Rispolept^® (Tablets, Solution) Instructions for Use

ATC Code

N05AX08 (Risperidone)

Active Substance

Risperidone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Antipsychotic drug (neuroleptic).

Risperidone is a selective monoaminergic antagonist with high affinity for serotonin 5-HT₂ and dopamine D₂ receptors. It also binds to α₁-adrenergic receptors and, to a lesser extent, to histamine H₁ receptors and α₂-adrenergic receptors. It has no affinity for cholinergic receptors.

Risperidone reduces the productive symptoms of schizophrenia, causes less suppression of motor activity and induces catalepsy to a lesser extent than classical neuroleptics. The balanced central antagonism to serotonin and dopamine probably reduces the tendency to extrapyramidal side effects and extends the therapeutic effect of the drug to the negative and affective symptoms of schizophrenia.

Pharmacokinetics

Absorption

After oral administration, Risperidone is completely absorbed from the gastrointestinal tract. C_max in plasma is reached in 1-2 hours. The absolute bioavailability of risperidone after oral administration is 70%. The relative bioavailability of oral risperidone in tablet form is 94% compared to risperidone in solution form. Food does not affect the absorption of the drug, so Rispolept^® can be administered regardless of meals.

Distribution

Risperidone is rapidly distributed in the body. V_d is 1-2 l/kg. In plasma, Risperidone binds to albumin and alpha₁-glycoprotein. Risperidone is 90% bound to plasma proteins, 9-hydroxyrisperidone is 77% bound.

The C_ss of risperidone in the body is reached within 1 day in most patients. The C_ss of 9-hydroxyrisperidone is reached within 4-5 days.

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

Metabolism

Risperidone is metabolized by the CYP2D6 isoenzyme to form 9-hydroxyrisperidone, which has a pharmacological action similar to risperidone. Risperidone and 9-hydroxyrisperidone constitute the active antipsychotic fraction. The CYP2D6 isoenzyme is subject to genetic polymorphism. In patients with extensive metabolism via the CYP2D6 isoenzyme, Risperidone is rapidly converted to 9-hydroxyrisperidone, while in patients with poor metabolism this transformation occurs much more slowly. Although patients with extensive metabolism have a lower concentration of risperidone and a higher concentration of 9-hydroxyrisperidone than patients with poor metabolism, the overall pharmacokinetics of risperidone and 9-hydroxyrisperidone (the active antipsychotic fraction) after single or multiple doses are similar in patients with extensive and poor CYP2D6 metabolism.

Another pathway of risperidone metabolism is N-dealkylation. In vitro studies on human liver microsomes have shown that Risperidone, at clinically significant concentrations, generally does not inhibit the metabolism of drugs undergoing biotransformation by P450 system isoenzymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

Excretion

One week after starting the drug, 70% of the dose is excreted in the urine, 14% in the feces. In urine, Risperidone together with 9-hydroxyrisperidone account for 35-45% of the dose. The remainder consists of inactive metabolites.

After oral administration in patients with psychosis, Risperidone is eliminated from the body with a T_1/2 of about 3 hours. The T_1/2 of 9-hydroxyrisperidone and the active antipsychotic fraction is 24 hours.

Pharmacokinetics in special clinical cases

After a single dose of risperidone in elderly patients, plasma concentrations of the active antipsychotic fraction were on average 43% higher, T_1/2 lasted 38% longer, and clearance decreased by 30%.

In patients with renal failure, an increase in plasma concentration and a decrease in clearance of the active antipsychotic fraction by an average of 60% were observed.

In patients with hepatic insufficiency, plasma concentrations of risperidone did not change, but the mean concentration of the free fraction of risperidone increased by 35%.

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

Indications

• Treatment of schizophrenia in adults and children from 13 years of age;
• Treatment of moderate to severe manic episodes associated with bipolar disorder in adults and children from 10 years of age;
• Short-term (up to 6 weeks) treatment of persistent aggression in patients with moderate to severe Alzheimer’s dementia that is not amenable to non-pharmacological correction methods and when there is a risk of the patient harming himself or others;
• Short-term (up to 6 weeks) symptomatic treatment of persistent aggression in the structure of behavioral disorders in children from 5 years of age with intellectual disability diagnosed according to DSM-IV, in which the severity of aggression or other destructive behavior requires drug treatment. Pharmacotherapy should be part of a broader treatment program, including psychological and educational measures. Risperidone should be prescribed by a specialist in child neurology and child psychiatry or a physician well acquainted with the treatment of behavioral disorders in children and adolescents.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. Food intake does not affect the absorption of the drug.

