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

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-histaminergic and α₂-adrenergic receptors. Risperidone does not have tropism for cholinergic receptors. Risperidone reduces the productive symptoms of schizophrenia, causes less inhibition of motor activity and to a lesser degree induces catalepsy than classical antipsychotics. A balanced central antagonism to serotonin and dopamine probably reduces the propensity to extrapyramidal side effects and expands the therapeutic effect of the drug to include negative and affective symptoms of schizophrenia.

Pharmacokinetics:

Suction

Risperidone after oral administration is completely absorbed, reaching the maximum concentrations in the 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 in the form of a solution. Food does not affect the absorption of the drug, so risperidone can be administered regardless of food intake. The equilibrium concentration of risperidone in the body in most patients is reached within 1 day. The equilibrium concentration of 9-hydroxyrisperidone is reached within 4-5 days.

Distribution

Risperidone is rapidly distributed in the body. The volume of distribution is 1-2 l / kg. In the plasma risperidone binds to albumin and alpha₁acid glycoprotein. Risperidone 90% bound by plasma proteins, 9-hydroxyrisperidone - by 77%.

Metabolism and excretion

Risperidone is metabolized by isoenzyme 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. Although patients with intensive metabolism have a lower concentration of risperidone and a higher concentration of 9-hydroxyrisperidone 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, in general, does not inhibit the metabolism of drugs that undergo biotransformation with P450 isoenzymes, including CYP 1A2, CYP 2A6, CYP 2C8 / 9/10, CYP 2D6, CYP 2E1, CYP 3A4 and CYP 3A5. A week after the start of 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 oral administration in patients with psychosis risperidone is excreted from the body with a half-life (T_1/2) for about 3 hours. T_1/2 9-hydroxyrisperidone and the active antipsychotic fraction is 24 hours.

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 plasma was on average 43% higher, the half-life lasted 38% longer, and the clearance decreased by 30%.

In patients with renal insufficiency, an increase in plasma concentration and a decrease in the clearance of the active antipsychotic fraction was observed on average by 60%. In patients with hepatic insufficiency, the concentrations of risperidone in the plasma did not change, however, the average concentration of the free fraction of risperidone increased by 35%.

Children

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

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 and children from 13 years;

- treatment of manic episodes associated with bipolar disorder, moderate and severe in adults and children 10 years of age;

- short-term (up to 6 weeks) treatment of persistent aggression in patients with dementia due to Alzheimer's disease, moderate to severe,not amenable to non-pharmacological methods of correction, and when there is a risk of harming the patient to himself or others;

- Short-term (up to 6 weeks) symptomatic treatment of persistent aggression in the structure of behavioral disorder in children from 5 years of age with mental retardation diagnosed according to DSM-IV, in which, due to the severity of aggression or other destructive behavior, medication 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:

- Individual hypersensitivity to risperidone or any other ingredient of this drug;

- phenylketonuria.

Carefully:

- 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 (including in the anamnesis);

- severe renal or hepatic insufficiency (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 QT interval);

- Brain tumor, intestinal obstruction, cases of acute drug overdose, Reye's syndrome (antiemetic effect of risperidone may mask the symptoms of these conditions);

- risk factors for thromboembolism of venous vessels;

- disease of diffuse Levi bodies;

- elderly patients with cerebrovascular dementia;

- Pregnancy.

Pregnancy and lactation:

Pregnancy

There were no full-scale studies on the use of risperidone in pregnant women. According to observations in the postmarketing period, with risperidone during the last trimester of pregnancy, the newborn has reversible extrapyramidal symptoms, so newborns should be closely monitored.In animal studies risperidone did not have a teratogenic effect, however, other types of toxic effects on the reproductive system were observed. The potential risk to people is unknown. Rispolept® can be used during pregnancy only if the expected benefit of using the drug for a pregnant woman outweighs the potential risk to the fetus. If it is necessary to stop taking the drug during pregnancy, the drug should be discontinued gradually.

Lactation

In studies in animals risperidone and 9-hydroxyrisperidone penetrated into breast milk. It was also demonstrated that risperidone and 9-hydroxyrisperidone penetrate into human milk in small amounts. There are no data on side effects in infants who are breastfeeding. Therefore, the issue of breastfeeding should be addressed in the light of the possible risk to the child.

Dosing and Administration:

Schizophrenia

Adults

Rispolept® can be given once or twice a day.

The initial dose of Rispolept® is 2 mg per day. On the second day, the dose can 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 a lower initial and maintenance dose 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 should not be used.

