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

Composition per ml:
Active ingredient: risperidone - 1.00 mg.
Excipients: tartaric acid - 7.50 mg; sodium benzoate - 2.36 mg; sodium hydroxide - to pH 3.0 + 0.2; water - up to 1 ml.

Description:Colorless, clear liquid with a weak characteristic odor.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.X Other antipsychotics

N.05.A.X.08 Risperidone

Pharmacodynamics:

Risperidone is a selective monoaminergic antagonist, has a high affinity for serotonergic 5-HT₂ and dopaminergic D₂receptors. Risperidone is also associated with α₁-adrenergic receptors and, somewhat weaker, with H₁-gistaminergic and α₂-adrenergic receptors. Risperidone does not have tropism for cholinergic receptors.

Antipsychotic action is due to the blockade D₂dopaminergic receptors of the mesolimbic and mesocortical systems.

Sedative action is caused by blockade of adrenoreceptors of the reticular formation of the brainstem; antiemetic action - blockade of dopamine D₂- receptors of the trigger zone of the vomiting center; hypothermic action - blockade dopamine receptors of the hypothalamus.

Risperidone reduces the productive symptoms of schizophrenia (delirium, hallucinations), aggressiveness, automatism, it causes less inhibition of motor activity and to a lesser degree induces catalepsy than classical antipsychotics. A balanced central antagonism to serotonin and dopamine can reduce the propensity to extrapyramidal side effects and extend the therapeutic effect of the drug to cover the negative and affective symptoms of schizophrenia.

Pharmacokinetics:

Suction

Risperidone after oral intake is completely absorbed, reaching the maximum concentration in the blood plasma after 1-2 hours. Food does not affect the absorption of the drug, so risperidone can be administered regardless of food intake. Absolute bioavailability of risperidone after oral administration is 70%.

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 alpha₁glycoprotein. Risperidone 90% bound by plasma proteins, 9-hydroxyrisperidone - by 77%. The equilibrium concentration of risperidone in the body in most patients is reached within 1 day. The equilibrium concentration of 9-hydroxyrisperidone is reached after 4-5 days. The concentration of risperidone in the blood plasma is proportional to the dose of the drug (within therapeutic doses).

Metabolism and excretion

Risperidone is metabolized by cytochrome isoenzyme P-450 CYP2D6 up to 9-hydroxyrisperidone, which has a pharmacological action similar to risperidone. Risperidone and 9-hydroxyrisperidone constitute the active antipsychotic fraction. Isozyme CYP2D6 is subject to genetic polymorphism. In patients with intensive isoenzyme metabolism CYP2D6 risperidone quickly turns into 9-hydroxyrisperidone, while in patients with weak metabolism this transformation occurs much more slowly. Patients with intensive metabolism have a lower concentration of risperidone and more high concentration of 9-hydroxyrisperidone than patients with poor metabolism, but the total pharmacokinetics of risperidone and 9-hydroxyrisperidone (active antipsychotic fraction) after taking one or more doses is similar in patients with intensive and weak metabolism CYP2D6. Another way of metabolizing risperidone is N-dealkylation. Research in vitro on microsomes of the human liver showed that risperidone in clinically significant concentrations, in general, does not inhibit the metabolism of drugs that undergo biotransformation with cytochrome P450 isoenzymes, including CYP 1A2, CYP 2A6, CYP 2c8 / 9/10, CYP 2D6, CYP 2E1, CYP 3A4 and CYP AP5.

After oral administration in patients with psychosis, the half-life of risperidone (T1 / 2) is about 3 hours. T1 / 2 metabolite of 9-hydroxyrisperidone and active antipsychotic fraction is 24 hours.

After a week of taking the drug, 70% of the dose is excreted in the urine, 14% - with feces. In the urine risperidone together with 9-hydroxyrisperidone constitute 35-45% of the dose. The rest is made up of inactive metabolites.

Linearity

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

Elderly patients and patients with hepatic and renal insufficiency

After a single dose of risperidone in elderly patients, the concentration of the active antipsychotic fraction in the blood plasma was on average 43% higher, the half-life lasted 38% longer, and the clearance decreased by 30%. When the renal function of moderate to severe severity was observed, the plasma concentration increased and the clearance of the active antipsychotic fraction decreased by an average of 60%.

The concentration of risperidone in plasma in patients with hepatic insufficiency was normal, but the average concentration of free fraction of risperidone in blood plasma increased by 35%.

Children

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

Influence of sex, race and smoking

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

Indications:

- Treatment of schizophrenia in adults and children aged 13 years.