When prescribing the drug in doses less than 1 mg, it is recommended to use Rispolept^®, oral solution.

Schizophrenia

For adults, Rispolept^® can be prescribed once or twice a day. The initial dose of Rispolept^® is 2 mg/day. On the second 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, a slower dose increase and lower initial and maintenance doses may be justified.

Doses above 10 mg/day have not shown higher efficacy compared to lower doses and may cause extrapyramidal symptoms. Since the safety of doses above 16 mg/day has not been studied, doses above this level should not be used.

For patients with persistent drowsiness, it is recommended to take half the daily dose twice a day.

For elderly patients, the drug is prescribed at an initial dose of 0.5 mg twice a day. The dose can be individually increased by 0.5 mg twice a day to 1-2 mg twice a day.

For children from 13 years of age, an initial dose of 0.5 mg per dose once a day in the morning or evening is recommended. If necessary, the dose can be increased no less than 24 hours later by 0.5-1 mg/day to the recommended dose of 3 mg/day with good tolerance. Despite the efficacy demonstrated in the treatment of schizophrenia in adolescents with the drug at doses of 1-6 mg/day, no additional efficacy was observed when using the drug at doses above 3 mg/day, and higher doses caused more side effects. The use of the drug in doses above 6 mg/day has not been studied.

Manic episodes associated with bipolar disorder

The recommended initial dose of the drug for adults is 2 mg/day in a single dose. If necessary, this dose can be increased no less than 24 hours later by 1 mg/day. For most patients, the optimal dose is 1-6 mg/day. The use of the drug in doses above 6 mg/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 assessed and confirmed.

For patients with persistent drowsiness, it is recommended to take half the daily dose twice a day.

For elderly patients, the initial dose is 0.5 mg twice a day. The dose can be individually increased by 0.5 mg twice a day to 1-2 mg twice a day. Caution is required due to limited experience with the drug in elderly patients.

For children from 10 years of age, an initial dose of 0.5 mg per dose once a day in the morning or evening is recommended. If necessary, the dose can be increased no less than 24 hours later by 0.5-1 mg/day to the recommended dose of 1-2.5 mg/day with good tolerance. Despite the efficacy demonstrated in the treatment of manic episodes associated with bipolar disorder in children with the drug at doses of 0.5-6 mg/day, no additional efficacy was observed when using doses above 2.5 mg/day, and higher doses caused more side effects. The use of the drug in doses above 6 mg/day has not been studied.

Persistent aggression in patients with dementia due to Alzheimer’s disease

An initial dose of 0.25 mg twice a day is recommended. The dose can be individually increased by 0.25 mg twice a day if necessary, no more often than every other day. For most patients, the optimal dose is 0.5 mg twice a day. However, some patients are shown to take 1 mg twice 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, patients’ condition should be assessed on a regular basis, as well as the need for continued therapy.

Persistent aggression in the structure of behavioral disorder

For children from 5 to 18 years of age (with a body weight of 50 kg or more), an initial dose of 0.5 mg once a day is recommended. If necessary, this dose can be increased by 0.5 mg/day, no more often than every other day. For most patients, the optimal dose is 1 mg/day. However, for some patients, a dose of 0.5 mg/day is preferable, while some require an increase in dose to 1.5 mg/day.

For children from 5 to 18 years of age (with a body weight of less than 50 kg), an initial dose of 0.25 mg once a day is recommended. If necessary, this dose can be increased by 0.25 mg/day, no more often than every other day. For most patients, the optimal dose is 0.5 mg/day. However, for some patients, a dose of 0.25 mg/day is preferable, while some require an increase in dose to 0.75 mg/day.

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

Use in children under 5 years of age is not recommended due to lack of data.

Special patient groups

In patients with impaired renal function, the ability to excrete the active antipsychotic fraction is reduced compared to other patients.

In patients with impaired liver function, there is an increased concentration of the free fraction of risperidone in the blood plasma.

The initial and maintenance dose according to the indications should be halved, and the dose increase in patients with liver and kidney diseases should be carried out more slowly. Rispolept^® should be prescribed with caution in this category of patients.

Drug withdrawal

Discontinuation of the drug is recommended to be carried out gradually. Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia, have been very rarely observed after abrupt discontinuation of antipsychotic drugs in high doses.