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.

Children from 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 dosage 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 observed at doses above 3 mg per day, and higher doses caused more side effects. The use 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.

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 in patients with manic episodes has not been studied.

As with any other symptomatic therapy, the advisability of continuing treatment with Rispolept® should be regularly evaluated and confirmed.

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. Care should be taken in connection with the limited experience of the drug in elderly patients.

Children from 10 years

It is recommended that the initial dose of 0.5 mg once a day in the morning or evening. If necessary, the dosage can be increased at least in 24 hours by 0.5-1 mg per day to the recommended dose of 1-2.5 mg per day with good tolerability.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. The use 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.

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

Recommended initial dose of 0.25 mg per reception twice a day. Dosage, if necessary, can individually increase by 0.25 mg 2 times 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.

Rispolept® 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 should be assessed on a regular basis, as well as the need to continue therapy.

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, not more often than every other day. For most patients, the optimal dose is a dose of 1 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 1.5 mg per day.

Patients weighing less than 50 kg - the recommended initial dose of the drug - 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 0.25 mg per day, while some require an increase in the dose to 0.75 mg per day.

As with any other symptomatic therapy, the advisability of continuing treatment with Rispolept® should be regularly evaluated and confirmed. Use in children under 5 years is not recommended due to lack of data.

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.

Rispolept® should be administered with caution in this category of patients.

Mode of application

Inside. Eating does not affect the absorption of the drug.

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 of antipsychotics.

Transition from therapy with other antipsychotic drugs

At the beginning of treatment with Rispolept® it is recommended to gradually abolish previous therapy if it is clinically justified. In this case, if patients are transferred from the therapy of depot forms of antipsychotics, then Rispolept® therapy should be started 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 ≥ 10%) were: parkinsonism, headache and insomnia.

The side effects of Rispolept® in therapeutic doses are given with a frequency distribution and organ systems. The frequency of side effects was classified as follows: very frequent (≥1/10 cases), frequent (≥1 / 100 and <1/10 cases), infrequent (≥1 / 1000 and <1/100 cases), rare (≥1 / 10000 and <1/1000 cases), very rare (<1/10000 cases) and with unknown frequency (it is impossible to estimate the frequency from the available data).

In each frequency group, side effects are presented in order of decreasing importance.

Violations laboratory and instrumental indicators:

often - an increase in the level of prolactin, an increase in body weight;

infrequent - lengthening of the interval QT on the electrocardiogram, ECG deviations, increase in the level of transaminases, a decrease in the number of leukocytes in the blood, increased body temperature, an increase in the number of eosinophils in the blood, a decrease in the level of hemoglobin, an increase in the level of creatine phosphokinase, an increase in cholesterol concentration;

rarely - lowering body temperature, increasing the concentration of triglycerides.

From the side of the cardiovascular system:

often - tachycardia, arterial hypertension;

infrequently - atrioventricular blockade, bundle bundle blockage, atrial fibrillation, palpitations, impaired conduction of the heart;

rarely - sinus bradycardia, pulmonary embolism, deep vein thrombosis.

Hematological violations and disorders of the lymphatic system:

infrequently - anemia, thrombocytopenia;

rarely - granulocytopenia, agranulocytosis.

From the nervous system:

very often - parkinsonism², headache, drowsiness, sedation;

often - akathisia², dizziness², tremor², dystonia², lethargy, dyskinesia²;

infrequent - lack of response to stimuli, loss of consciousness, fainting, impaired consciousness, stroke, transient ischemic attack, dysarthria, attention disturbance, hypersomnia, postural dizziness, imbalance, tardive dyskinesia, speech impairment, coordination disorder, hypesthesia, taste disorders, perversion taste, convulsions, cerebral ischemia, impaired movement;

rarely - malignant neuroleptic syndrome, diabetic coma, cerebrovascular disorders, tremor of the head.

Ophthalmic disorders:

often - blurred vision, conjunctivitis;

infrequent - redness of the eyes, visual impairment, discharge from the eyes, edema around the eyes, dry eyes, increased lacrimation, photophobia;

rarely - reduced visual acuity, involuntary sprains of eyeballs, glaucoma, intraoperative syndrome of flabby iris.

From the ear and the labyrinth:

infrequently - pain in the ear, noise in the ears.

