Risset^® Quitab (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Kutno S.A. (Poland)

ATC Code

N05AX08 (Risperidone)

Active Substance

Risperidone (Rec.INN registered by WHO)

Dosage Form

Risset® Quitab

Tablets, dispersible in the oral cavity, 2 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Tablets, dispersiblein the oral cavity, round, flat-cylindrical, white in color with a smooth or porous surface and rough edges.

Excipients: mannitol (sorbitol 50C) – 174.85 mg, mannitol (sorbitol 200SD) – 16.15 mg, sodium carboxymethyl starch (type A) – 6 mg, mint flavor (HF84 NAT, WONF-SD491) – 1 mg.

14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Antipsychotic drug (neuroleptic), a benzisoxazole derivative. It also has sedative, antiemetic, and hypothermic effects. A selective monoaminergic antagonist, it has high affinity for serotonin 5-HT₂ receptors and dopamine D₂ receptors, 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.

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

It suppresses productive 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 effect of the drug to cover negative and affective symptoms of schizophrenia.

Pharmacokinetics

Absorption

After oral administration, absorption is rapid and complete (food does not affect the completeness and rate of absorption). The absolute bioavailability of risperidone is 70%, the relative bioavailability of risperidone tablets is 94% compared to the solution. T_max in blood plasma is reached in 1-2 hours.

Risperidone plasma concentration is dose-dependent.

Distribution

Plasma protein binding (with alpha₁-acid glycoprotein and albumin) of risperidone is 88%, of 9-hydroxyrisperidone is 77%. Risperidone is rapidly and well distributed in the body. V_d is 1-2 l/kg.

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

Metabolism

It is metabolized in the liver with the participation of the CYP2D6 isoenzyme. The main pathway of biotransformation is hydroxylation to form the main active metabolite 9-hydroxyrisperidone, which has pharmacological properties similar to risperidone. Another pathway of metabolism, of minimal significance, is N-dealkylation. Risperidone and 9-hydroxyrisperidone form the active antipsychotic fraction.

Although the hydroxylation of risperidone is subject to genotypic polymorphism, the differences in the pharmacokinetics and effect of active metabolites in different phenotypes are minimal.

Excretion

T_1/2 of risperidone with active metabolism is 3 hours, with slow metabolism – 20 hours, T_1/2 of 9-hydroxyrisperidone with active metabolism is 21 hours, with slow metabolism – 30 hours; of the active antipsychotic fraction in both phenotypes – 20 hours.

After one week of administration, 70% of the taken risperidone is excreted by the kidneys, 14% – with feces. 35-45% of the fraction excreted in the urine consists of unchanged risperidone and 9-hydroxyrisperidone.

Pharmacokinetics in special clinical cases

Pharmacokinetics in adults and children does not differ.

In elderly patients, after a single dose, a 30% decrease in plasma clearance and a 38% increase in T_1/2 are observed.

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

In patients with hepatic insufficiency, the plasma concentration of risperidone did not differ from other patients, despite the fact that the free fraction of risperidone was increased on average by about 35%.

Indications

• Schizophrenia;
• Treatment of moderate to severe manic episodes due to bipolar disorder.

ICD codes

Dosage Regimen

The drug is taken orally. The Risset^® Quitab tablets for dispersion are very fragile, they should not be divided or chewed. Remove the tablets from the blister with dry hands by pulling the edge of the foil upwards and immediately place them on the tongue. If the tablets are taken with meals, there should be no food in the mouth when the patient places the tablet on the tongue. The tablets begin to disintegrate in the mouth within a few seconds, and after that they can be swallowed immediately without water. If necessary, the tablet can be washed down with water or another liquid.

Schizophrenia

It is recommended to take the drug 1-2 times/day. The initial dose is 2 mg/day. On day 2, the dose can 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 using Risset^® Quitab in doses above 10 mg/day, no enhancement of the therapeutic effect was observed compared to lower doses, while the likelihood of extrapyramidal symptoms increased. The maximum daily dose is 16 mg/day.

For elderly patients, Risset^® Quitab is recommended at a dose of 2-4 mg/day.

Treatment of moderate to severe manic episodes due to bipolar disorder

It is recommended to take the drug once a day. The initial dose is 2 mg/day. If a dose increase is necessary, it should be done no earlier than after 24 hours. The recommended dose range is from 2 to 6 mg/day. The appropriateness of further use of Risset^® Quitab in patients with this condition should be regularly assessed.

For elderly patients, Risset^® Quitab is recommended at a dose of 2-4 mg/day.

For liver and kidney diseases, a dose of 2-4 mg/day is recommended.

Adverse Reactions

Definition of the frequency of adverse reactions (according to WHO): very common (≥ 10%), common (≥ 1%, but < 10%), uncommon (≥ 0.1%, but < 1%), rare – (≥ 0.01%, but < 0.1%), very rare, including isolated cases (< 0.01%); frequency unknown (insufficient data to estimate frequency in the population).