Transition from therapy with other antipsychotic drugs

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

Solution

Schizophrenia

Adults

Rispolept^® may be prescribed 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 point, the dose can either be maintained at the same level or individually adjusted if necessary. The optimal dose is usually 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 have not shown higher efficacy compared to lower doses and may cause extrapyramidal symptoms. Since the safety of doses above 16 mg per day has not been studied, doses above this level are not recommended.

Elderly patients

An initial dose of 0.5 mg per dose twice a day is recommended. The dosage can be individually increased by 0.5 mg twice a day to 1-2 mg twice a day.

Children from 13 years of age

An initial dose of 0.5 mg per dose once a day in the morning or evening is recommended. If necessary, the dosage can be increased no less than 24 hours later by 0.5-1 mg per day to the recommended dose of 3 mg per day with good tolerance. Despite the efficacy demonstrated in the treatment of schizophrenia in adolescents with 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.

For patients with persistent drowsiness, it is recommended to take half the daily dose twice a day.

Manic episodes associated with bipolar disorder

Adults

The recommended initial dose of the drug is 2 mg per day in a single dose. If necessary, this dose can be increased no less than 24 hours later by 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 assessed and confirmed.

Elderly patients

An initial dose of 0.5 mg per dose twice a day is recommended. The dosage can be individually increased by 0.5 mg twice a day to 1-2 mg twice a day. Caution is required due to limited experience with the drug in elderly patients.

Children from 10 years of age

An initial dose of 0.5 mg per dose once a day in the morning or evening is recommended. If necessary, the dosage can be increased no less than 24 hours later by 0.5-1 mg per day to the recommended dose of 1-2.5 mg per day with good tolerance. Despite the efficacy demonstrated 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.

For patients with persistent drowsiness, it is recommended to take half the daily dose twice a day.

Persistent aggression in patients with dementia due to Alzheimer’s disease

An initial dose of 0.25 mg per dose twice a day is recommended. The dosage can be individually increased by 0.25 mg 2 times a day if necessary, no more often than every other day. For most patients, the optimal dose is 0.5 mg twice a day. However, some patients are shown to take 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, patients’ condition should be assessed on a regular basis, as well as the need for continued therapy.

Persistent aggression in the structure of behavioral disorder

Children from 5 to 18 years of age

Patients with a body weight of 50 kg or more – the recommended initial dose of the drug is 0.5 mg once a day. If necessary, this dose can be increased by 0.5 mg per day, no more often than every other day. For most patients, the optimal dose is 1 mg per day. However, for some patients, a dose of 0.5 mg per day is preferable, while some require an increase in dose to 1.5 mg per day.

Patients with a body weight of less than 50 kg – the recommended initial dose of the drug is 0.25 mg once a day. If necessary, this dose can be increased by 0.25 mg per day, no more often than every other day. For most patients, the optimal dose is 0.5 mg per day. However, for some patients, a dose of 0.25 mg per day is preferable, while some require an increase in dose to 0.75 mg per day.

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

Use in children under 5 years of age is not recommended due to lack of data.

Liver and kidney diseases

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

The initial and maintenance dose according to the indications should be reduced by half; dose increase in patients with liver and kidney diseases should be performed more slowly.

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

Method of administration

Orally. Food intake does not affect the absorption of the drug.

Discontinuation of the drug is recommended to be carried out gradually. Acute “withdrawal” symptoms, including nausea, vomiting, sweating, and insomnia, were observed very rarely after abrupt discontinuation of high doses of antipsychotic drugs.

Transition from therapy with other antipsychotic drugs

At the beginning of treatment with Rispolept^®, it is recommended to gradually discontinue previous therapy if clinically justified. Furthermore, if patients are switched from therapy with depot forms of antipsychotic drugs, it is recommended to start therapy with Rispolept^® instead of the next scheduled injection. The need for continuation of current therapy with antiparkinsonian drugs should be periodically assessed.

Adverse Reactions

The most frequently observed side effects (incidence ≥10%) were: parkinsonism, headache, and insomnia.

Side effects of Rispolept^® at therapeutic doses are presented with distribution by frequency and organ systems. The frequency of side effects was classified as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10000) and frequency not known (cannot be estimated from the available data). Within each frequency group, adverse effects are presented in order of decreasing importance.

Infections: common – pneumonia, influenza, bronchitis, upper respiratory tract infections, urinary tract infections, sinusitis, ear infections; uncommon – viral infections, tonsillitis, cellulitis, otitis media, eye infections, localized infections, acarodermatitis, respiratory tract infections, cystitis, onychomycosis; rare – chronic otitis media.

Immune system disorders: uncommon – hypersensitivity; rare – drug hypersensitivity, anaphylactic reaction.