- Treatment of manic episodes associated with bipolar disorder of moderate and severe degree in adults and children aged 10 years.

- 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 correction methods, and when there is a risk of harm to the patient or others.

- Short-term (up to 6 weeks) symptomatic treatment of persistent aggression in the structure of behavioral disorder in children aged 5 years with mental retardation diagnosed according to DSM-IV, in which due to the severity of aggression or other destructive behavior, drug treatment is required. Pharmacological treatment should be an integral part of a wider treatment program, including psychosocial and educational activities. Risperidone should be appointed by a specialist in the field of pediatric neurology of child and adolescent psychiatry or a physician familiar with the treatment of behavioral disorders in children and adolescents.

- Behavioral disorders in patients with dementia.

Contraindications:

Individual hypersensitivity to risperidone or any other component of the drug.

Carefully:

Use with caution under the following conditions:

- diseases of the cardiovascular system (chronic heart failure, suffered myocardial infarction, conduction disorders of the heart muscle);

- dehydration and hypovolemia;

- disorders of cerebral circulation;

- Parkinson's disease;

- convulsions and epilepsy (including in the anamnesis);

- severe renal or hepatic impairment (see section "Method of administration and dose");

- drug abuse or drug dependence;

- conditions predisposing to the development of tachycardia such as "pirouette" (bradycardia, electrolyte imbalance, concomitant medication prolonging the interval QT);

- brain tumor;

- intestinal obstruction;

- cases of acute drug overdose;

- Reye syndrome (antiemetic effect of risperidone can mask the symptoms of these conditions);

- pregnancy;

- patients with risk factors for venous thromboembolism;

- disease of diffuse Levi bodies;

- elderly patients with cerebrovascular dementia;

- pregnancy;

- hyperglycemia;

- application in combination with furosemide;

- combination with other drugs of central action.

Pregnancy and lactation:

The safety of Risperidone in pregnant women has not been studied. In animals risperidone not had a direct toxic effect on the reproductive system, but caused some indirect effects, mediated by the influence on the central nervous system and concentration of prolactin. According to observations in the post-marketing period, with risperidone during the last trimester of pregnancy There were irreversible extrapyramidal symptoms in the newborn, so neonates, must be carefully monitored. These

Newborns are at risk of extrapyramidal disorders and / or withdrawal syndrome of varying severity.These symptoms may include agitation, Hypertension, hypotension, tremor, drowsiness, respiratory disorders and violation feeding. In animal experiments risperidone did not render teratogenic effect, but other types of toxic effects on reproductive system. The potential risk to people is unknown. Risperidone can be used during pregnancy only in those cases where the potential benefit to the mother outweighs the possible risk to the fetus. If it is necessary to stop taking the drug during pregnancy, the drug should be withdrawn gradually.

Lactation

In studies in animals risperidone and 9-hydroxyrisperidone penetrated into the milk. It was also demonstrated that risperidone and 9-hydroxyrisperidone penetrate the breast milk of women. Data on adverse events in infants who are breastfed are absent. Women who use risperidone, you should stop breastfeeding.

Influence on reproductive function

Due to the fact that risperidone can increase the concentration of prolactin in the blood plasma,hyperprolactinemia can inhibit the production of gonadotropin-releasing hormone by the hypothalamus, which leads to a decrease in the secretion of gonadotrophin by the pituitary gland. This in turn can reduce the reproductive function due to a violation of the synthesis of hormones in the sex glands in patients both female and male. In preclinical studies, no significant effects were observed.

Dosing and Administration:

Inside, regardless of food intake.

Schizophrenia.

Adults.

Risperidone may be given once or twice a day.

The initial dose of the drug is 2 mg per day. On the second day, the dose should be increased to 4 mg per 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 per day. In some cases, a slower dose increase and lower initial and maintenance doses may be justified.

Doses above 10 mg per day did not show a higher efficacy compared with smaller doses and may cause extrapyramidal symptoms. Because, that the safety of doses above 16 mg per day has not been studied, doses above this level should be applied it is impossible.

Elderly patients.

Recommended initial dose of 0.5 mg per reception twice a day. Dosage can individually be increased by 0.5 mg twice a day to 1-2 mg twice a day.

Adolescents are over 13 years old.

It is recommended that the initial dose of 0.5 mg once a day in the morning or evening. If necessary, the dose can be increased at least after 24 hours by 0.5-1 mg per day to a recommended dose of 3 mg per day with good tolerability. Despite the efficacy shown in the treatment of schizophrenia in adolescents at doses of 1-6 mg per day, no additional efficacy was seen at doses exceeding 3 mg per day, and higher doses caused more side effects. Safety of doses above 6 mg per 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 is absent.

