interval of 95%. The mechanism of increasing the risk is unknown. Increased risk is not excluded for other antipsychotics, as well as for other patient populations. Risperidone Use with caution in patients with risk factors for stroke. The risk of cerebrovascular adverse events is much higher in patients with mixed or vascular dementia compared with patients with Alzheimer's dementia. Therefore, patients with dementia of any type other than Alzheimer's should not take risperidone. Physicians should evaluate the risk / benefit ratio of risperidone in elderly patients with dementia, taking into account the precursors of stroke risk, individually for each patient. Patients and caregivers should be warned that it is necessary to immediately report symptoms of cardiovascular events such as sudden weakness or immobility / insensitivity in the face, legs, hands, as well as difficulty speaking and eye problems. All possible treatment options should be considered, including discontinuation of risperidone. Risperidone can be used only for short-term treatment of persistent aggression in patients with dementia due to Alzheimer's disease, moderate and severe as a supplement to non-pharmacological methods of correction, in case of their inefficiency or limited effectiveness and when there is a risk of harming the patient to himself or others. It is necessary to constantly assess the condition of patients and the need to continue therapy with risperidone.

Orthostatic hypotension

Risperidone has α-blocking activity and therefore can cause orthostatic hypotension in some patients, especially during the initial dose selection. Clinically significant hypotension was observed when combined with antihypertensive drugs. It is recommended to evaluate the possibility of reducing the dose in the event of hypotension. Risperidone should be used with caution in patients with diseases of the cardiovascular system (eg, heart failure, myocardial infarction, conduction disorders, dehydration, hypovolemia or cerebrovascular disease).In patients with diseases of the cardiovascular system, as well as during dehydration, hypovolemia or cerebrovascular disorders, the dose of risperidone should be increased gradually. Corresponding dose adjustment is also necessary.

Leukopenia, neutropenia and agranulocytosis

The cases of leukopenia, neutropenia and agranulocytosis have been described with the use of antipsychotics, including the use of risperidone. Agranulocytosis was very rare (<1 / 100,000 patients) during post-registration follow-up. Patients with a clinically significant decrease in the number of leukocytes or drug-induced leukopenia / neutropenia in anamnesis should be observed in the first few months after the initiation of therapy, and when the first signs of clinically significant reduction in the number of white blood cells appear, in the absence of other factors, treatment should be discontinued.

Patients with clinically significant neutropenia should be closely monitored for fever or other symptoms of the infection and should immediately begin treatment if such symptoms occur.Patients with severe neutropenia (absolute neutrophil count <1∙10%) should stop taking risperidone until the number of white blood cells is restored.

Late dyskinesia and extrapyramidal disorders

Drugs that have the properties of dopamine receptor antagonists can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, predominantly of the tongue and / or mimic musculature. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If the patient has objective or subjective symptoms indicating tardive dyskinesia, it is necessary to consider the desirability of abolishing all antipsychotics, including risperidone.

Malignant neuroleptic syndrome

In therapy with antipsychotic drugs, including risperidone, it is possible to develop malignant neuroleptic syndrome, which is characterized by hyperthermia, rigidity of muscles, instability in the function of the autonomic nervous system, depression of consciousness, and an increase in concentration

kreatinfosfokinazy in the blood serum.In patients with this syndrome, myoglobinuria (rhabdomyolysis) and acute renal failure may also occur. If a patient experiences objective or subjective symptoms of a malignant neuroleptic syndrome, all antipsychotics should be immediately discontinued, including risperidone.

Parkinson's disease and dementia with Levi bodies

The use of antipsychotics, including risperidone, patients with Parkinson's disease or dementia with Levy bodies should be treated with caution, as both groups of patients have increased risk of developing neuroleptic syndrome and increased sensitivity to antipsychotics (including blunting of pain sensitivity, confusion, postural instability with frequent falls and extrapyramidal symptoms ). When taking risperidone, there may be a worsening of the course of Parkinson's disease.

Hyperglycemia and diabetes mellitus

The cases of development of hyperglycemia, diabetes mellitus and aggravation of the course of diabetes mellitus are described. In some cases, a previous increase in body weight,which can be regarded as a predisposing factor.

In very rare cases observed the development of ketoacidosis and rarely - diabetic coma. As with any antipsychotic medication, patients should be under the supervision of a physician, symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness) should be monitored. Patients with diabetes should regularly monitor the concentration of glucose in the blood serum.

Weight gain

In the treatment with risperidone, a significant increase in body weight was observed. It is necessary to conduct regular monitoring of body weight of patients.