Cardiac disorders: common – tachycardia, arterial hypertension; uncommon – arterial hypotension, orthostatic hypotension, flushing, AV block, bundle branch block, atrial fibrillation, palpitations, cardiac conduction disorder; rare – sinus bradycardia, pulmonary embolism, deep vein thrombosis.

Blood and lymphatic system disorders: uncommon – anemia, thrombocytopenia; rare – granulocytopenia, agranulocytosis.

Nervous system disorders: very common – parkinsonism², headache, somnolence, sedative effect; common – akathisia², dizziness², tremor², dystonia², lethargy, dyskinesia²; uncommon – unresponsiveness to stimuli, loss of consciousness, syncope, disturbance in consciousness, stroke, transient ischemic attack, dysarthria, attention disturbance, hypersomnia, postural dizziness, balance disorder, tardive dyskinesia, speech disorder, coordination abnormal, hypoesthesia, taste disorders, taste distortion, convulsions, cerebral ischemia, movement disorder; rare – neuroleptic malignant syndrome, diabetic coma, cerebrovascular disorders, head tremor.

Psychiatric disorders: very common – insomnia; common – agitation, restlessness, sleep disorders, anxiety; uncommon – confusion, mania, decreased libido, listlessness, nervousness; rare – anorgasmia, affective flattening.

Eye disorders: common – blurred vision, conjunctivitis; uncommon – eye redness, visual impairment, eye discharge, periorbital edema, dry eye, increased lacrimation, photophobia; rare – visual acuity reduced, nystagmus, glaucoma, intraoperative floppy iris syndrome.

Ear and labyrinth disorders: uncommon – ear pain, tinnitus.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, epistaxis, cough, nasal congestion, pain in the larynx and pharynx; uncommon – wheezing, aspiration pneumonia, pulmonary congestion, respiratory disorder, rales, airway obstruction, dysphonia; rare – sleep apnea syndrome, hyperventilation.

Gastrointestinal disorders: common – vomiting, diarrhea, constipation, nausea, abdominal pain, dyspepsia, dry mouth, stomach discomfort, hypersalivation; uncommon – dysphagia, gastritis, fecal incontinence, fecaloma, gastroenteritis, flatulence; rare – intestinal obstruction, pancreatitis, lip edema, cheilitis.

Hepatobiliary disorders: rare – jaundice.

Renal and urinary disorders: common – enuresis; uncommon – urinary retention, dysuria, urinary incontinence, pollakiuria.

Skin and subcutaneous tissue disorders: common – rash, erythema; uncommon – skin lesion, skin disorder, pruritus, acne, acneiform eruption, skin discoloration, alopecia, seborrheic dermatitis, dry skin, hyperkeratosis; rare – dandruff; very rare – angioedema.

Musculoskeletal and connective tissue disorders: common – arthralgia, back pain, pain in extremity; uncommon – muscle weakness, myalgia, neck pain, joint swelling, posture abnormal, joint stiffness, musculoskeletal chest pain; rare – rhabdomyolysis.

Metabolism and nutrition disorders: common – increased appetite, decreased appetite; uncommon – diabetes mellitus³, anorexia, polydipsia, hyperglycemia; rare – syndrome of inappropriate antidiuretic hormone secretion, hypoglycemia, water intoxication; very rare – diabetic ketoacidosis.

General disorders and administration site conditions: common – pyrexia, fatigue, peripheral edema, generalized edema, asthenia, chest pain; uncommon – face edema, gait disturbance, malaise, slowness, influenza-like illness, thirst, chest discomfort, chills; rare – hypothermia, withdrawal syndrome, cold extremities.

Reproductive system and breast disorders: uncommon – amenorrhea, sexual dysfunction, erectile dysfunction, ejaculation disorder, galactorrhea, gynecomastia, menstrual disorder, vaginal discharge; rare – priapism.

Pregnancy, puerperium and perinatal conditions: rare – neonatal withdrawal syndrome.

General disorders and administration site conditions: common – pyrexia, fatigue, peripheral edema, generalized edema, asthenia, chest pain; uncommon – face edema, gait disturbance, malaise, slowness, influenza-like illness, thirst, chest discomfort, chills; rare – hypothermia, withdrawal syndrome, cold extremities.

Investigations: common – increased prolactin level¹, increased body weight; uncommon – QT prolongation on ECG, ECG abnormalities, increased transaminases, decreased white blood cell count, increased body temperature, increased blood eosinophils, decreased hemoglobin, increased CPK level, increased cholesterol; rare – decreased body temperature, increased triglycerides.

