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

Pharmacodynamics:Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotonergic 5-HT₂receptors and dopaminergic D₂receptors. Risperidone is also associated with α₁-adrenergic receptors and somewhat weaker with H₁-histaminergic and α₂-adrenergic receptors. Risperidone does not have an affinity 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 reduces the likelihood of developing extrapyramidal side effects and expands the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.

Pharmacokinetics:

Suction

Risperidone after intake is completely absorbed, reaching a maximum concentration (FROM_max) in the blood plasma after 1-2 hours. Absolute bioavailability of risperidone after oral administration is 70%. The relative bioavailability after oral administration of risperidone in the form of tablets is 94% when compared with risperidone administered intravenously in the form of a solution. Food does not affect the absorption of the drug, so risperidone can be used regardless of food intake. The equilibrium concentration of risperidone in plasma in most patients is reached within 1 day.The equilibrium concentration of the main active metabolite (9-hydroxyrisperidone) in blood plasma 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 blood plasma risperidone binds to albumin and alpha₁acid glycoprotein. Risperidone 90% bound by plasma proteins, 9-hydroxyrisperidone - by 77%.

Metabolism and excretion

Risperidone is metabolized by isoenzyme CYP2D6 to 9-hydroxyrisperidone, which has a pharmacological action analogous to risperidone. Risperidone and 9-hydroxyrisperidone constitute the active antipsychotic fraction. Isozyme CYP2D6 is susceptible to genetic polymorphism. In patients with intensive isoenzyme metabolism CYP2D6 risperidone quickly turns into 9-hydroxyrisperidone, while in patients with reduced 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 in the blood plasma than patients with poor metabolism,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 does not inhibit the metabolism of drugs that undergo biotransformation with cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. One week after starting 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. After ingestion in patients with psychosis risperidone is excreted from the body with a half-life (T_1/2) for about 3 hours. T_1/29-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.

Elderly patients and patients with impaired liver and kidney function

After a single dose of risperidone inwards in elderly patients, concentrations of the active antipsychotic fraction in the blood plasma were on average 43% higher, T_1/2lasted 38% longer, and the clearance decreased by 30%. In patients with moderate renal insufficiency, the clearance of the active antipsychotic fraction was about 48% of the clearance in healthy young volunteers. In patients with severe renal insufficiency, the clearance of the active antipsychotic fraction was approximately 31% of that of healthy young volunteers. T_1/2 The active antipsychotic fraction was 16.7 hours in young volunteers. 24.9 hours in patients with moderate renal insufficiency (about 1.5 times higher compared with young volunteers) and 28.8 hours in patients with severe renal failure (approximately 1.7 times higher in comparison with young patients ). In patients with hepatic insufficiency, the concentration of risperidone in the blood plasma did not change, but the average concentration of the free fraction of risperidone increased by 37.1%.

Clearance and T_1/2risperidone and active antipsychoticfraction at ingestion in patients with moderate and severe impairment of liver function did not significantly differ from these parameters in healthy young volunteers.

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 the active pharmacokinetic fraction.

Indications:

- Treatment of schizophrenia in adults;

- treatment of manic episodes associated with bipolar disorder of moderate to severe in adults;

- short-term (up to 6 weeks) symptomatic 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 and others (this dosage form is not applicable to start treatment and at a stage of escalation of a dose in connection with impossibility of maintenance of the minimal effective dose of 0,25 mg);

- short-term (up to 6 weeks) symptomatic treatment of persistent aggression in the structure of behavioral disorder in children aged 5 years and adolescents with mental retardation (with a body weight of more than 50 kg for this dosage form due to the inability to provide the minimum effective dose (0.25 mg) and at the stage of escalation of the dose), diagnosed in accordance with DSM-IV (Manual on Diagnostics and Statistics of Mental Disorders, 4th edition, USA), in which due to the severity of aggression or other destructive behavior, drug 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:

- Hypersensitivity to risperidone or any other component of the drug;

- intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption.

Carefully:

- In patients with diseases of the cardiovascular system (chronic heart failure, a previous myocardial infarction, cardiac conduction abnormalities);

- with dehydration and hypovolemia;

- with simultaneous application of furosemide (see section "Interaction with other drugs");

- in patients with impaired cerebral circulation;

- in patients with Parkinson's disease;

- with convulsions (including anamnesis);

- in patients with severe renal or hepatic insufficiency (see section "Method of administration and dose");

- at abuse of medicines or drug dependence;

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

- in patients with neutropenia;

- in patients with diabetes mellitus;

- with hyperglycemia;

- in patients with hyperprolactinaemia;

- before the operation to remove cataracts;

- in patients with a brain tumor, intestinal obstruction, with acute drug overdose, with Reys syndrome (the antiemetic effect of risperidone can mask the symptoms of these conditions);

- in patients with risk factors for venous thromboembolism;

- in patients with dementia with Levy bodies:

- in elderly patients with cerebrovascular dementia;

- during pregnancy and breastfeeding.