Treatment of manic episodes associated with bipolar disorder.

Adults.

The recommended initial dose of the drug is 2 mg per day at a time. If necessary, this dose can be increased at least 24 hours per 1 mg per day. For most patients, the optimal dose is 1-6 mg per day.The use of doses above 6 mg per day has not been studied. As with any symptomatic therapy during treatment, one should evaluate and confirm the advisability of continuing treatment with the drug Risperidone.

Elderly patients.

For elderly patients, an initial dose of 0.5 mg 2 times a day is recommended. If necessary, increase the dose by 0.5 mg twice a day to 1-2 mg twice a day. Due to the lack of experience in the elderly, caution should be taken in this age group.

Teenagers and children over 10 years old.

It is recommended that the initial dose of 0.5 mg once a day in the morning or evening. When the dose can be increased not less than 24 hours by 0.5-1 mg per day up to recommended dose of 1-2.5 mg per day with good tolerability. For most patients, the optimal dose is 0.5 to 6 mg per day. Despite the efficacy shown in the treatment of manic episodes associated with bipolar disorder in children with doses of 0.5-6 mg per day, no additional efficacy was observed at doses above 2.5 mg per day, and higher doses caused more side effects. Safety of doses above 6 mg per 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 bipolar disorders in children under 10 years is absent.

Short-term (up to 6 weeks) treatment of incessant aggression in patients with dementia due to Alzheimer's disease

It is recommended that the initial dose be 0.25 mg twice a day in the morning or evening. If necessary, the dosage can be increased at least 24 hours by 0.25 mg twice a day, not more often than every other day. For most patients, the optimal dose is 0.5 mg 2 times a day. However, some patients receive 1 mg twice daily. Risperidone should not be administered for more than 6 weeks in patients with persistent aggression in patients with dementia due to Alzheimer's disease. During treatment, the condition of patients should be regularly assessed and the need to continue therapy should be considered.

Short-term (up to 6 weeks) symptomatic treatment of incessant aggression in the structure of behavioral disorders in children from 5 years with mental retardation

Children from 5 to 18 years old

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, this dose may be increased by 0.5 mg per day, not more often than every other day. For most patients, the optimal dose is a dose of 1 mg in day. However, for some patients it is preferable to take 0.5 mg per day, whereas some require an increase in the dose to 1.5 mg per day. As with any symptomatic therapy during treatment, the advisability of continuing treatment drug Risperidone must be regularly evaluated and confirmed.

Patients weighing less than 50 kg - the recommended initial dose of the drug is 0.25 mg once a day. If necessary, this dose can be increased by 0.25 mg per day, not more often than every other day. For most patients, the optimal dose is 0.5 mg per day. However, for some patients it is preferable to take 0.5 mg per day, while some require an increase in the dose to 0.75 mg per day.

Long-term use of the drug in adolescents should be carried out under the constant supervision of a doctor.

Use in children under 5 years of age has not been studied.

Behavioral disorders in patients with dementia.

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

Once the optimal dose is reached, the drug may be recommended once a day.

Diseases of the liver and kidneys.

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, increasing the dose in patients with liver and kidney disease should be slower.

The drug should be administered with caution in this category of patients.

Termination of risperidone should be carried out gradually. Acute withdrawal symptoms, including nausea, vomiting, increased sweating and insomnia, were very rarely seen after a sharp discontinuation of high doses of antipsychotics, including risperidone.Possible relapse of psychotic symptoms and the emergence of involuntary movements.

Transition from therapy with other antipsychotic drugs

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

Side effects:

The most frequently observed side effects (incidence> 5%) were: parkinsonism, headache, insomnia, anxiety, upper respiratory tract infections.

Dose-dependent adverse reactions are parkinsonism and akathisia.

Side effects of the drug in therapeutic doses are given with a frequency distribution and system-organ classes. The incidence of adverse events was classified as follows: very frequent (≥1 / 10 cases), frequent (≥1 / 100 and <1/10 cases), infrequent (≥1 / 1000 and <1/100 of the cases), rare (≥1 / 10000 and <1/1000 cases) and very rare (<1/10000 cases) and with unknown frequency (it is not possible to estimate the frequency from the available data).

From the cardiovascular system: often - tachycardia, arterial hypertension; infrequently - atrioventricular block, left or right bundle bundle blockage, atrial fibrillation, palpitations, conduction disturbance, lengthening of the interval QT on ECG, abnormalities on the ECG, bradycardia, hypotension, orthostatic hypotension, hot flashes; rarely - sinus arrhythmia, sinus bradycardia, deep vein thrombosis, pulmonary embolism.