¹– hyperprolactinemia in some cases may lead to gynecomastia, menstrual disorders, amenorrhea and galactorrhea.

²– extrapyramidal disorders may manifest as: parkinsonism (hypersalivation, musculoskeletal stiffness, drooling, cogwheel rigidity, bradykinesia, hypokinesia, mask-like face, muscle tension, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal), akathisia (restlessness, hyperkinesia and restless legs syndrome), tremor, dyskinesia (muscle twitching, choreoathetosis, athetosis and myoclonus), dystonia.

The term “dystonia” includes dystonia, muscle spasms, hypertonia, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, eye rolling, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm and trismus. Tremor includes tremor and parkinsonian rest tremor. It should also be noted that there is a wider range of symptoms that are not always of extrapyramidal origin.

³– in placebo-controlled studies, diabetes mellitus was observed in 0.18% of patients taking Risperidone compared to 0.11% of patients in the placebo group. The overall incidence of diabetes mellitus based on all clinical trials was 0.43% of all patients taking Risperidone.

Below are additionally listed side effects observed during clinical trials of the prolonged injectable form of risperidone – Rispolept^® Consta^®, but not manifested with the use of oral dosage forms of risperidone. This list does not include side effects related to the composition or injectable route of administration of the drug.

Investigations: decreased body weight, increased GGT level, increased hepatic enzymes.

Cardiac disorders: bradycardia.

Blood and lymphatic system disorders: neutropenia.

Nervous system disorders: paresthesia, convulsions.

Eye disorders: blepharospasm, retinal artery occlusion.

Ear and labyrinth disorders: vertigo.

Gastrointestinal disorders: toothache, tongue spasm.

Skin and subcutaneous tissue disorders: eczema.

Musculoskeletal and connective tissue disorders: gluteal pain.

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

Injury, poisoning and procedural complications: fall.

Vascular disorders: arterial hypertension.

General disorders and administration site conditions: pain.

Psychiatric disorders: depression.

Class-effects

As with the use of other antipsychotic drugs, very rare cases of QT interval prolongation have been noted in post-marketing surveillance. Other class-effects from the cardiovascular system observed with the use of antipsychotic drugs that contribute to QT interval prolongation include: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and torsade de pointes.

Venous thromboembolism

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

Increased body weight

In placebo-controlled studies in patients with schizophrenia, an increase in body weight of at least 7% after 6-8 weeks was observed in 18% of patients taking Rispolept^® and in 9% of patients taking placebo. In placebo-controlled clinical studies in patients with manic episodes, the number of cases of body weight increase 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 it was slightly higher (3.5%).

In children with behavioral disorders during long-term clinical studies, body weight increased on average by 7.3 kg after 12 months of therapy. The expected weight gain in normally developing children aged 5-12 years is 3-5 kg per year. From 12-16 years, the amount of weight gain should be 3-5 kg per year for girls and about 5 kg per year for boys.

Additional information on special patient populations

Side effects that were noted with greater frequency in elderly patients with dementia and in children than in adult patients are described below.

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

Children: the following side effects were noted in children (from 5 to 17 years old) with a frequency of ≥5% and with a frequency at least twice that in other patient populations during clinical studies: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infections, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhea, enuresis.

Contraindications

• Phenylketonuria;
• Hypersensitivity to risperidone or any other component of the drug.

With caution

• Cardiovascular diseases (chronic heart failure, history of myocardial infarction, cardiac conduction disorders);
• Dehydration and hypovolemia;
• Cerebrovascular disorders;
• Parkinson’s disease;
• Convulsions (including history);
• Severe renal or hepatic impairment;
• Drug abuse or drug dependence;
• Conditions predisposing to the development of torsade de pointes tachycardia (bradycardia, electrolyte imbalance, concomitant use of drugs that prolong the QT interval);
• Brain tumor, intestinal obstruction, cases of acute drug overdose, Reye’s syndrome (the antiemetic effect of risperidone may mask the symptoms of these conditions);
• Risk factors for the development of venous thromboembolism;
• Dementia with Lewy bodies;
• Elderly patients with cerebrovascular dementia;
• Pregnancy.

Use in Pregnancy and Lactation

Adequate studies on the use of risperidone in pregnant women have not been conducted. According to post-marketing surveillance data, when risperidone was used in the third trimester of pregnancy, reversible extrapyramidal symptoms occurred in the newborn, so newborns should be under close observation. 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 humans is unknown. Rispolept^® can be used during pregnancy only if the expected benefit of the drug for the pregnant woman outweighs the potential risk to the fetus. If it is necessary to discontinue the drug during pregnancy, the drug should be withdrawn gradually.