Pregnancy and lactation:

Pregnancy

Comprehensive studies on the use of risperidone in pregnant women do not was conducted. In newborns who were exposed during the third trimester pregnancy, the effects of antipsychotic drugs (including risperidone), after birth, there was an increased risk of developing unwanted reactions in the form of extrapyramidal symptoms and / or withdrawal syndrome of varying severity and duration. There have been reports of anxiety, lability of blood pressure (BP), tremor, drowsiness, respiratory distress syndrome, or eating disorders. Newborns whose mothers took risperidone in the third trimester of pregnancy, should be under careful medical supervision.

Risperidone Zentiva may be used during pregnancy only if absolutely necessary, if the expected benefit to the mother exceeds the potential risk to the fetus.If it is necessary to stop treatment during pregnancy, the drug should be withdrawn gradually.

Breastfeeding period

In animal studies, it was found that risperidone and 9-hydroxyrisperidone penetrated into breast milk. It is proved that in human breast milk risperidone and 9-hydroxyrisperidone penetrates in small amounts. These adverse reactions in infants who are breastfed are absent. Breastfeeding with risperidone is not recommended.

Fertility

As with other antagonists D₂-receptors dopamine, risperidone increases the content of prolactin in the blood plasma. Hyperprolactinemia can inhibit the production of hypothalamic gonadotropin-releasing hormone, which leads to a decrease in the secretion of the pituitary gonadotropin. This, in turn, can depress the reproductive function by disrupting the synthesis of sex hormones in both women and men.

In the course of preclinical studies, the corresponding phenomena were not observed.

Dosing and Administration:

The drug is taken internally, regardless of the reception of the food.

Tablet drug Risperidone Zentiva 1 mg has a risk for dividing into equal doses of 0.5 mg. If the recommended initial dose is 0.25 mg, therapy must be started with another risperidone containing the preparation, having the necessary dosage.

Schizophrenia

Adults

The drug Risperidone Zentiva 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. Due to the fact that safety of doses above 16 mg per day has not been studied, doses above this level are prohibited.

Elderly patients

Recommended initial dose of 0.5 mg per reception 2 times a day. Dosage can individually increase by 0.5 mg 2 times a day to 1-2 mg 2 times a day.

Children

Due to the lack of safety and efficacy data, Risperidone Zentiva is not recommended for use in children under the age of 18 suffering from schizophrenia.

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 per day. For most patients, the optimal dose is 1-6 mg per day, depending on the efficacy and tolerability. The use of doses above 6 mg per day in patients with manic episodes has not been studied.

The expediency of continuing treatment with Risperidon Zentiva should be regularly evaluated and confirmed by a specialist doctor.

Elderly patients

The recommended initial dose is 0.5 mg 2 times a day. Dosage can individually increase by 0.5 mg 2 times a day to 1-2 mg 2 times a day. Care should be taken in connection with the limited experience of the drug in elderly patients.

Children

Due to the lack of safety data, Risperidone Zentiva is not recommended for use in children under 18 years of age suffering from bipolar disorder.

Continuous aggression in patients with dementia due to Alzheimer's disease

For most patients, the optimal dose is 0.5 mg 2 times a day. However, some patients receive 1 mg twice daily.

The Risperidone Zentiva drug should not be used 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 and the need to continue therapy should be regularly evaluated by a medical specialist.

Continuous aggression in the structure of conduct disorder

Children from 5 to 18 years old

Patients with a body weight of 50 kg or more - the recommended initial dose of the drug - 0.5 mg once a day. If necessary, this dose can be increased by 0.5 mg per day. The interval for correcting the dose should be at least 48 hours. For most patients, the optimal dose is a dose of 1 mg 1 time per day. However, for some patients, a dose of 0.5 mg 1 time per day is more preferable, while some need to increase the dose to 1.5 mg per day.

As for any other symptomatic therapy, the desirability of continuing treatment with the Risperidone Zentiva drug should be regularly evaluated and confirmed.

The use of the drug in children younger than 5 years is not recommended because of lack of data on efficacy and safety.

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 of the Risperidone Zentiva preparation should be reduced 2-fold in accordance with the indications in this group of patients, the increase in the dose in patients with liver and kidney diseases should be slower.

Risperidone Zentiva should be administered with caution in this category of patients.

The "cancellation" syndrome

Termination of the drug is recommended to be carried out gradually. Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia, were very rare after a sharp discontinuation of high doses. Perhaps the re-emergence of psychotic symptoms, there are also reports of the occurrence of disorders associated with involuntary movements (such as akathisia, dystonia and dyskinesia).

