Risset^® (Tablets) Instructions for Use

ATC Code

N05AX08 (Risperidone)

Active Substance

Risperidone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; other antipsychotics

Pharmacological Action

An antipsychotic drug (neuroleptic), a benzisoxazole derivative. It also has sedative, antiemetic, and hypothermic effects. It is a selective monoaminergic antagonist with high affinity for serotonin 5-HT₂ receptors and dopamine D₂ receptors; it also binds to α₁-adrenergic receptors and, with somewhat lower affinity, to histamine H₁ receptors and α₂-adrenergic receptors. It has no affinity for cholinergic receptors.

The antipsychotic effect is due to the blockade of dopamine D₂ receptors in the mesolimbic and mesocortical systems. The sedative effect is due to the blockade of adrenergic receptors in the brainstem reticular formation; the antiemetic effect is due to the blockade of dopamine D₂ receptors in the trigger zone of the vomiting center; the hypothermic effect is due to the blockade of dopamine receptors in the hypothalamus.

It suppresses positive symptoms (delusions, hallucinations, aggressiveness), automatism. It causes less suppression of motor activity and induces catalepsy to a lesser extent than classical neuroleptics. Balanced central antagonism to serotonin and dopamine may reduce the tendency to extrapyramidal side effects and expand the therapeutic impact of the drug to cover negative and affective symptoms of schizophrenia. It may induce a dose-dependent increase in plasma prolactin concentration.

Pharmacokinetics

Absorption

After oral administration, absorption is rapid and complete (food does not affect the completeness and rate of absorption). Absolute bioavailability is 74%, relative bioavailability is 94%. T_max of risperidone is 1 h, of 9-hydroxyrisperidone is 3 h (with high activity of the CYP2D6 isoenzyme) and 17 h (with low activity of the CYP2D6 isoenzyme).

Distribution

C_ss of risperidone in the body is reached in most patients within 1 day, and of 9-hydroxyrisperidone within 4-5 days. Plasma concentrations of risperidone and 9-hydroxyrisperidone are proportional to the drug dose (within the range of 1-16 mg/day). It is rapidly distributed in the body, penetrates the CNS, and breast milk. V_d is 1-2 l/kg. Plasma protein binding (with alpha₁-acid glycoprotein and albumin) is 90% for risperidone and 77% for 9-hydroxyrisperidone.

Metabolism

It is metabolized by the CYP2D6 isoenzyme to the active metabolite 9-hydroxyrisperidone (Risperidone and 9-hydroxyrisperidone constitute the active antipsychotic fraction). Another metabolic pathway is N-dealkylation.

Excretion

T_1/2 of risperidone is 3 h (with high activity of the CYP2D6 isoenzyme) and 20 h (with low activity of the CYP2D6 isoenzyme), T_1/2 of 9-hydroxyrisperidone is 21 h (with high activity of the CYP2D6 isoenzyme) and 30 h (with low activity of the CYP2D6 isoenzyme); of the active antipsychotic fraction – 20 h.

It is excreted by the kidneys 70% (35-45% as a pharmacologically active antipsychotic fraction) and with bile (14%).

Pharmacokinetics in special clinical cases

In chronic renal failure, the clearance of the active antipsychotic fraction is reduced by 60%.

In hepatic insufficiency, the plasma concentration of risperidone increases by 35%.

In elderly patients, clearance is reduced and T_1/2 is prolonged.

Indications

Relief of acute episodes and long-term maintenance therapy

• Acute and chronic schizophrenia and other psychotic disorders with positive and negative symptoms;
• Affective disorders in schizophrenia;
• Behavioral disorders in patients with dementia manifesting symptoms of aggressiveness (outbursts of anger, physical violence), activity disturbances (agitation, delirium) or psychotic symptoms;
• Behavioral disorders in adolescents from 15 years of age and adult patients with intellectual disability or mental retardation, in cases where destructive behavior (aggressiveness, impulsivity, self-aggression) is predominant in the clinical picture of the disease.