In animal studies, Risperidone and 9-hydroxyrisperidone passed into breast milk. It has also been demonstrated that Risperidone and 9-hydroxyrisperidone pass into human breast milk in small amounts. Data on adverse effects in breastfed infants are lacking. Therefore, the issue of breastfeeding should be decided taking into account the possible risk to the child.

Use in Hepatic Impairment

In patients with impaired liver function, an increased concentration of the free fraction of risperidone in blood plasma is observed.

The initial and maintenance dose according to the indications should be reduced by half; dose increase in patients with liver diseases should be performed more slowly. Rispolept^® should be prescribed with caution in this category of patients.

The drug should be used with caution in patients with severe hepatic impairment.

Use in Renal Impairment

In patients with impaired renal function, the ability to excrete the active antipsychotic fraction is reduced compared to other patients. The initial and maintenance dose according to the indications should be reduced by half; dose increase in patients with kidney diseases should be performed more slowly. Rispolept^® should be prescribed with caution in this category of patients.

The drug should be used with caution in patients with severe renal impairment.

Pediatric Use

Use in children under 5 years of age is not recommended due to lack of data.

Geriatric Use

For elderly patients, the initial dose is 0.5 mg twice a day. The dose can be individually increased by 0.5 mg twice a day to 1-2 mg twice a day. Caution is necessary due to limited experience with the drug in elderly patients.

The drug should be prescribed with caution to elderly patients with cerebrovascular dementia.

Special Precautions

Increased mortality in elderly patients with dementia

Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in studies of atypical antipsychotic drugs, including Risperidone. When risperidone was used for this population, the mortality rate was 4.0% for patients taking Risperidone compared to 3.1% for placebo. The average age of deceased patients is 86 years (range 67-100 years). Data collected from two large observational studies show that elderly patients with dementia undergoing treatment with typical antipsychotic drugs also have a slightly increased risk of death compared to patients not undergoing treatment. Currently, there is insufficient data to accurately assess this risk. The reason for the increase in this risk is also unknown. The extent to which the increased mortality may be applicable to antipsychotic drugs, rather than to the characteristics of this patient group, has also not been determined.

Concomitant use with furosemide

In elderly patients with dementia, increased mortality was observed with the simultaneous use of oral furosemide and risperidone (7.3%, average age 89 years, range 75-97 years) compared to the group taking only Risperidone (3.1%, average age 84 years, range 70-96 years) and the group taking only furosemide (4.1%, average age 80 years, range 67-90 years). Increased mortality in patients taking Risperidone concomitantly with furosemide was observed in 2 out of 4 clinical studies. Concomitant use of risperidone with other diuretics (mainly low-dose thiazide diuretics) was not accompanied by increased mortality.

No pathophysiological mechanisms explaining this observation have been established. Nevertheless, special caution should be exercised when prescribing the drug in such cases. The risk/benefit ratio should be carefully assessed before prescribing. No increase in mortality was found in patients simultaneously taking other diuretics together 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, an increase in cerebrovascular adverse effects (acute and transient cerebrovascular accidents), including fatal cases in patients (average age 85 years, range 73-97 years), was observed with the use of risperidone compared to placebo.

Cardiovascular Effects

In placebo-controlled clinical studies in patients with dementia taking some atypical antipsychotic drugs, an approximately 3-fold increase in the risk of cerebrovascular adverse effects was observed. Pooled data from 6 placebo-controlled studies, which mainly included elderly patients with dementia (age over 65 years), demonstrate that cerebrovascular adverse 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 95% confidence interval. The mechanism for the increased risk is unknown. An increased risk cannot be ruled out for other antipsychotic drugs, as well as for other patient populations. Rispolept^® should be used with caution in patients with risk factors for stroke.

The risk of cerebrovascular adverse effects is much higher in patients with mixed or vascular dementia compared to 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 using Rispolept^® in elderly patients with dementia, taking into account the individual patient’s precursors of stroke risk. Patients and their caregivers should be warned to immediately report signs and symptoms of cardiovascular events: such as sudden weakness or immobility/numbness in the face, legs, arms, as well as difficulty speaking and vision problems. All possible treatment options, including discontinuation of risperidone, should be considered.