Transition from therapy with other antipsychotic drugs

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

Side effects:

When using risperidone, the following side effects may occur, which are divided according to the system-organ classes in accordance with the classification of the Medical Dictionary for regulatory activities (MedDRA). The WHO classification was used to indicate the incidence of adverse events: very often (≥ 10%); often (≥ 1% and <10%); infrequently (≥ 0.1% and <1%); rarely (≥ 0.01% and <0.1%); very rarely (<0.01%); the frequency is unknown (it is not possible to determine the incidence of side effects from the available data).

Infectious and parasitic diseases: often - pneumonia, bronchitis, upper respiratory tract infection, sinusitis, urinary tract infection, ear infection, influenza; infrequently - respiratory infections, cystitis, eye infections, tonsillitis, onychomycosis, local inflammation of the subcutaneous tissue, viral infections, acarobacteria; rarely - an infection.

Violations of the blood and lymphatic system: infrequently - neutropenia, a decrease in the number of leukocytes, thrombocytopenia, anemia, a decrease in hematocrit, an increase in the relative content of eosinophils; rarely - agranulocytosis⁴.

Immune system disorders: infrequently - hypersensitivity reactions; rarely anaphylactic reactions⁴.

Disorders from the endocrine system: often - hyperprolactinaemia¹; rarely - a violation of the secretion of antidiuretic hormone, glucosuria.

Disorders from the metabolism and nutrition: often - weight gain, increased appetite, decreased appetite; infrequently - diabetes mellitus³hyperglycemia, polydipsia, weight loss, anorexia, hypercholesterolemia; rarely - hyperhydration⁴, hypoglycaemia, hyperinsulinemia⁴, hypertriglyceridemia; very rarely diabetic ketoacidosis.

Disorders of the psyche: very often - insomnia²; often - sleep disorders, depression, agitation, anxiety; infrequently - mania, confusion, decreased libido, nervousness, nightmares; rarely - blunted affect, anorgasmia.

Disturbances from the nervous system: very often sedation / drowsiness, Parkinsonism², headache; often - akathisia², dystonia², dizziness, dyskinesia², tremor; infrequently - tardive dyskinesia, cerebral ischemia, lack of response to stimuli, loss of consciousness, decreased level of consciousness, convulsions², fainting, psychomotor hyperactivity, imbalance, poor coordination, postural dizziness, attention disturbance, articulation disorder, dysgeusia, hypesthesia, paresthesia; rarely malignant neuroleptic syndrome, cerebrovascular disorders, diabetic coma, trembling of the head.

Disturbances on the part of the organ of sight: often - conjunctivitis, blurred vision; infrequent - photophobia, dry eyes, increased lacrimation, hyperemia of the eyes; rarely - glaucoma, violation of the movement of the eyeballs, crust formation on the edge of the eyelid, intraoperative syndrome of the "flabby" iris, occlusion of the artery of the mesh shell.

Heart Disease: often - tachycardia; infrequent - atrioventricular block, conduction disorders, QT interval elongation, changes in electrocardiogram, bradycardia, palpitations, atrial fibrillation; rarely - sinus arrhythmia.

Hearing disorders and labyrinthine disorders: infrequently - vertigo, noise in the ears, pain in the ears.

Vascular disorders: often - increased blood pressure; infrequently - a decrease in blood pressure, orthostatic hypotension, hot flashes; rare - thromboembolism of the pulmonary artery, venous thrombosis.

Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, sore throat, cough, nosebleed, nasal congestion; infrequently - aspiration pneumonia, congestion in the lungs, the syndrome of "waterlogging" of the respiratory tract, wheezing in the lungs, stertorous breathing, dysphonia, respiratory disorders; rarely - sleep apnea syndrome, hyperventilation.

Disorders from the gastrointestinal tract: often - abdominal pain, gastrointestinal discomfort, nausea, vomiting, constipation, diarrhea, indigestion, dry mouth, toothache; infrequently - fecal incontinence, fecaloma, gastroenteritis, dysphagia, bloating; rarely - pancreatitis, intestinal obstruction, swelling of the tongue, cheilitis; very rarely - ileus.

Disturbances from the liver and bile ducts: infrequently increased activity of "hepatic" transaminases, increased activity of gamma-glutamyl transferase (GGT); rarely - jaundice.

Disturbances from the skin and subcutaneous tissues: often - a rash, erythema; infrequently - urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrheic dermatitis, skin disorders, damage to the skin; rarely - drug-induced rash, dandruff; very rarely - Quincke's edema.