Respiratory, thoracic disorders and disorders of the mediastinum:

often - shortness of breath, nosebleed, cough, nasal congestion, pain in the larynx and pharynx;

infrequently - wheezing, aspiration pneumonia, congestion in the lungs, impaired breathing, wet wheezing, impaired airway, dysphonia;

rarely - sleep apnea syndrome, hyperventilation.

From the gastrointestinal tract:

often - vomiting, diarrhea, constipation, nausea, abdominal pain, indigestion, dry mouth, stomach discomfort, hypersalivation;

infrequently - dysphagia, gastritis, fecal incontinence, fecaloma, gastroenteritis, flatulence;

rarely - intestinal obstruction, pancreatitis, edema of lips, cheilitis.

From the side of the kidneys and urinary tract:

often - enuresis;

infrequent - urinary retention, dysuria, urinary incontinence, pollakiuria.

From the skin and subcutaneous tissues:

often - a rash, erythema;

infrequently - skin lesions, skin disorders, itching, acne, acne, skin discoloration, alopecia, seborrheic dermatitis, dry skin, hyperkeratosis;

rarely - dandruff;

very rarely - Quincke's edema.

From the musculoskeletal system and connective tissue:

often - arthralgia, back pain, pain in the limbs;

infrequently - muscle weakness, myalgia, pain in the neck, swelling of the joints, violation of posture, stiffness in the joints, muscle pain in the chest;

rarely rhabdomyolysis.

From the endocrine system:

rarely - disruption of production antidiuretic hormone.

Metabolic and nutritional disorders:

often - increased appetite, decreased appetite;

infrequently - diabetes mellitus³anorexia, polydipsia, hyperglycemia;

rarely - hypoglycemia, water intoxication;

very 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.

Vascular disorders:

infrequently - hypotension, orthostatic hypotension, hot flashes.

Are common violations and phenomena, caused by the administration of the drug:

often - pyrexia, fatigue, peripheral edema, generalized edema, asthenia, pain in the chest area;

infrequent - swelling of the face, gait disturbance, poor health, sluggishness, flu-like condition, thirst, discomfort in the chest, chills;

rarely - hypothermia, withdrawal syndrome, cold extremities.

From the immune system:

infrequently - hypersensitivity;

rarely - drug hypersensitivity, anaphylactic reaction.

Hepatobiliary disorders:

rarely - jaundice.

From the side of the reproductive system and mammary glands:

infrequently - amenorrhea, sexual dysfunction, erectile dysfunction, ejaculation disorder, galactorrhea, gynecomastia, menstrual cycle disorder, vaginal discharge;

rarely - priapism.

Pregnancy, postpartum and neonatal periods:

rarely - the syndrome of "cancellation" in newborns.

Mental disorders:

very often insomnia;

often - anxiety, agitation, sleep disturbances, anxiety;

infrequently - confusion, mania, decreased libido, lethargy, nervousness;

rarely - anorgasmia, flattening of affect.

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

²- extrapyramidal disorders may manifest as: Parkinsonism (hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, rigidity as a "cogwheel", bradykinesia, hypokinesia, masculine face, muscle tension, akinesia, stiff neck, muscle stiffness, parkinsonic gait, violations of the glabellar reflex), akathisia (akathisia, restlessness, 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,movement of the eyeball, paralysis of the tongue, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurototonus, spasm of the tongue and trism.

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.

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 the results of all clinical trials was 0.43% of all patients taking risperidone.

The following side effects are further described in the clinical trials of a prolonged injection of risperidone - Rispolept Konsta®, but not shown with the use of oral dosage forms of risperidone. This list does not include side effects related to the composition or injection of the drug:

Violations of laboratory indicators: a decrease in body weight, an increase in the level of gamma-glutamyltransferase, an increase in hepatic enzymes.

From the side of the cardiovascular system: bradycardia.

On the part of the blood and lymphatic system: neutropenia.

From the nervous system: paresthesia, convulsions.

From the eyes: blepharospasm, occlusion of the retina artery.

From the ear and the labyrinth: Vertigo.

From the gastrointestinal tract: toothache, spasm of the tongue.

From the skin and subcutaneous tissues: eczema.

From the musculoskeletal system and connective tissue: pain in the buttocks.

Infections: lower respiratory infections, infections, gastroenteritis, subcutaneous abscess.

Injuries and poisonings: a fall.

Vascular disorders: arterial hypertension.

General disorders and phenomena caused by the administration of the drug: pain.

Mental disorders: depression.