For mood stabilization in the treatment of mania in bipolar affective disorders (as an adjunctive therapy).

ICD codes

Dosage Regimen

Tablets

Schizophrenia

The drug is administered orally, 1 or 2 times/day. The initial dose is 2 mg/day. On the 2nd day, the dose should be increased to 4 mg/day. From this point, the dose can either be maintained at the same level or individually adjusted if necessary. The optimal dose is usually 4-6 mg/day. In some cases, for example, in patients with a first episode of the disease, a slower dose increase and lower initial and maintenance doses may be justified.

When used in doses above 10 mg/day, no enhancement of the therapeutic effect was observed compared to lower doses, while extrapyramidal symptoms may appear. The maximum daily dose is 16 mg/day.

For elderly patients, the recommended initial dose is 500 mcg 2 times/day. If necessary, the dose can be increased to 1-2 mg 2 times/day.

For liver and kidney diseases, the recommended initial dose is 500 mcg 2 times/day. This dose can gradually be increased to 1-2 mg 2 times/day.

Behavioral disorders in patients with dementia

For most patients, the optimal dose is 500 mcg 2 times/day. The dose can be increased by no more than 500 mcg, no more frequently than every other day. However, some patients are indicated to take 1 mg 2 times/day. Once the optimal dose is reached, once-daily administration may be recommended.

Behavioral disorders in patients with mental retardation

The initial dose is 500 mcg once a day. The dose can be increased by no more than 500 mcg, no more frequently than every other day. The usual maintenance dose is 1 mg once a day. The dosing interval is 0.5-1.5 mg once a day.

Mania in bipolar affective disorders

For adults, the initial dose is 2 mg once a day. Then the dose is selected individually, increasing it by 1 mg/day, no more frequently than every other day. In most cases, the optimal dose is from 2 to 6 mg/day.

As with any symptomatic therapy, during treatment, the effectiveness should be assessed and the dosing regimen adjusted if necessary.

For elderly patients, the recommended initial dose is 500 mcg 2 times/day. If necessary, the dose is increased to 1-2 mg 2 times/day.

For liver and kidney diseases, the recommended initial dose is 500 mcg 2 times/day. The dose is gradually increased to 1-2 mg 2 times/day.

Adverse Reactions

From the nervous system insomnia, agitation, anxiety, headache, drowsiness, increased fatigue, dizziness, decreased ability to concentrate, blurred vision, mania, hypomania, extrapyramidal symptoms (tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia).

In patients with schizophrenia – hypervolemia (either due to polydipsia or due to the syndrome of inappropriate ADH secretion), tardive dyskinesia (involuntary rhythmic movements mainly of the tongue and/or face), NMS (hyperthermia, muscle rigidity, instability of autonomic functions, impaired consciousness and increased CPK activity), thermoregulation disorders and epileptic seizures.

From the digestive system constipation, dyspepsia, nausea or vomiting, abdominal pain, increased activity of liver transaminases, dry oral mucosa, hypo- or hypersalivation, anorexia, increased appetite.

From the cardiovascular system orthostatic hypotension, reflex tachycardia, increased BP, QT interval prolongation, torsades de pointes ventricular arrhythmia, ventricular fibrillation, stroke and transient ischemic attacks (in elderly patients with dementia), venous thromboembolism, incl. pulmonary embolism and deep vein thrombosis.

From the hematopoietic system neutropenia, thrombocytopenia.

From the endocrine system galactorrhea, gynecomastia, menstrual cycle disorders, amenorrhea, increase or decrease in body weight, hyperglycemia and exacerbation of pre-existing diabetes mellitus.

From the reproductive system priapism, erectile dysfunction, ejaculation disorders, anorgasmia.

From the urinary system urinary incontinence, urinary tract infection.

From the skin dry skin, hyperpigmentation, itching, seborrhea.

Allergic reactions rhinitis, rash, angioedema, photosensitivity.

Other arthralgia.

Contraindications

• Children under 15 years of age (efficacy and safety not established);
• Mania in bipolar affective disorders in children under 18 years of age (efficacy and safety not established);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Lactation period;
• Hypersensitivity to the drug components.