Disturbances from musculoskeletal and connective tissue: often - muscle spasms, muscle pain, back pain, arthralgia: infrequently - increased activity of creatine phosphokinase (CK) in the blood plasma, poor posture, joint stiffness, joint swelling, muscle weakness, neck pain; rarely rhabdomyolysis.

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

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

Violations of the genitals and mammary gland: infrequently - erectile dysfunction, ejaculation disorder, amenorrhea, menstrual irregularity², oligomenorrhoea, gynecomastia, galactorrhea, sexual disorders, breast tenderness, discomfort in the mammary glands, vaginal discharge; rarely - priapism⁴, delay of menstruation, engorgement of the mammary glands, enlargement of mammary glands, discharge from the mammary glands.

General disorders and disorders at the site of administration: often - edema², fever, chest pain, asthenia, fatigue, pain; infrequent - edema of the face, chills, hyperthermia, gait disturbance, discomfort in the chest, malaise, deterioration of well-being, discomfort; rarely - hypothermia, cold extremities, "withdrawal" syndrome, compaction of organs and tissues⁴.

Trauma, intoxication and complications of manipulation: often - falling; infrequently - pain during the procedure.

¹Hyperprolactinemia can in some cases lead to gynecomastia, menstrual disorders, amenorrhea, anovulation, galactorrhea, impaired fertility, decreased libido, erectile dysfunction.

² Extrapyramidal disorders can manifest as: parkinsonism hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, rigidity as a "cogwheel", bradykinesia, hypokinesia, masculine face, muscle tension, akinesia, stiff neck, muscle rigidity.Parkinsonian gait, positive glabellar reflex, Parkinsonian tremor of rest), akathisia (akathisia, anxiety, hyperkinesia and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis and myoclonus), dystonia.

Dystonia includes: proper dystonia, muscle spasms, muscle hypertonia, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, rotational movements of the eyeballs, paralysis of the tongue, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurototonus (postural deformity), spasm language and trism. It should also be noted that there is a wider range of symptoms that do not always have extrapyramidal origin.

Insomnia includes: violation of falling asleep, intrasomnic disorder.

Seizures include: convulsions by type grand mal.

Disorders of the menstrual cycle include: irregular menstruation, oligomenorrhoea.

Edema include: generalized edema, peripheral edema and 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 the results of all clinical trials was 0.43% of all patients taking risperidone.

⁴ Undesirable effects were not observed in clinical studies of risperidone, but were registered in the post-marketing period of application of risperidone.

Adverse events, marked for dosage forms of paliperidone Paliperidone is active metabolite of risperidone, therefore the safety profiles of these compounds (including dosage forms for oral administration and for parenteral administration) may be related to each other. In addition to the undesirable reactions described above, nIn the use of paliperidone preparations, the following undesirable reaction was noted, the development of which may be expected with the use of risperidone.

Heart disorders: postural orthostatic tachycardia syndrome.

Class Effects

As with other antipsychotics, very rare cases of elongation of the tooth QT on the ECG were observed in the post-registration period of observation.Other class-effects from the cardiovascular system, observed with the use of antipsychotics, which increase the length of the tooth QT, include: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and pirouette tachycardia.

Venous thromboembolism

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

Weight gain

In placebo-controlled studies in adult patients with schizophrenia, an increase in body weight of 7% or more was observed after 6-8 weeks of therapy in 18% of patients taking 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 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 is 3-5 kg per year for girls and about 5 kg per year for boys.

Additional information about specific populations of patients

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 other patient populations: urinary tract infections, peripheral edema, inhibition and cough.

Children

In children (5 to 17 years) with a frequency ≥ 5% and with a frequency of at least 2 times that in clinical studies in adult patients, the following adverse reactions were noted: drowsiness / sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, fever, tremor, diarrhea, enuresis. The effect of prolonged use of risperidone on puberty and growth has not been sufficiently well studied (see section "Special instructions").

Overdose:

Symptoms:

In general, the observed symptoms of overdose represent the already known pharmacological effects of risperidone in a more severe form: drowsiness, sedation, tachycardia, lowering of blood pressure, extrapyramidal symptoms. The lengthening of the interval QT and convulsions. "Piroetnaya" tachycardia was noted in the joint intake of an increased dose of risperidone and paroxetine. In the case of acute overdose, the possibility of an overdose from taking several drugs should be considered.

Treatment:

It is necessary to achieve and maintain airway patency to ensure adequate supply of oxygen and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and taking activated charcoal together with a laxative should be done only if the drug was taken no more than an hour ago. Immediately begin monitoring the ECG to identify possible arrhythmias.