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

Metabolism and nutrition disorders: common – increased/decreased appetite, weight gain; uncommon – anorexia, polydipsia, increased body temperature; rare – decreased body temperature; very rare – diabetic ketoacidosis; frequency unknown – water intoxication.

Blood and lymphatic system disorders: uncommon – anemia, thrombocytopenia, eosinophilia, decreased hemoglobin; rare – granulocytopenia; very rare – neutropenia; frequency unknown – agranulocytosis.

Immune system disorders: uncommon – hypersensitivity reaction; frequency unknown – anaphylactic reaction.

Nervous system disorders: very common – insomnia, parkinsonism (including extrapyramidal disorders, musculoskeletal stiffness, cogwheel syndrome, akinesia, bradykinesia, hypokinesia, muscle rigidity); common – anxiety, nervousness, confusion, lethargy, akathisia, tremor, sedative effect, dystonia (including muscle spasms, involuntary muscle contractions, muscle contracture, eye movements, tongue paralysis), lethargy, postural bleeding, dyskinesia (including muscle twitching, chorea and choreoathetosis), syncope, transient ischemic attack, depressed state, salivation, stroke, attention disturbance; uncommon – agitation, affective flattening, sleep disorders, decreased libido, anorgasmia, unresponsiveness to stimuli, impaired coordination, loss of consciousness, speech disorder, hypesthesia, movement disorder, tardive dyskinesia, NMS, diabetic coma; very rare – mania.

Gastrointestinal disorders: common – nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, dry mouth, stomach discomfort; uncommon – dysphagia, gastritis, fecaloma, increased activity of liver transaminases; rare – intestinal obstruction, jaundice, pancreatitis, cheilitis, aptyalism.

Cardiac disorders: common – tachycardia; uncommon – orthostatic hypotension, AV block, palpitations, sinus bradycardia, bundle branch block, flushing, QT interval prolongation on ECG; rare – stroke and transient ischemic attack (mainly in elderly patients with dementia-related psychosis); frequency unknown – venous thromboembolism.

Eye disorders: common – blurred vision; uncommon – conjunctivitis, eye hyperemia, dry eye, increased lacrimation, orbital edema, photophobia; rare – glaucoma, decreased visual acuity, rotatory nystagmus.

Ear and labyrinth disorders: uncommon – pain, tinnitus.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, epistaxis, cough, nasal congestion, sore throat; uncommon – rhinitis, breathing disorder, dysphonia, wheezing, aspiration pneumonia, productive cough, airway obstruction, moist rales, nasal edema; very rare – hyperventilation, sleep apnea syndrome.

Endocrine disorders: common – increased plasma prolactin concentration; uncommon – hyperglycemia; rare – inappropriate ADH secretion.

Reproductive system and breast disorders: uncommon – amenorrhea, sexual dysfunction, erectile dysfunction, ejaculation disorder, galactorrhea, gynecomastia, menstrual cycle disorder; frequency unknown – priapism.

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

Skin and subcutaneous tissue disorders: common – skin rash, erythema; uncommon – skin pigmentation disorder, itching, acne, skin lesion, erythematous rash, alopecia, seborrheic dermatitis, dry skin, hyperkeratosis; rare – dandruff.

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

General disorders and administration site conditions: common – fatigue, asthenia, peripheral edema, gait disturbance; uncommon – thirst, influenza-like illness, malaise, slowness, chills, cold extremities, facial edema, general edema.

Contraindications

• Children and adolescents under 18 years of age;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug.

With caution: chronic heart failure; coronary artery disease; history of myocardial infarction; AV block; 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; cerebrovascular accident; brain tumor (including pituitary prolactinoma); intestinal obstruction; acute drug overdose; Reye’s syndrome (the antiemetic effect of risperidone may mask the symptoms of these conditions).

Use in Pregnancy and Lactation

The safety of risperidone use during pregnancy has not been sufficiently studied. According to post-marketing studies, the use of risperidone in the third trimester of pregnancy may cause the development of reversible extrapyramidal symptoms in newborns. The use of Risset^® Quitab during pregnancy is contraindicated.

Since Risperidone and 9-hydroxyrisperidone are excreted in breast milk, if it is necessary to use Risset^® Quitab during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

For liver diseases, a dose of 2-4 mg/day is recommended.

Use in Renal Impairment

For kidney diseases, a dose of 2-4 mg/day is recommended.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

For elderly patients, Risset^® Quitab is recommended at a dose of 2-4 mg/day.

Special Precautions

In schizophrenia, at the beginning of treatment with Risset^® Quitab, 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 for continuation of current therapy with antiparkinsonian drugs should be periodically assessed.

Concomitant use of risperidone with furosemide in elderly patients with dementia was associated with increased mortality. The mechanism of this interaction has no clear explanation. Nevertheless, caution should be exercised in such cases.