With caution: cardiovascular diseases (chronic heart failure, history of myocardial infarction, cardiac conduction disorders); conditions predisposing to the development of torsades de pointes tachycardia (bradycardia, electrolyte imbalance, concomitant use of drugs that prolong the QT interval); risk factors for the development of venous thromboembolism; dehydration and hypovolemia; cerebrovascular accident; brain tumor (incl. pituitary prolactinoma); Parkinson’s disease; Lewy body dementia; seizures (incl. in history); severe renal failure; severe hepatic failure; drug abuse or drug dependence; intestinal obstruction; acute drug overdose; Reye’s syndrome (the antiemetic effect of risperidone may mask the symptoms of these conditions); pregnancy; elderly patients with dementia.

Use in Pregnancy and Lactation

The safety of risperidone use during pregnancy has not been studied. The use of the drug Risset^® during pregnancy is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. Since Risperidone and 9-hydroxyrisperidone penetrate into breast milk, if it is necessary to use the drug Risset^® during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

In liver diseases, the recommended initial dose is 500 mcg 2 times/day. This dose can gradually be increased to 1-2 mg 2 times/day.

Use in Renal Impairment

In kidney diseases, the recommended initial dose is 500 mcg 2 times/day. This dose can gradually be increased to 1-2 mg 2 times/day.

Pediatric Use

Contraindicated in children under 15 years of age (efficacy and safety not established).

Geriatric Use

For elderly patients, the recommended initial dose is 500 mcg 2 times/day. If necessary, the dose can be increased to 1-2 mg 2 times/day.

Use with caution in elderly patients with dementia.

Special Precautions

In schizophrenia, before treatment with the drug Risset^®, it is recommended to gradually discontinue previous therapy if clinically justified. If patients are switched from therapy with depot forms of antipsychotic drugs, administration should be started instead of the next scheduled injection. The need to continue current therapy with antiparkinsonian drugs should be periodically assessed.

Risset^® must be used with caution in elderly patients with dementia, incl. when taking furosemide and other diuretic agents.

A meta-analysis of the results of 17 controlled clinical trials showed increased mortality in elderly patients with dementia (mean age 86 years) receiving atypical antipsychotic drugs, incl. Risperidone, compared with placebo. Among patients receiving Risperidone and placebo, mortality was 4% and 3.1%, respectively.

For elderly patients with dementia taking Risperidone, increased mortality was observed in patients taking furosemide and Risperidone compared to the group taking only Risperidone and the group taking only furosemide. No pathophysiological mechanisms explaining this observation have been established. No increase in mortality was found in elderly patients simultaneously 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.

In placebo-controlled studies, an increased incidence of cerebrovascular events (stroke and/or transient ischemic attacks), incl. fatal, was found in elderly patients with dementia receiving some atypical antipsychotic drugs, incl. Risperidone, compared with the use of placebo.

In patients with cardiovascular diseases, as well as with dehydration, hypovolemia, or cerebrovascular disorders, the dose should be increased gradually. If orthostatic hypotension occurs, especially in the initial dose titration period, a dose reduction should be considered.

Antipsychotic drugs, incl. Risperidone, contribute to the development of thromboembolic complications in patients predisposed to thrombosis. Before starting therapy with risperidone, all possible risk factors for the development of venous thromboembolism should be identified and appropriate measures taken to prevent the development of thromboembolic complications.

The risk of developing mania or hypomania can be significantly reduced by using low doses or their gradual increase.

If signs and symptoms of tardive dyskinesia or NMS occur, all antipsychotic drugs, incl. Risperidone, should be discontinued, symptomatic therapy should be carried out, and the resumption of therapy with antipsychotic drugs should be considered. To prevent the development of neuroleptic malignant syndrome during treatment with antipsychotic drugs, regular adjustment of the dose taken is necessary. The potential benefit and possible risk should be carefully assessed before using risperidone in patients with Lewy body dementia and Parkinson’s disease, as such patients may have an increased risk of developing NMS and increased sensitivity to antipsychotic drugs.