Specific antidote does not exist, appropriate symptomatic therapy should be conducted. A sharp drop in blood pressure and vascular collapse should be eliminated by intravenous fluid infusions and / or sympathomimeticpreparations. When developing severe extrapyramidal symptoms, anticholinergic drugs should be prescribed. Continuous medical surveillance and monitoring of the ECG should continue until the symptoms of intoxication disappear completely.

Interaction:

Pharmacodynamic interaction

Preparations, causing an elongation interval QT

As with other antipsychotics, caution should be exercised when using risperidone together with drugs that extend the interval QT, such as antiarrhythmic drugs (eg, quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (for example, amitriptyline), tetracyclic antidepressants (for example, maprotiline), some antihistamines, other antipsychotics, some antimalarial drugs (quinine, mefloquine and others), drugs that cause electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or drugs that inhibit 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 agonists

Risperidone may decrease the effectiveness of levodopa and other dopamine agonists. In the event that a joint admission is required, especially at a late stage of Parkinson's disease, the lowest effective dose of each drug should be given.

Drugs that lower blood pressure

With the use of risperidone in conjunction with antihypertensive drugs, a clinically significant decrease in blood pressure was observed in the post-marketing period.

Paliperidone

It is not recommended to apply risperidone together with paliperidone because paliperidone is an active metabolite of risperidone, and co-administration can lead to an increase in the concentration of the active antipsychotic fraction in the blood plasma.

Pharmacokinetic interactions

Risperidone is metabolized predominantly with the participation of isoenzyme CYP2D6 and to a lesser extent with the participation of isoenzyme CYP3A4. Risperidone and its active metabolite 9-hydroxyrisperidone are substrates of the P-glycoprotein. Substances causing a change in the activity of the isoenzyme CYP2D6 or substances that cause a potent inhibition or induction of isoenzyme activity CYP3A4 and / or P-glycoprotein may affect the pharmacokinetics of the active antipsychotic fraction.

Powerful inhibitors of isoenzyme CYP2D6

The combined use of risperidone with potent inhibitors of isoenzyme CYP2D6 can cause an increase in the plasma concentration of risperidone and a less active antipsychotic fraction. Higher doses of a potent inhibitor of isoenzyme CYP2D6 are able to cause an increase in the active antipsychotic fraction (for example, paroxetine). It is expected that other isoenzyme inhibitors CYP2D6, such as quinidine. can affect the plasma concentration of risperidone in a similar manner. When appointing or canceling joint use with paroxetine. fluoxetine, quinidine or other potent inhibitors of isoenzyme CYP2D6, especially in high doses, it is necessary to adjust the dose of Risperidone Zentiva.

Inhibitor inhibitors CYP3A4 and / or P-glycoprotein

The combined use of risperidone with potent inhibitors of isoenzyme CYP3A4 and / or P-glycoprotein can lead to a significant increase in plasma concentrations of the active antipsychotic fraction. In the appointment or cancellation of joint use with itraconazole or other potent inhibitors of isoenzyme CYP3A4 and / or P-glycoprotein, the dose of Risperidone Zentiva should be adjusted.

Inductors of isoenzyme CYP3A4 and / or P-glycoprotein

Joint application of risperidone with powerful isoenzyme inducers CYP3A4 and / or P-glycoprotein can lead to a decrease in plasma concentrations of the active antipsychotic fraction. In the appointment or withdrawal of a joint application with carbamazepine or other potent inducers of isoenzyme CYP3A4 and / or P-glycoprotein, the dose adjustment of Risperidone Zentiva is required. Effect of inducers of isoenzyme CYP3A4 depends on time: the time to achieve the maximum effect after the start of use can be at least 2 weeks. At the same time, with cancellation of therapy, the duration of the decrease in induction of the isoenzyme CYP3A4 can also take at least 2 weeks.

Preparations with a high degree of binding to blood plasma proteins

When using risperidone with drugs with a high degree of binding to plasma proteins, there is no clinically significant change in the degree of association with plasma proteins of any of the drugs.

When using drugs together, you should carefully read the information on their use for the possible need for dose adjustment.

The effect of other drugs on the pharmacokinetics of risperidone

Antibacterial drugs

Erythromycin, a moderate isoenzyme inhibitor CYP3A4 and P-glycoprotein does not alter the pharmacokinetics of risperidone and the active antipsychotic fraction.

Rifampicin, a powerful isoenzyme inducer CYP3A4 and P-glycoprotein, reduced plasma concentrations of the active antipsychotic fraction.

Preparations with anticholinesterase activity

Donepezil and galantamine, which are substrates of isoenzymes CYP3A4 and CYP2D6, did not show a clinically significant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

Antiepileptic drugs

Carbamazepine, a powerful isoenzyme inducer CYP3A4 and the inducer of the P-glycoprotein, reduces the plasma concentrations of the active antipsychotic fraction.Similar effects can be observed, for example, with the use of phenytoin and phenobarbital, which also cause induction of the isoenzyme CYP3A4 and P-glycoprotein.