Hematologic disorders and disorders of the 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, agranulocytosis.

From the nervous system: Often - drowsiness, sedation, headache, Parkinsonism²; often - akathisia², dizziness², tremor², dystonia², lethargy, dyskinesia²; infrequently - lack of response to stimuli, loss of consciousness, decreased level of consciousness, fainting,impaired consciousness, transient ischemic attack, stroke, dysarthria, attention disturbance, hypersomnia, postural dizziness, imbalance, tardive dyskinesia, speech impairment, coordination disorder, taste disorder, taste distortion, seizures, cerebral ischemia, impaired movement, hypoesthesia, psychomotor agitation, paresthesia; rarely - cerebrovascular disorders, malignant neuroleptic syndrome, tremor head, diabetic coma.

From the side of the organ of vision: often - conjunctivitis, blurred vision; infrequently - hyperemia conjunctiva, visual impairment, discharge from the eyes, periorbital edema, dry eyes, increased lacrimation, photophobia; rarely - decreased visual acuity, eye movement disorder, involuntary eyeball rotation, crust formation at the edge of the eyelid, glaucoma, intraoperative syndrome of the "flabby" iris, occlusion of the retinal artery.

From the side of the organ of hearing and labyrinth: infrequently - pain in the ear, tinnitus, vertigo.

From the respiratory system, organs of the thorax and mediastinum: often - nasal congestion, dyspnea, epistaxis, cough, pain in the larynx and pharynx; infrequently - wheezing, aspiration pneumonia, congestion in the lungs, dysphonia, violation of airway patency, respiratory failure, wet wheezing; rarely - hyperventilation, sleep apnea syndrome.

From the gastrointestinal tract: often - vomiting, diarrhea, nausea, constipation, abdominal pain, indigestion, dry mouth, abdominal discomfort, hypersalivation, toothache; infrequently - Dysphagia, gastritis, fecal matter, flatulence, fecal incontinence, gastroenteritis; rarely - pancreatitis, swelling of the lips, swelling of the tongue, cheilitis, intestinal obstruction; rarely - ileus.

From the nochek and urinary tract: often - enuresis, urinary incontinence; infrequently - delay of urination, dysuria, pollakiuria.

From the skin and subcutaneous tissues: often - skin rash, erythema; infrequently - urticaria, skin lesions, breach of skin integument, itching, acne, acne, dry skin, seborrheic dermatitis, hyperkeratosis, discoloration, alopecia; rarely - drug rash, dandruff; rarely - Quincke's edema.

From the osteomuscular system and connective tissue: often - muscle spasms, musculoskeletal pain, back pain, arthralgia, pain in the buttocks, pain in the limbs; infrequently - increase in the level of creatine phosphokinase, muscle pain in the chest, joint stiffness, muscle weakness, neck pain, posture disorder, joint swelling, myalgia; rarely - rhabdomyolysis.

From the endocrine system: often - an increase in the level of prolactin¹; rarely - disturbance of the production of antidiuretic hormone, glucosuria.

Metabolic and nutritional disorders: often - loss of appetitethat, increased appetite, increase in body weight; infrequently - weight reduction, polydipsia, anorexia, diabetes³, hyperglycemia, increased cholesterol concentration; rarely - water intoxication, hypoglycemia, increased insulin, increased concentration of triglycerides; rarely - Diabetic ketoacidosis.

Infections: 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 - chronic otitis media, lower respiratory infections, infections, subcutaneous abscess.

General disorders and phenomena caused by the administration of the drug: often - edema, pyrexia, fatigue, asthenia, pain in the chest, peripheral edema, generalized edema, pain; infrequently - edema of the face, gait disturbance, poor health, sluggishness, flu-like condition, malaise, thirst, discomfort in the chest, chills, fever, discomfort; rarely - withdrawal syndrome, hypothermia, lower body temperature, cold extremities, induration.

From the immune system: infrequently - hypersensitivity reactions; rarely - drug hypersensitivity, anaphylactic reaction.

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.

On the part of the reproductive system and mammary glands: infrequently - amenorrhea, sexual dysfunction, erectile dysfunction, ejaculation disorder, galactorrhea, gynecomastia, menstrual cycle disorder, vaginal discharge, pain in the mammary gland, discomfort in the mammary gland; rarely - priapism, delay in menstruation, engorgement of the mammary glands,an increase in the mammary glands, secretions from the mammary glands.

Influence on the course of pregnancy, postpartum and perinatal conditions: rarely - withdrawal syndrome in newborns.