Risperidone should be used with caution in elderly patients with a history of cerebrovascular disorders, as there is a risk of stroke or transient ischemic attack.

Antipsychotic drugs, including Risperidone, contribute to the development of thromboembolic complications in patients predisposed to thrombosis. Before starting therapy with Risset^® Quitab, 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 risperidone in low doses or by gradually increasing the dose.

If orthostatic hypotension occurs, especially during the initial dose titration period, a dose reduction should be considered.

In patients with cardiovascular diseases, as well as with dehydration, hypovolemia or cerebrovascular disorders, the dose should be increased gradually.

Antipsychotic drugs, including Risset^® Quitab, should be used with caution in patients with congenital long QT syndrome, coronary artery disease, conduction disorders, arrhythmia or concomitant use of drugs that cause QT interval prolongation, as well as in hypokalemia.

If signs and symptoms of tardive dyskinesia/extrapyramidal symptoms occur, discontinuation of all antipsychotic drugs should be considered.

If NMS develops, all antipsychotic drugs, including Risset^® Quitab, should be discontinued and symptomatic treatment should be carried out. After the condition normalizes, the doctor decides on the resumption of risperidone therapy. To prevent the development of NMS during treatment with antipsychotic drugs, regular adjustment of the taken dose is necessary.

The potential benefit and possible risk should be carefully evaluated when using risperidone in patients suffering from dementia with Lewy bodies or Parkinson’s disease, as such patients may have an increased risk of developing NMS and increased sensitivity to antipsychotic drugs.

In patients with diabetes mellitus or at risk of developing diabetes mellitus, blood glucose concentration should be monitored.

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

In rare cases, when the dose of antipsychotic drugs, including risperidone, is increased, symptoms of nausea, vomiting, increased sweating and drowsiness may appear. It is necessary to either suspend the drug until the symptoms disappear or reduce its dose.

Use in pediatrics

There are no data on the efficacy and safety of risperidone use in children and adolescents under 18 years of age.

Effect on the ability to drive vehicles and operate machinery

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

Overdose

Symptoms intensification of pharmacological effects – drowsiness, sedative effect, tachycardia, decreased blood pressure, extrapyramidal symptoms. Ingestion of the drug in a dose of up to 360 mg has been reported. The obtained data suggest a wide safety profile of the drug. In rare cases, QT interval prolongation was noted with overdose. In case of acute overdose during combined 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 initiated immediately to detect possible arrhythmia. There is no specific antidote. Appropriate symptomatic therapy aimed at maintaining the function of the central nervous system and cardiovascular system, as well as detoxification therapy, should be carried out. In case of marked decrease in blood pressure or vascular collapse, intravenous infusion solutions should be administered and/or sympathomimetic medicinal products should be used. In case of acute extrapyramidal symptoms, anticholinergic drugs should be used. Continuous medical monitoring of vital functions should continue until the symptoms of intoxication disappear.

Drug Interactions

Given that antipsychotic drugs, including Risperidone, primarily affect the central nervous system, they should be used with caution in combination with other centrally acting drugs.

Risperidone enhances the effects 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 and 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, no dose adjustment is required for such combinations.

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 reconsidered.

The drug should not be prescribed together with carbamazepine to patients with mania in bipolar affective disorder. When using carbamazepine, a decrease in the concentration of the active antipsychotic fraction of risperidone in plasma is noted.

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.

Carbamazepine, rifampicin, St. John’s wort, phenytoin, phenobarbital are inducers of the CYP3A4 isoenzyme and reduce the plasma concentration of the antipsychotic fraction of risperidone. When discontinuing carbamazepine and other inducers of the CYP3A4 isoenzyme, the dose of risperidone should be reduced.

Verapamil, being a CYP3A4 inhibitor, increases the plasma concentration of risperidone.

Cimetidine and ranitidine increase the plasma concentration of risperidone, but the antipsychotic effect does not increase because the binding of active metabolites is reduced.

The alpha₁-adrenergic blocking effect of risperidone may increase blood pressure, reducing the effectiveness of phenoxybenzamine, labetalol and other alpha-adrenergic blocking sympathomimetics, reserpine, methyldopa and other centrally acting antihypertensive drugs. In contrast, the antihypertensive effect of guanethidine is blocked.

Simultaneous administration of risperidone with medicinal products that prolong the QT interval, such as other neuroleptics, antiarrhythmic drugs of classes I A and III, moxifloxacin, methadone, mefloquine, erythromycin, tricyclic antidepressants, lithium and cisapride, requires attention and caution.

Caution is required when using risperidone concomitantly with medicinal products that can cause electrolyte imbalance, such as thiazide diuretics (hypokalemia). Such a combination increases the risk of malignant arrhythmia.

When using risperidone together with other drugs that are highly bound to plasma proteins, clinically significant displacement of any active substance from the plasma protein fraction is not observed.

Storage Conditions

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

Shelf Life

Shelf life is 2 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.