Topiramate caused a moderate decrease in the bioavailability of risperidone, but not an active antipsychotic fraction. Thus, the clinical significance of this interaction is unlikely.

Antifungal medicines

Itraconazole, a potent inhibitor of the isoenzyme CYP3A4 and a P-glycoprotein inhibitor at a dose of 200 mg per day caused an increase in plasma concentrations of the active antipsychotic fraction by approximately 70% when combined with risperidone at doses of 2 to 8 mg per day.

Ketoconazole, a potent inhibitor of isoenzyme CYP3A4 and an inhibitor of P-glycoprotein, at a dose of 200 mg per day caused an increase in plasma concentrations of risperidone and a decrease in the plasma concentration of 9-hydroxyrisperidone.

Neuroleptics

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

Antiviral drugs

HIV protease inhibitors: special studies of drug interactions were not conducted.Taking into account the fact that ritonavir is a potent inhibitor of isoenzyme CYP3A4 and a weak isoenzyme inhibitor CYP2D6, the potential for ritonavir and other ritonavir-boosted HIV protease inhibitors to be increased, plasma concentrations of risperidone and active antipsychotic fraction to be increased.

Beta-blockers

Some beta-blockers may increase the plasma concentration of risperidone, the concentration of the active antipsychotic fraction remains unchanged.

Calcium channel blockers

Verapamil, a moderate isoenzyme inhibitor CYP3A4 and P-glycoprotein inhibitor, increases plasma concentrations of risperidone and active antipsychotic fraction.

Drugs acting on the gastrointestinal tract

Antagonists of H₂-receptors: cimetidine and ranitidine. weak inhibitors of isoenzymes CYP3A4 and CYP2D6, increase the bioavailability of risperidone, however, the increase in bioavailability of the active antipsychotic fraction remains within the upper limit of the norm.

Selective serotonin reuptake inhibitors and tricyclic antidepressants

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

Paroxetine, a potent inhibitor of the isoenzyme CYP2D6, increases the plasma concentration of risperidone, in doses up to 20 mg per day, an increase in the concentration of the active antipsychotic fraction is observed to a lesser extent. At the same time, higher doses of paroxetine may cause an increase in the concentration of the active antipsychotic fraction in the blood plasma.

Tricyclic antidepressants can increase the concentration of risperidone in the blood plasma, there was no effect on the concentration of the active antipsychotic fraction.

Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.

Sertraline, a weak isoenzyme inhibitor CYP2D6 and fluvoxamine, weak isoenzyme inhibitor CYP3A4, at doses up to 100 mg per day do not have a clinically significant effect on the concentration of the active antipsychotic fraction. However, in doses above 100 mg per day sertraline or fluvoxamine can cause an increase in the concentration of the active antipsychotic fraction in the blood plasma.

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 and topiramate preparations.

Neuroleptics

Aripiprazole is metabolized with the participation of isoenzymes CYP2D6 and CYP3A4. The use of risperidone inside or in injections did not affect the pharmacokinetics of aripiprazole and its active metabolite, dehydroaripiprazole.

Digoxin

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.

Furosemide

There are data on increased mortality among elderly patients with dementia, who took furosemide simultaneously with risperidone (see section "Special instructions").

Use in children

The study of drug interaction was conducted only in adult patients.

The combined use of psychostimulants (eg, methylphenidate) and risperidone in children and adolescents does not alter the pharmacokinetics and efficacy of risperidone.

Special instructions:

Use in elderly patients with dementia

Increased mortality in elderly patients with dementia

Based on the results of clinical studies in elderly patients with dementia in the treatment of atypical antipsychotic agents, including risperidone, there is an increased mortality in comparison with placebo. When using risperidone in this population, the incidence of fatalities was 4.0% for patients taking risperidone, compared with 3.1% for patients taking placebo. The risk ratio was 1.21 (0.7, 2.1) with a confidence interval of 95%. The average age of the deceased patients is 86 years (range 67-100 years). 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 with 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

In elderly patients with dementia, increased mortality was observed with simultaneous application of 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%, mean age 80 years, range 67-90 years). Increased mortality among 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. Nevertheless, special care should be taken when prescribing the drug in such cases. Before appointment, the risk / benefit ratio must be carefully assessed.

There was no increase in mortality among patients concurrently taking other diuretics with risperidone.

Regardless of treatment, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

Cerebrovascular side effects

In placebo-controlled, randomized clinical trials in patients with dementia who took some atypical antipsychotics, an increased risk of cerebrovascular adverse reactions was approximately 3-fold. Combined data from 6 placebo-controlled trials, including mainly elderly patients with dementia (age over 65), show 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 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. The drug Risperidone Zentiva should be used with caution in patients with risk factors for stroke.