Disorders from the psyche: Often - Insomnia; often - anxiety, agitation, sleep disorders, anxiety, depression; infrequently - confusion, decreased libido, mania, lethargy, nervousness, nightmares; rarely anorgasmia, flattening of affect.

Injuries, poisonings, complications during procedures: often - a fall, infrequently - pain during procedures.

¹ - giperprolaktinemiya in some cases can lead to gynecomastia, menstrual disorders, amenorrhea and galactorrhea.

²- extrapyramidal disorders can manifest as: parkinsonism (hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, rigidity of the "cogwheel" type, bradykinesia, hypokinesia, masculine face, muscle tension, akinesia, rigidity of the occipital muscles, muscle rigidity, parkinsonic gait, glabellar reflex abnormalities), akathisia (akathisia , anxiety, hyperkinesia and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis and myoclonus), dystonia.

The term "dystonia" includes dystonia, muscle spasms, hypertension, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, eyeball movements, paralysis of the tongue, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurotone, spasm of tongue 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.

³- in 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.

Class Effects

As with the use of other antipsychotics, there were very few cases of an increase in the tooth QT. Other class-effects from the cardiovascular system, observed with the use of antipsychotics, which increase the prong QT, include: ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation, cardiac arrest and bidirectional ventricular tachycardia, sudden death.

Venous thromboembolism

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

Weight gain

In 6-8 weeks of placebo-controlled trials in patients with schizophrenia, a clinically significant increase in body weight of 7% or more was observed in the risperidone group (18%), higher than in the placebo group (9%). In placebo-controlled clinical trials in adult patients with manic episodes, the number of cases of weight gain of 7% or more after 3 weeks of treatment was comparable 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 size of the increase in body weight was 3-5 kg per year for girls and about 5 kg for boys.

Additional data on side effects in special groups

Side effects that have been observed with greater frequency in elderly patients with dementia and in children than in adult patients are described below.

Elderly patients with dementia

Transient ischemic attack and stroke were observed in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following side effects were observed in elderly patients with dementia with a frequency of ≥5% and at a frequency at least twice that in the other patient groups: urinary tract infections, peripheral edema, lethargy and cough.

Children

Side effects observed in children aged 5-17 years with greater frequency (with a frequency of ≥5% and a frequency at least twice that in the other groups of patients) in clinical trials: drowsiness / sedation ,fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, fever, tremor, diarrhea, enuresis.

Overdose:

Symptoms: drowsiness, oppression of consciousness, sedation, tachycardia, decrease arterial pressure, extrapyramidal symptoms, rarely - lengthening of the interval QT and convulsions. Bi-directional ventricular tachycardia (of the "pirouette" type) was noted in a simultaneous application of an increased dose of risperidone and paroxetine.

In case of an overdose, the possibility of an overdose from taking several drugs should be considered.

Treatment.

It is necessary to achieve and maintain free airway patency to ensure adequate intake of oxygen and ventilation, do gastric lavage (after intubation, if the patient is unconscious) and appoint Activated carbon together with a laxative within an hour after an overdose. Immediately begin monitoring the ECG to identify possible arrhythmias and continue it until the symptoms of intoxication disappear completely.

Specific antidote does not exist, appropriate symptomatic therapy should be conducted, aimed at maintaining vital body functions. Reduction of blood pressure and collapse should be eliminated by intravenous fluid infusions and / or adrenomimetics. In case of development of acute extrapyramidal symptoms, m-holinoblokatory (for example, trihexyphenidyl). Continuous medical supervision should continue until the symptoms of an overdose disappear.

Interaction:

Interactions associated with the pharmacodynamics of the drug

Drugs that increase the interval QT

As with other antipsychotic drugs, caution should be exercised when using the drug together Risperidone with drugs that increase the interval QT, for example, with antiarrhythmic agents (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 because of 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 together with antihypertensive drugs, clinically significant hypotension was observed.

Paliperidone

It is not recommended to apply the drug at the same time 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 isoenzyme CYP2D6 and to a lesser extent isoenzyme CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of 3-glycoprotein (P-gp). Drugs affecting the activity of the isoenzyme CYP2D6, and preparations that largely inhibit or induce isoenzyme activity CYP3A4 and / or P-gp, can influence the pharmacokinetics of the active antipsychotic fraction of risperidone.