Class Effects

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

Venous thromboembolism

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

Weight gain

In placebo-controlled studies in patients with schizophrenia, an increase in body weight of at least 7% at 6-8 weeks was observed in 18% of patients taking Rispolept® 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 taking Rispolept® (2.5%) and in the placebo group (2 , 4%), while in the active control group there was slightly more (3.5%).

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

Additional information about specific populations of patients

Side effects that have been observed more frequently 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 during 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, lethargy, and cough.

Children

The following side effects were observed in children (5 to 17 years) with a frequency ≥ 5% and at a frequency at least twice that in other patient populations in clinical trials: drowsiness / sedation, fatigue, headache, appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhea, enuresis.

Overdose:

Symptoms

In general, the observed overdose symptoms represented the already known pharmacological effects of risperidone in a strengthened form: drowsiness, sedation, tachycardia, arterial hypotension, extrapyramidal symptoms.There was an extension of the QT interval and convulsions. Bi-directional ventricular 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 free airway to ensure adequate oxygen supply 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. Arterial hypotension and vascular collapse should be eliminated by intravenous fluid infusions and / or sympathomimetic drugs. When developing severe extrapyramidal symptoms, anticholinergic drugs should be prescribed. Continuous medical surveillance and monitoring should continue until the symptoms of intoxication disappear.

Interaction:

Interactions, Related pharmacodynamics preparation

Drugs that increase the interval QT

As with other antipsychotics, caution should be exercised when Rispolept® is administered jointly with drugs that increase the range 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

Rispolept® 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

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

Hypotensive drugs

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

Paliperidone

It is not recommended to use Rispolept® 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, related from 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 P-glycoprotein (P-gp).

Drugs affecting the activity of the isoenzyme CYP2D6, and preparations that significantly inhibit or induce isoenzyme activity CYP3A4 and / or P-gp, may 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, the plasma concentration of risperidone and, to a lesser extent, the active antipsychotic fraction may increase. Higher doses of a potent inhibitor of isoenzyme CYP2D6 can increase the concentration of the active antipsychotic fraction of risperidone (for example, paroxetine, see below).

It is expected that other isoenzyme inhibitors CYP2D6, such as quinidine, may have a similar effect on the concentration of risperidone in plasma. When initiating or canceling therapy with a combination of risperidone and paroxetine, quinidine or another potent inhibitor of isoenzyme CYP2D6, especially at higher doses, the dose of Rispolept® should be adjusted.

Inhibitor inhibitors CYP3A4 and / or P-gp

Joint use of Rispolept® and powerful 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 the dose of Rispolept® should be adjusted.

Inductors of isoenzyme CYP3A4 and / or P-gp

Joint application of Rispolept® with 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, the dose of Rispolept® should be adjusted. Action of inducers of isoenzyme CYP3A4 shows up over time, so it may take up to 2 weeks before the maximum effect is achieved after the onset of admission. Accordingly, with the cancellation of the isoenzyme inducer CYP3A4 may take up to 2 weeks before the effect disappears.

Preparations that bind strongly to plasma proteins

When Rispolept® is used together with preparations with 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 Rispolept® 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, moderate isoenzyme inhibitor CYP3A4 and P-gp, does not affect the pharmacokinetics of risperidone and the active antipsychotic fraction.

- Rifampicin, a powerful isoenzyme inducer CYP3A4 and P-gp, causes a decrease in the concentration of active a I pi of the psychotic fraction in plasma.

Anticholinesterase drugs

- Donepezil and galantamine, which are substrates of the isoenzymes CYP2D6 and CYP3A4, do not have a clinically significant effect on the pharmacokinetics of risperidone and the 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, increases the concentration of the active antipsychotic fraction in plasma by about 70% at a dose of 200 mg / day 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-hydroxyrisperidoya 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, potentiated with ritonavir, 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 inhibitor of the isoenzyme CYP3A4 and P-gp, increases the concentration of risperidone and the active antipsychotic fraction in plasma.

Gastrointestinal drugs

- Antagonists of H₂-receptors: 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 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.

Impact risperidone on 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 CYP2D6 and CYP3A4: risperidone does not affect the pharmacokinetics of aripiprazole and its active metabolite, dehydroaripiprazole.

Cardiac glycosides

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

Lithium preparations

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

Simultaneous application of from 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 for a given population, the incidence of fatalities was 4.0% for patients taking risperidone, compared with 3.1% for placebo. The average age of the deceased patients is 86 years (range 67-100 years). Data collected as a result of two extensive observationalstudies 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

In elderly patients with dementia, there was an increased mortality with simultaneous furosemide and risperidone taken orally (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. 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 in patients taking other diuretics simultaneously with risperidone. Regardless of treatment, dehydration is a common risk factor for mortality and should be carefully monitored in elderly patients with dementia.