The risk of developing cerebrovascular adverse reactions is much higher in patients with mixed or vascular dementia, compared with patients with dementia of the Alzheimer's type.Therefore, patients with dementia of any type other than Alzheimer's should not take Risperidone Zentiva. Physicians should individually evaluate the risk / benefit ratio of using Risperidone Zentiva in elderly patients with dementia, taking into account the precursors of stroke risk. Patients and caregivers should be warned that it is necessary to immediately report the signs and symptoms of cerebrovascular events such as sudden weakness or numbness in the face, legs, hands, as well as difficulty speaking and visual impairment. In this case, all possible treatment options should be considered, including discontinuation of the drug. Risperidone Zentiva may be used only for short-term treatment of persistent aggression in patients with dementia due to Alzheimer's disease, moderate and severe, as an adjunct to non-pharmacological correction methods, in case of inefficiency or limited effectiveness, and when there is a risk of self-harm to the patient or other persons.

Evaluation of patients and the need to continue therapy with the drug Risperidone Zentiva should be performed regularly by a doctor.

Orthostatic hypotension

Risperidone has α-blocking activity, and therefore can cause orthostatic hypotension in some patients, especially during the initial dose selection. A clinically significant decrease in blood pressure was observed in the post-marketing period with the simultaneous use of risperidone with antihypertensive drugs. The Risperidone Zentiva drug should be used with caution in patients with existing cardiovascular diseases (eg, heart failure, myocardial infarction, cardiac conduction disorders, dehydration, hypovolemia or cerebrovascular disease). In addition, appropriate dose adjustment is recommended. It should be assessed the possibility of reducing the dose in the event of a decline in blood pressure.

Tardive dyskinesia and extrapyramidal disorders

Drugs with the properties of dopamine receptor antagonists can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements,predominantly of the tongue and / or mimic muscles. 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 feasibility of abolishing all antipsychotics, including Risperidone Zentiva.

Leukopenia, neutropenia and agranulocytosis

When using antipsychotic drugs, including risperidone, reported the occurrence of leukopenia, neutropenia and agranulocytosis. During post-registration surveillance, very rarely reported agranulocytosis (<1/10000 patients).

Patients with a clinically significant low white blood cell count or drug-induced leukopenia / neutropenia should be observed during the first few months of therapy. At the appearance of the first sign of clinically significant decrease in the white blood cell count in the blood and in the absence of other causative factors, it is necessary to consider the option of stopping the treatment with Risperidone Zentiva.

Patients with clinically significant neutropenia should be monitored for fever or other symptoms of the infection, and if such signs or symptoms develop, treatment should be started immediately. Patients with severe neutropenia (absolute neutrophil count <1x10⁹/ l) should stop treatment with the drug Risperidon Zentiva and be under the supervision of the content of leukocytes in the blood until it is fully restored.

Malignant neuroleptic syndrome (CNS)

Antipsychotic drugs, including risperidone, can cause malignant neuroleptic syndrome (CNS), which is characterized by hyperthermia, rigidity of muscles, instability of autonomic nervous system function, depression of consciousness, as well as increased concentration of CK in blood plasma. In patients with ZNS, myoglobinuria (rhabdomyolysis) and acute renal failure may also occur.

If a patient experiences objective or subjective symptoms of the NSA, all antipsychotics, including Risperidone Zentiva, should be immediately discontinued.

Parkinson's disease and dementia with Levi bodies

The administration of antipsychotics to patients with Parkinson's disease or dementia with Lewy bodies should be carried out with caution, since both groups of patients have increased risk of developing CNS and increased sensitivity to antipsychotics (including blunting of pain sensitivity, confusion, poor coordination of movements with frequent falls and extrapyramidal symptoms ). When taking Risperidone Zentiva, there may be a worsening of the course of Parkinson's disease.

Hyperglycemia and diabetes mellitus

In the treatment with risperidone, hyperglycemia, diabetes mellitus and exacerbation of already existing diabetes 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 (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes should be monitored regularly for impaired glucose control in the blood.

Weight gain

In the treatment with risperidone, a significant increase in body weight was observed.

Patients should avoid overeating and regularly monitor body weight.

Hyperprolactinemia

Hyperprolactinemia is a frequent side effect of risperidone. Determination of prolactin concentration in blood plasma is recommended in patients with symptoms, possibly caused by prolactin (gynecomastia, menstrual irregularities, anovulation, impaired fertility, decreased libido, erectile dysfunction and galactorrhea).