Powerful inhibitors of isoenzyme CYP2D6

With the simultaneous use of risperidone and potent inhibitors of the isoenzyme CYP2D6 plasma risperidone concentrations may be increased, and to a lesser extent - active antipsychotic fraction. Higher doses of a potent inhibitor isoenzyme CYP2D6 can increase the concentration of active antipsychotic fractions of risperidone (eg, paroxetine, see below).It is expected that others inhibitors of isoenzyme CYP2D6, such as quinidine, can exert similar influence on the concentration of risperidone in plasma. When initiating or canceling therapy a combination of risperidone and paroxetine, quinidine or another potent inhibitor isoenzyme CYP2D6, especially at higher doses, the dose should be adjusted preparation Risperidone.

Inhibitor inhibitors CYP3A4 and / or P-gp

Joint use of the drug Risperidone and potent inhibitors of isoenzyme CYP3A4 and / or P-gp 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 isoenzyme CYP3A4 and / or P-gp should adjust the dose of the drug Risperidone.

Inductors of isoenzyme CYP3A4 and / or P-gp

Joint use of Risperidone with a powerful isoenzyme inducer CYP3A4 and / or P-gp can 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 isoenzyme inducer CYP3A4 and / or P-gp, should adjust the dose of the drug Risperidone. Action of inducers of isoenzyme CYP3A4 manifests itself over time, so it may take up to 2 weeks before the maximum effect is achieved after the start of the treatment.

Accordingly, with the cancellation of the isoenzyme inducer CYP3A4 it may take up to 2 weeks for the effect to disappear.

Preparations that bind strongly to plasma proteins

When the drug is used together Risperidone with preparations having a high bond 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 isoenzyme inhibitor CYP3A4 and P-gp, not affects pharmacokinetics of risperidone and active antipsychotic fraction.

- Rifampicin, a powerful isoenzyme inducer 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 isoenzymes CYP2D6 and CYP3A4, not have a clinically significant effect on the pharmacokinetics of risperidone and active antipsychotic fraction.

Antiepileptic drugs

- Carbamazepine, a powerful isoenzyme inducer 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 active antipsychotic fraction in the plasma by about 70% with risperidone at a dose of 2 to 8 mg / day.

- Ketoconazole, a potent inhibitor of isoenzyme CYP3A4 and P-gp, in a dose of 200 mg / day increases the concentration of risperidone in plasma and reduces the concentration of 9-hydroxyrisperidone in plasma.

Neuroleptics

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

Antiviral drugs

- Inhibitors of protease: official research data are not available. As ritonavir is a potent inhibitor of isoenzyme CYP3A4 and a weak isoenzyme inhibitor CYP2D6, ritonavir and protease inhibitors, ritonavir-enhanced, may lead to an increase in the concentration of the active antipsychotic fraction of risperidone.

Beta-blockers

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

Calcium channel blockers

- Verapamil, a moderate isoenzyme inhibitor CYP3A4 and P-gp, increases the concentration of risperidone and the active antipsychotic fraction in plasma.

Gastrointestinal drugs

- H2-receptor antagonists: cimetidine and ranitidine, which are weak inhibitors of isoenzymes CYP2D6 and CYP3A4, increase the bioavailability of risperidone, but have a minimal effect on the concentration of the active antipsychotic fraction.

Serotonin reuptake inhibitors and tricyclic antidepressants

- Fluoxetine, a potent inhibitor of the isoenzyme CYP2D6, increases the concentration of risperidone in plasma, but to a lesser extent affects the concentration of the active antipsychotic fraction.

- Paroxetine, a potent inhibitor of the isoenzyme CYP2D6, 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 the 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 isoenzyme inhibitor CYP2D6, a fluvoxamine - a weak inhibitor of 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 of valproic acid or topiramate.

Neuroleptics

- Aripiprazole, a substrate of isoenzymes CYP3A4 and CYP2D6: risperidone is not has an effect on the pharmacokinetics of aripiprazole and its active metabolite dehydroaripiprazole.

Cardiac glycosides

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

Lithium preparations

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

Simultaneous application with furosemide

See information on increased mortality in elderly patients with dementia who simultaneously take furosemide, in the section "Special instructions".