In elderly patients with dementia, there was an increase in the side effects from the cerebrovascular system (acute and transient circulatory disorders), including deaths in patients (mean age 85 years, range 73-97 years) with risperidone compared with placebo.

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 studies,which included mainly elderly patients with dementia (age over 65 years) demonstrate 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) with 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. Rispolept® 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 should not take risperidone.

Physicians should evaluate the risk / benefit ratio of Rispolept® in elderly patients with dementia, taking into account the precursors of stroke risk individually for each patient.

Patients and persons caring for them should be warned that,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. All possible treatment options should be considered, including discontinuation of risperidone.

Rispolept® can 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 harm to the patient himself or to other persons.

It is necessary to constantly assess the condition of patients and the need to continue therapy with risperidone.

Orthostatic hypotension

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

Late dyskinesia and extrapyramidal disorders

Drugs that have the properties of dopamine receptor antagonists can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, predominantly of the tongue and / or 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, it is necessary to consider the desirability of abolishing all antipsychotics, including Rispolept®, a solution for oral administration.

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 increase in serum concentrations of creatine phosphokinase. In patients with ZNS, myoglobinuria (rhabdomyolysis) and acute renal failure may also occur. If the patient experiences objective or subjective symptoms of the NSA, all antipsychotics, including Rispolept®, should be immediately discontinued.

Parkinson's disease and dementia with Levi bodies

The administration of antipsychotics, including Rispolept®, to patients with Parkinson's disease or dementia with Lewy bodies should be carried out with caution, since in both groups of patients, the risk of neuroleptic malignant syndrome increased and sensitivity to antipsychotics increased (including blunting of pain sensitivity, confusion, postural instability with frequent falls and extrapyramidal symptoms). When taking risperidone, there may be a worsening of the course of Parkinson's disease.

Hyperglycemia and diabetes mellitus

In the treatment with Rispolept®, hyperglycemia, diabetes mellitus, and 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 (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes should be monitored regularly for impaired glucose control.

Weight gain

When treated with Rispolept®, a significant increase in body weight was observed. 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.Rispolept® should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

Interval lengthening QT

Interval lengthening QT very rarely observed in the postmarketing period of follow-up. As with other antipsychotics, caution should be exercised when prescribing Rispolept® to patients with known cardiovascular disease, lengthening the interval QT in a family history, bradycardia, electrolyte balance disorders (hypokalemia, hypomagnesemia), since this may increase the risk of arrhythmogenic effect; and when combined with drugs that extend the interval QT.

Convulsions

Rispolept® should be used with caution in patients with a history of seizures or other medical conditions in which the convulsive threshold may be reduced.

Priapism

Priapism may occur when taking risperidone due to alpha-adrenergic blocking effects.

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 Rispolept® to patients with conditions that may contribute to increased internal body temperature, such as intense physical activity, dehydration, exposure to high external temperatures, or simultaneous use of drugs with anticholinergic activity.

Venous thromboembolism

When using antipsychotic drugs, cases of venous thromboembolism were noted. Because patients who take antipsychotics often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with Rispolept®, and precautionary measures should be taken.

Children and teens

Before prescribing Rispolept® to children or adolescents with mental retardation, it is necessary to carefully evaluate their condition for the presence of physical or social causes of aggressive behavior, such as pain or inadequate demands of the social environment.

The sedative effect of risperidone should be carefully monitored in this population because of the possible effect on learning ability.The change in the time of risperidone intake 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.

During treatment with risperidone, regular monitoring of the presence of extrapyramidal symptoms and other movement disorders should be performed.

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

Rispolept®, oral solution, may have little or moderate effect on the ability to drive vehicles and mechanisms.Patients should be advised not to drive the car and from work with the mechanisms to determine their individual sensitivity to the drug.

Form release / dosage:

Solution for oral administration, 1 mg / ml.

Packaging:

For 30 or 100 ml of the drug in a bottle of dark glass with a screw cap.

The bottle, graduated pipette and instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of 15 to 30 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N012226 / 01

Date of registration:14.07.2011

Expiration Date:Unlimited

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN PHARMACEUTICA, N.V. Belgium

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp22.12.2016

Illustrated instructions

Instructions

Rispolept® (Rispolept®)