Rispolept^® may only be used for the short-term treatment of persistent aggression in patients with moderate to severe Alzheimer’s dementia as an adjunct to non-pharmacological correction methods, if they are ineffective or of limited effectiveness, and when there is a risk of the patient harming themselves or others.

The condition of patients and the need to continue risperidone therapy should be constantly assessed.

Orthostatic Hypotension

Risperidone has alpha-blocking activity and therefore may cause orthostatic hypotension in some patients, especially during the initial dose titration period. Clinically significant hypotension has been observed in the post-marketing period when used concomitantly with antihypertensive drugs. Rispolept^® should be used with caution in patients with known cardiovascular diseases (e.g., heart failure, myocardial infarction, conduction disorders, dehydration, hypovolemia, or cerebrovascular disease). Appropriate dose adjustment is also necessary. The possibility of dose reduction should be considered if hypotension occurs.

Tardive Dyskinesia and Extrapyramidal Disorders

Drugs with dopamine receptor antagonist properties may cause tardive dyskinesia, characterized by rhythmic involuntary movements, predominantly of the tongue and/or facial muscles. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If a patient develops objective or subjective symptoms suggestive of tardive dyskinesia, the advisability of discontinuing all antipsychotic drugs, including Rispolept^®, should be considered.

Neuroleptic Malignant Syndrome (NMS)

Antipsychotic drugs, including Risperidone, may cause neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, depressed consciousness, and elevated serum CPK concentrations. Patients with NMS may also develop myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops objective or subjective symptoms of NMS, all antipsychotic drugs, including Rispolept^®, must be discontinued immediately.

Parkinson’s Disease and Dementia with Lewy Bodies

Prescription of antipsychotic drugs, including Rispolept^®, to patients with Parkinson’s disease or dementia with Lewy bodies should be done with caution, as both groups of patients have an increased risk of developing neuroleptic malignant syndrome and increased sensitivity to antipsychotic drugs (including blunted pain sensitivity, confusion, postural instability with frequent falls, and extrapyramidal symptoms). Taking risperidone may worsen the course of Parkinson’s disease.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes mellitus have been observed during treatment with Rispolept^®. It is likely that weight gain prior to treatment is also a predisposing factor. Ketoacidosis may occur very rarely and diabetic coma rarely. All patients should be clinically monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus should be regularly monitored for worsening glucose control.

Weight Gain

Significant weight gain has been observed during treatment with Rispolept^®. Patient weight should be monitored.

Hyperprolactinemia

Based on tissue culture study results, it has been suggested that the growth of breast tumor cells may be stimulated by prolactin. Although clinical and epidemiological studies have not established a clear association between hyperprolactinemia and antipsychotic drug use, caution should be exercised when prescribing risperidone to patients with a relevant history. Rispolept^® should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

QT Interval Prolongation

QT interval prolongation has been very rarely observed in the post-marketing surveillance period. As with other antipsychotic agents, caution should be exercised when prescribing Rispolept^® to patients with known cardiovascular disease, family history of QT prolongation, bradycardia, electrolyte imbalances (hypokalemia, hypomagnesemia), as this may increase the risk of arrhythmogenic effect; and when used concomitantly with drugs that prolong the QT interval.

Seizures

Rispolept^® should be used with caution in patients with a history of seizures or with other medical conditions that may lower the seizure threshold.

Priapism

Priapism may occur with risperidone due to its alpha-adrenergic blocking effects.

Body Temperature Regulation

Antipsychotic drugs are attributed with the undesirable effect of impairing the body’s ability to regulate temperature. Caution should be exercised when prescribing Rispolept^® to patients with conditions that may contribute to an increase in core body temperature, which include intense physical exertion, dehydration, exposure to high external temperatures, or concomitant use of drugs with anticholinergic activity.

Venous Thromboembolism

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with Rispolept^®, and preventive measures should be taken.

Excipients

Rispolept^® film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Rispolept^® film-coated tablets.

The 2 mg tablets contain the dye sunset yellow (E110), which may cause allergic reactions.

Use in Pediatrics

Before prescribing Rispolept^® to children or adolescents with intellectual disability, a thorough assessment of their condition should be conducted for physical or social causes of aggressive behavior, such as pain or inadequate social environmental demands.

The sedative effect of risperidone should be carefully monitored in this population due to the potential impact on learning ability. Changing the time of risperidone administration may improve control of the sedative effect on attention in adolescents and children.

The use of risperidone has been associated with a mean increase in body weight and body mass index. Changes in height during long-term studies were within expected age norms. The effect of long-term risperidone use on sexual development and growth has not been fully studied.