Special instructions:

Use in elderly patients with dementia

Increased mortality in elderly patients with dementia

In elderly patients with dementia in the treatment of atypical antipsychotics, there is an increased mortality compared with placebo in studies of atypical antipsychotics, including risperidone. When using risperidone in this population, the incidence of fatalities was 4% for patients taking risperidone, compared with 3.1% for placebo. The average age of the deceased patients is 86 years (range 67-100 years). The data collected from two extensive observational studies show that elderly patients with dementia who are treated with typical antipsychotics also have a slightly increased risk of death compared to patients who do not receive 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

For elderly patients with dementia who took oral forms of risperidone, there was an increased mortality among patients taking furosemide and risperidone (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 a group that only took furosemide (4.1%, average age 80 years, range 67-90 years). Increased mortality of patients taking risperidone together with furosemide, was observed during 2 out of 4 clinical trials. Joint 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. However, special care should be taken when using the drug in such cases. Before appointment, the risk / benefit ratio must be carefully assessed. There was no increase in mortality in patients taking other diuretics simultaneously with risperidone. Regardless of the treatment, in elderly patients with dementia, dehydration is a common risk factor for mortality and should be carefully monitored.Regardless of treatment, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

When risperidone was used in comparison with placebo, elderly patients with dementia experienced an increase in side effects from the cerebrovascular system (acute and transient cerebral circulatory disorders), including deaths (mean age 85 years, range 73-97 years). therefore risperidone Use with caution in patients at risk of stroke.

Cardiovascular effects

In placebo-controlled clinical trials in patients with dementia, taking some atypical antipsychotics, an increased risk of cerebrovascular side effects was approximately 3-fold.

Combined data from 6 placebo-controlled trials, including mainly elderly patients with dementia (age over 65 years), demonstrated that cerebrovascular side effects (serious and non-serious) occurred in 3.3% (33/1009) of patients taking risperidone, and in 1.2% (8/712) of the patients taking placebo.The risk ratio was 2.96 (1.34, 7.50) with a confidence interval 95%. The mechanism of increasing the risk is unknown. Increased risk is not excluded for other antipsychotic drugs, as well as for other patient populations.

Risperidone should be used with caution in patients with risk factors for stroke. The risk of cerebrovascular side effects 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 dementia 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 the signs and symptoms of cardiovascular events: such as sudden weakness or immobility / numbness in the face, legs, hands, as well as speech difficulties and vision problems.In this case, all possible treatment options should be considered, including discontinuation of the drug. 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, if they are ineffective or limited effectiveness 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.

Transition from therapy with other antipsychotic drugs

At the beginning of risperidone treatment for schizophrenia, if clinically justified, it is recommended that the previous therapy be gradually phased out. 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 therapy should be evaluated.

Orthostatic hypotension.

In connection with the α-adrenoblocking action of risperidone, orthostatic hypotension may occur, especially during the initial dose selection.Clinically significant reduction in blood pressure in the postmarketing period is observed with the simultaneous use of risperidone with antihypertensive drugs. With a decrease in blood pressure should consider reducing the dose of one or both drugs. In patients with known cardiovascular diseases (heart failure, myocardial infarction, conduction of cardiac muscle, dehydration, hypovolemia or cerebrovascular disease), and also with dehydration, hypovolemia or cerebrovascular disorders, a dose should be increased gradually, according to the recommendations.

Extrapyramidal symptoms and tardive dyskinesia.

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 facial musculature. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If the patient has objective or subjective symptoms that indicate tardive dyskinesia,should consider the feasibility of the abolition of all antipsychotic drugs, including Risperidone.

Malignant neuroleptic syndrome.

In the case of malignant neuroleptic syndrome characterized by hyperthermia, muscle rigidity, autonomic nervous system instability, impaired consciousness and increased serum creatinine phosphokinase activity (myoglobinuria (rhabdomyolysis) and acute renal failure may also occur), all antipsychotics should be discontinued including risperidone.

Leukopenia, neutropenia and agranulocytosis.

When using antipsychotic drugs, including risperidone, cases of leukopenia, neutropenia and agranulocytosis were observed. Agranulocytosis was very rare (less than 1 / 10,000 patients) in post-marketing surveillance. Patients with a clinically significant decrease in the number of blood leukocytes or with drug-induced leukopenia / neutropenia should be observed during the first few months of treatment. At the first signs of a decrease in the number of white blood cells (in the absence of other causes), the question of the abolition of risperidone should be considered.Patients with a clinically significant decrease in the number of white blood cells should be observed for possible fever or other signs of infection. Patients with severe neutropenia (absolute number of neutrophils less than 1 * 10⁹) require the withdrawal of risperidone and in observation until the normal level of neutrophils is restored.

Parkinson's disease il and dementia with Levy bodies.

The use of antipsychotics, including risperidone, patients with illness Parkinson's disease or dementia with Lewy bodies should be done with caution, because the both groups of patients increased the risk of developing a malignant neuroleptic syndrome and increased sensitivity to antipsychotics (including dullness of pain sensitivity, confusion, postural instability with frequent falls and extrapyramidal symptoms). When you receive risperidone may worsen the course of Parkinson's disease.

Intraoperative syndrome of trembling iris.