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. Despite the fact that in clinical and epidemiological studies there was no clear connection between hyperprolactinaemia and the use of antipsychotics, caution should be exercised when prescribing Risperidone Zentiva to patients with a history of history.

The drug Risperidone Zentiva should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors (see "With caution").

Interval lengthening QT

Interval lengthening QT very rarely observed in the post-registration period of follow-up. Caution should be exercised when using the Risperidone Zentiva drug together with drugs that extend the interval QT, as well as in the appointment of patients with existing cardiovascular diseases: lengthening the interval QT in family history, bradycardia, electrolyte balance disorders (hypokalemia, hypomagnesemia), since this may increase the risk of arrhythmogenic effect.

Convulsions

The Risperidone Zentiva drug should be used with caution in patients with a history of seizures or with other medical conditions in which the convulsive threshold may be reduced.

Priapism

Priapism may occur when taking risperidone due to α-adrenergic blocking effects of the drug.

Regulation of body temperature

Antipsychotic drugs attributed to such an undesirable effect as a violation of the ability of the body to regulate the temperature. Caution should be exercised when prescribing Risperidone Zentiva to patients with conditions,which can contribute to an increase in the body's internal temperature: intense physical activity, dehydration of the body, exposure to high external temperatures, or simultaneous use of drugs with anticholinergic activity.

Antiemetic effect

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

Renal and hepatic impairment

In patients with renal insufficiency, there is a decreased ability to excrete an active neuroleptic fraction in comparison with adult patients with normal renal function. In patients with hepatic insufficiency, an increase in the concentration of the free fraction of risperidone in blood plasma is observed.

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 detected before and during treatment with the drug Risperidone Zentiva, and preventive measures should be taken in a timely manner.

Intraoperative syndrome of "flabby" iris

During the operation to remove cataracts in patients treated with drugs with the effect of ar blockers, including risperidone, reported cases of intraoperative syndrome "flabby" iris.

Intraoperative syndrome of "flabby" iris can increase the risk of complications during and after surgery. It is necessary to inform the ophthalmologist about the current appointment or use in the past α₁adrenoblockers. Possible benefits of discontinuing treatment α₁-adrenoblockers before the cataract surgery has not been studied, and should be evaluated taking into account the risk of discontinuing antipsychotic treatment for the patient.

Children and teens

Before prescribing Risperidone Zentiva, children or adolescents with mental retardation should carefully assess their condition for the presence of physical or social causes of aggressive behavior, such as pain or inadequate requirements of the social environment.The sedative effect of Risperidone Zentiva should be carefully monitored in this population because of the possible impact on learning ability. Changing the time of taking the drug Risperidone Zentiva 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. 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 studied. Due to the possible impact of prolonged hyperprolactinemia on growth and sexual development in children and adolescents, a regular clinical evaluation of the hormonal status should be carried out, including measurement of height, weight, monitoring of sexual development, menstrual cycle and other possible prolactin-dependent effects.

The results of a post-registration follow-up study showed that patients between the ages of 8 and 16 who received risperidone, were on average 3.0-4.8 cm higher in comparison with patients receiving other atypical antipsychotics.The results of this study do not allow us to determine whether risperidone has any effect on final growth and whether this result was related to the direct effect of risperidone on bone growth or the result of a major disease, whether this was due to improved control of the underlying disease, leading to an increase in growth rates.

During the treatment with the Risperidone Zentiva drug, regular check should be made of the presence of extrapyramidal symptoms in patients.

Excipients

Preparation Risperidone Zentiva, coated tablets, contains lactose. Patients with rare hereditary diseases associated with galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not be prescribed Risperidone Zentiva, film-coated tablets.

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

The drug Risperidone Zentiva may have little or moderate effect on the ability to drive vehicles and mechanisms (dizziness, fatigue, visual impairment).During the administration of the drug, patients should abandon the management of vehicles and work with the mechanisms to determine their individual sensitivity to the drug.

Form release / dosage:

Coated tablets, 1 mg, 2 mg, 3 mg and 4 mg.

Packaging:

For 10 tablets in a blister of PVC / PVDC / Al.

For 2, 3 or 5 blisters are placed in a cardboard box together with instructions for use.

Storage conditions:

Store at a temperature of up to 25 ° C, in a dry place.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-002126/08

Date of registration:27.03.2008 / 01.11.2012

Expiration Date:Unlimited

Date of cancellation:2017-11-28

The owner of the registration certificate:Zentiva c.s.Zentiva c.s. Czech Republic

Manufacturer: & nbsp

ZENTIVA, k.s. Czech Republic

Representation: & nbspZENTIVA PHARMA, LLCZENTIVA PHARMA, LLC

Information update date: & nbsp28.11.2017

Illustrated instructions

Instructions

Risperidone Zentiva (Risperidone Zentiva)