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

Regular checking for extrapyramidal symptoms and other movement disorders should be performed during treatment with risperidone.

Effect on Ability to Drive and Use Machines

Rispolept^® may to a minor or moderate degree affect the ability to drive vehicles and operate machinery. Patients should be advised to refrain from driving cars and operating machinery until their individual sensitivity to the drug is determined.

Overdose

Symptoms in general, the symptoms of overdose observed were the known pharmacological effects of risperidone in an enhanced form: drowsiness, sedation, tachycardia, arterial hypotension, extrapyramidal symptoms. QT interval prolongation and seizures were observed. Bidirectional ventricular tachycardia was noted with concomitant use of risperidone and paroxetine in increased doses.

In case of acute overdose, the possibility of multiple drug overdose should be considered.

Treatment a patent airway should be established and maintained to ensure adequate oxygen supply and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be performed only if the drug was taken no more than 1 hour ago. ECG monitoring should be initiated immediately to detect possible arrhythmias. There is no specific antidote; appropriate symptomatic therapy should be administered. Arterial hypotension and vascular collapse should be treated with IV fluid infusions and/or sympathomimetic drugs. If severe extrapyramidal symptoms develop, anticholinergic drugs should be prescribed. Continuous medical supervision and monitoring should be continued until the symptoms of intoxication resolve.

Drug Interactions

As with other antipsychotic drugs, caution should be exercised when co-prescribing Rispolept^® with drugs that increase the QT interval, for example, class Ia antiarrhythmics (quinidine, disopyramide, procainamide, etc.), class III antiarrhythmics (amiodarone, sotalol, etc.), tricyclic antidepressants (amitriptyline, etc.), tetracyclic antidepressants (maprotiline, etc.), some antihistamines, other antipsychotics, some antimalarial drugs (quinine, mefloquine, etc.), drugs that cause electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, or inhibit the hepatic metabolism of risperidone. This list is not exhaustive.

Effect of Rispolept^® on other drugs

Rispolept^® should be used with caution in combination with other centrally acting drugs and substances, especially ethanol, opioids, antihistamines, and benzodiazepines due to an increased risk of sedative effect.

Rispolept^® may reduce the effectiveness of levodopa and other dopamine agonists. If this combination is necessary, especially in the terminal stage of Parkinson’s disease, the lowest effective dose of each drug should be prescribed.

Clinically significant arterial hypotension has been observed in the post-marketing period with the concomitant use of risperidone and antihypertensive drugs.

Risperidone does not have a clinically significant effect on the pharmacokinetics of lithium, valproate, digoxin, or topiramate.

Effect of other drugs on Rispolept^®

The use of carbamazepine has been associated with a decrease in the plasma concentration of the active antipsychotic fraction of risperidone. Similar effects may be observed with the use of other inducers of hepatic enzymes and P-glycoprotein (e.g., rifampicin, phenytoin, phenobarbital). The dose of Rispolept^® should be adjusted upon initiation and after discontinuation of carbamazepine or other inducers of hepatic enzymes and P-glycoprotein.

Fluoxetine and paroxetine, which are inhibitors of the CYP 2D6 isoenzyme, increase the plasma concentration of risperidone, and to a lesser extent the concentration of the active antipsychotic fraction. It is assumed that other inhibitors of the CYP2D6 isoenzyme (e.g., quinidine) affect the concentration of risperidone in the same way. The dose of Rispolept^® should be adjusted upon initiation and after discontinuation of fluoxetine or paroxetine.

Verapamil, an inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, increases the plasma concentration of risperidone.

Galantamine and donepezil do not have a clinically significant effect on the pharmacokinetics of risperidone and its active antipsychotic fractions.

Phenothiazines, tricyclic antidepressants, and some beta-blockers may increase plasma concentrations of risperidone, but this does not affect the concentration of the active antipsychotic fraction.

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

Cimetidine and ranitidine increase the bioavailability of risperidone but minimally affect the concentration of the active antipsychotic fraction.

Erythromycin, an inhibitor of the CYP3A4 isoenzyme, does not affect the pharmacokinetics of risperidone and the active antipsychotic fraction.

Concomitant use of psychostimulants (e.g., methylphenidate) and Rispolept^® in children does not alter the pharmacokinetic parameters and efficacy of risperidone.

Concomitant use of Risperidone with paliperidone is not recommended because paliperidone is an active metabolite of risperidone, and such combination may lead to an increased concentration of the active antipsychotic fraction.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 30°C (86°F).

Shelf Life

The shelf life is 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.