This syndrome was observed in operations for cataracts in patients who received drugs that are antagonists α_1Aadrenoreceptors.Syndrome of trembling iris can increase the risk of eye complications during and after eye operations. The operating ophthalmologist should be advised of the patient's admission of antagonists α_1Aadrenoreceptors. Using α_1A-adrenoblockers before the operation for cataracts in patients receiving antagonists α₁-adrenoceptors has not been studied.

Antiemetic effect.

An antiemetic effect was observed in preclinical studies of risperidone. This effect in humans can mask the signs and symptoms of an overdose of certain drugs, as well as the symptoms of these conditions like intestinal obstruction, hepatocerebral syndrome or brain tumor.

Hyperglycemia, diabetes mellitus.

In the treatment with risperidone, hyperglycemia, diabetes mellitus, or exacerbation of already existing diabetes mellitus were observed. It is likely that the previous increase in body weight is also predisposing to this factor. It is very rare to have ketoacidosis and rarely - a diabetic coma. All patients need to be clinically monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia and weakness) and diabetes mellitus.All patients with diabetes should be monitored regularly for impaired glucose control.

Weight gain.

In the treatment with risperidone, a significant increase in body weight was observed. When treating risperidone, it is necessary to monitor the body weight of patients.

Hyperprolactinemia.

Based on the results of studies on tissue cultures, it has been suggested that the growth of breast tumor cells 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.

Caution is advised when using in patients with hyperprolactinaemia (including in anamnesis) or the risk of developing prolactin-dependent tumors, since risperidone can increase the concentration of prolactin in the blood.

Interval lengthening QT.

Interval lengthening QT very rarely observed in the postmarketing period. As with other antipsychotics, caution should be exercised in prescribing risperidone to patients with known cardiovascular diseases, lengthening the interval QT in a family history, bradycardia, electrolyte balance disorder (hypokalemia, hypomagnesemia) hack as this may increase the risk of arrhythmogenic effect; and with simultaneous application with drugs that increase the interval QT.

Convulsions.

The ability of typical neuroleptics to reduce the threshold of convulsive readiness is known, so caution should be given risperidone patients with epilepsy.

Priapism.

Due to blockade of α-adrenergic receptors risperidone can cause priapism.

Violation of thermoregulation.

Antipsychotic drugs can cause a violation of the regulation of body temperature. Care should be taken when prescribing the drug Risperidone patients with conditions that can contribute to increased body temperature, which include intense physical activity, dehydration, high temperatures, or simultaneously using drugs with anticholinergic activity.

Venous thromboembolism.

When using antipsychotic drugs, cases of venous thromboembolism were noted. Since patients taking antipsychotic drugs,often have a risk of developing venous thromboembolism, all possible risk factors should be detected before and during treatment with the drug Risperidone, and preventive measures should be taken.

Children and teenagers.

Before prescribing the drug Risperidone children or adolescents with mental retardation, a thorough assessment of their condition for physical or social causes of aggressive behavior, such as pain or inadequate requirements of the social environment. The sedative effect of risperidone should be be carefully monitored in this population because of the potential impact on training. The change in the time of taking the drug can improve the control of the effect of sedation on the attention of adolescents and children. The use of risperidone was associated with an average increase in body weight and body mass index. The change in growth during long-term studies was within the expected age norms. The effect of long-term taking Risperidon on sexual development and growth has not been fully studied. In connection with the possible influence of prolonged hyperprolactinemia on the growth and sexual development in children and adolescents,regular clinical evaluation of hormonal status should be carried out, including measurement of height, weight, monitoring of sexual development, menstrual cycle and other possible prolactin-dependent effects. During treatment with risperidone, a regular evaluation of the presence of extrapyramidal symptoms and other movement disorders should be performed.

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

During drug treatment it is not recommended to drive vehicles, as well as mechanisms, work with which is associated with increased concentration of attention.

Form release / dosage:

Solution for oral administration 1 mg / ml.

Packaging:

To 30 ml or 100 ml of solution in a bottle of orange glass glass or a bottle of polyethylene terephthalate or a polymer for medicines, equipped with an adapter, sealed with a polymer screw cap with a first opening control or a "push-turn" cover.

A label is attached to the vial on the basis of a self-adhesive film or a label of label paper.

One bottle together with instructions for use, as well as a syringe dispensing is placed in a cardboard package (pack) of cardboard for consumer packaging.

Storage conditions:

At a temperature of no higher than 25 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004227

Date of registration:04.04.2017

Expiration Date:04.04.2022

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp16.05.2017

Illustrated instructions

Instructions

Risperidone (Risperidone)