Hyperprolactinemia

Based on research results in vitro it was suggested that the growth of tumor cells of the breast can be stimulated by prolactin. Although clinical and epidemiological studies have not revealed a clear association between hyperprolactinaemia and antipsychotic medications, caution should be exercised in prescribing risperidone to patients with a history of history. The drug Risperidone-TL should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

QT interval extension

The prolongation of the QT interval was very rarely observed in the post-marketing period of observation. As with other antipsychotics, caution should be exercised when prescribing Risperidone-TL to patients with known cardiovascular diseases, prolonged QT interval in a family history, bradycardia, electrolyte balance disorders (hypokalemia, hypomagnesemia), as this may increase the risk of arrhythmogenic effect; and also when combined with drugs that extend the QT interval.

Convulsions

Risperidone should be used with caution in patients with seizures in the history or in conditions accompanied by a decrease in the threshold of convulsive activity.

Priapism

Because the risperidone possesses α-adrenoblokirujushchim effect, at its or his application development priapizma is possible.

Violation of body temperature regulation

When using antipsychotic drugs, an undesirable reaction is described, such as a violation of the body's ability to regulate the temperature. Caution should be exercised in prescribing risperidone to patients with conditions that may contribute to an increase in body internal temperature,which include intensive physical activity, dehydration of the body, exposure to high external temperatures, or simultaneous use of drugs with anticholinergic activity.

Venous thromboembolism

When using antipsychotic drugs, cases of venous thromboembolism were noted. Since patients taking antipsychotics often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with risperidone, and preventative measures should be taken.

Antiemetic effect

In preclinical studies of the use of risperidone, an antiemetic effect was observed. This effect in humans can mask the signs and symptoms of an overdose of some drugs or diseases such as intestinal obstruction, Reye's syndrome and brain tumor.

Impaired renal and hepatic function

In patients with impaired renal function, the ability to excrete the active antipsychotic fraction is lower than in adult patients with normal renal function. In patients with impaired liver function, the concentration of the free fraction of risperidone in the blood plasma increases.

Intraoperative syndrome of sagging iris

ISDR was observed during the operation for cataracts in patients receiving drugs with antagonism to α₁-adrenoceptors, including risperidone. The ISDR can increase the risk of complications from the visual organ during and after the operation. It is necessary to inform the ophthalmologist in advance about the use of drugs that have antagonism to α₁-adrenosceptors, now or in the past. Potential benefit of discontinuing therapy with drugs that have antagonism to α₁-adopreneceptors, before surgery for cataracts is not established. It is necessary to evaluate the relationship between the benefit and the risk of withdrawal of antipsychotic medications.

Children and teens

Before using risperidone in children or adolescents with mental retardation, it is necessary to carefully evaluate their condition for the presence of physical or social causes of aggressive behavior, such as pain or inadequate demands of the social environment. The sedative effect of risperidone should be carefully monitored in this population because of the possible effect on learning ability.The change in the time of taking risperidone can reduce the effect of sedation on the attention of adolescents and children.

The use of risperidone was associated with an increase in the average body weight and body mass index. Changes in growth during long-term studies were within the expected age norms. The long-term effect of risperidone on sexual development and growth has not been fully investigated.

Due to the possible impact of prolonged hyperprolactinemia on growth and sexual development in children and adolescents, a regular clinical assessment of hormonal status, including measurement of height, body weight, monitoring of sexual development, menstrual cycle and other possible prolactin-dependent parameters, should be carried out.

During treatment with risperidone, regular examination should be performed to identify extrapyramidal symptoms and other motor disorders.

Special information on excipients

The composition of the drug Risperidone-TL is lactose, and therefore the drug should not be used in patients with rare hereditary diseases associated with lactose intolerance,deficiency of lactase Lappa or syndrome of glucose-galactose malabsorption.

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

The drug Risperidone-TL may have little or moderate effect on the ability to drive vehicles and mechanisms. Patients should be advised not to drive the car and from working with the mechanisms to determine their individual sensitivity to the drug.

Form release / dosage:

Tablets, film-coated, 1 mg, 2 mg, 3 mg, 4 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 60 tablets in a can of polymer for medicines or a jar for medicines made of plastic.

Free space in the bank is filled with cotton wool hygroscopic or with a sterile cotton ball.

Each jar, 2 or 6 contour squares, together with the instruction for use, is placed in a pack of cardboard box.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003542

Date of registration:29.03.2016

Expiration Date:29.03.2021

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp23.08.16

Illustrated instructions

Instructions

Risperidone-TL (Risperidone)