When discontinuing carbamazepine and other inducers of liver microsomal enzymes, the dose of risperidone should be reduced.

Patients should be advised to refrain from overeating due to the possibility of weight gain.

Use in pediatrics

Risperidone for children should be prescribed only by a doctor with special training in child psychiatry.

Effect on ability to drive vehicles and operate machinery

During the treatment period, patients should be cautious when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms enhancement of pharmacological effects – drowsiness, sedative effect, tachycardia, decreased BP, extrapyramidal symptoms. Ingestion of the drug in doses up to 360 mg has been reported. The available data suggest a wide safety margin of the drug. In rare cases, QT interval prolongation was noted with overdose. In case of acute overdose during combination therapy, the possibility of ingestion of several drugs should be considered.

Treatment ensure a patent airway to maintain adequate oxygen supply and ventilation; gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with laxatives. ECG monitoring should be started immediately to detect possible arrhythmia. There is no specific antidote. Appropriate symptomatic therapy should be carried out. Decreased BP and collapse should be corrected by intravenous fluid infusions and/or adrenomimetics. In case of acute extrapyramidal symptoms, m-cholinergic blockers should be used. Continuous medical supervision and monitoring should continue until the symptoms of intoxication disappear.

Drug Interactions

Given that antipsychotic drugs, incl. Risperidone, primarily affect the CNS, they should be used with caution in combination with other centrally acting drugs.

Risperidone enhances the effect of ethanol, opioid analgesics, histamine H₁-receptor blockers and benzodiazepines.

Benzodiazepines can be added to risperidone therapy if additional sedative effect is required.

When treating with a combination of risperidone with other antipsychotic drugs, lithium, antidepressants, antiparkinsonian drugs, drugs with central anticholinergic effect, the risk of developing tardive dyskinesia increases.

Risperidone does not affect the clinical effect and pharmacokinetics of lithium, valproic acid, digoxin and topiramate, therefore, with such combinations, dose adjustment is not required.

Risperidone reduces the effectiveness of levodopa and other dopamine receptor agonists. A similar effect is possible when using risperidone in combination with other inducers of liver microsomal enzymes, such as barbiturates, rifampicin, phenytoin, and St. John’s wort. In this case, the dose of risperidone should be reviewed.

The drug should not be prescribed concomitantly with carbamazepine to patients with mania in bipolar affective disorder. The use of carbamazepine is associated with a decrease in the plasma concentration of the active antipsychotic fraction of risperidone.

Clozapine reduces the clearance of risperidone.

Phenothiazine derivatives, tricyclic antidepressants, and some beta-blockers may increase the plasma concentration of risperidone, while the concentration of the active antipsychotic fraction does not change.

Quinidine, fluoxetine, paroxetine, terbinafine, and other inhibitors of the CYP2D6 isoenzyme may increase the plasma concentration of risperidone and, to a lesser extent, the concentration of the active antipsychotic fraction.

Cimetidine and ranitidine increase the plasma concentration of risperidone, but the antipsychotic effect does not increase.

Concomitant use of risperidone with furosemide in elderly patients with cerebrovascular dementia was associated with increased mortality. The mechanism of this interaction is not clearly understood. The ratio of potential benefit to possible risk for these patients should be assessed when using risperidone and diuretic agents concomitantly, including furosemide.

Risperidone may increase blood pressure, reducing the effectiveness of phenoxybenzamine, labetalol, and other alpha-blockers, reserpine, methyldopa, and other centrally acting antihypertensive agents.

Risperidone blocks the hypotensive effect of guanethidine.

Concomitant administration of risperidone with drugs that prolong the QT interval, such as other antipsychotics, class I A and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, erythromycin, tricyclic antidepressants, lithium, and cisapride, requires attention and caution.

Caution is advised with the concomitant use of risperidone and drugs that can cause electrolyte imbalance, such as thiazide diuretics (hypokalemia). This combination increases the risk of malignant arrhythmia.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.