Janssen Products

Risperidone

Risperdal^TM

Description
Risperidone (Risperdal^TM) is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives. It is available as a 1, 2, 3 and 4 mg oral film-coated tablet. The inactive ingredients for the 1 mg tablet are lactose, maize starch, microcrystalline cellulose, hypromellose, magnesium stearate, colloidal anhydrous silica, sodium lauryl sulphate and propylene glycol.

The 2 mg tablet contains in addition talc, titanium dioxide and orange yellow S-aluminum lake, the 3 mg tablet talc, titanium dioxide and quinoline yellow and the 4 mg tablet talc, titanium dioxide, quinoline yellow and indigotindisulphonate - aluminum lake.

Properties
Pharmacodynamics
Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D2 antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical neuroleptics. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.

Pharmacokinetics
Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption is not affected by food and thus risperidone can be given with or without meals.

Risperidone is metabolized by cytochrome P-450 IID6 to 9-hydroxy-risperidone which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. Another metabolic pathway of risperidone is N-dealkylation.

After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.

Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing. Risperidone plasma concentrations are dose-proportional within the therapeutic dose-range.

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and alpha1-acid glycoprotein. The plasma protein binding of risperidone is 88%, that of 9-hydroxy-risperidone is 77%.

One week after administration, 70% of the dose is excreted in the urine and 14% in the feces. In urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the dose. The remainder are inactive metabolites.

A single-dose study showed higher active plasma concentrations and a slower elimination of risperidone in the elderly and in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency.

Indications
Risperidone (Risperdal^TM) is indicated for the treatment of a broad range of patients with schizophrenia, including first episode psychoses, acute schizophrenic exacerbations, chronic schizophrenia, and other psychotic conditions, in which positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), and/or negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech) are prominent. Risperidone (Risperdal^TM) alleviates affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia. In addition, risperidone (risperdal*) is also indicated as long-term therapy for the prevention of relapse (acute exacerbations) in chronic schizophrenic patients.

Contraindications
Risperidone (Risperdal^TM) is contraindicated in patients with a known hypersensitivity to the product.

Warnings and precautions
Due to the alpha-blocking activity of risperidone (Risperdal^TM), (orthostatic) hypotension can occur, especially during the initial dose-titration period. Risperidone (Risperdal^TM) should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see Dosage and administration). A dose reduction should be considered if hypotension occurs.

Drugs with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterized by rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. Because risperidone (Risperdal^TM) has a lower potential to induce extrapyramidal symptoms than classical neuroleptics, it should have a reduced risk of inducing tardive dyskinesia as compared to classical neuroleptics. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic drugs should be considered.

The Neuroleptic Malignant Syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels has been reported to occur with classical neuroleptics. In this event, all antipsychotic drugs, including risperidone (Risperdal^TM), should be discontinued.

It is recommended to have both the starting dose and the subsequent dose increments in geriatric patients and in patients with renal or liver insufficiency.

Caution is also due when prescribing risperidone (Risperdal^TM) to patients with Parkinson's disease since, theoretically, it might cause a deterioration of the disease.

Classical neuroleptics are known to lower the seizure threshold. Caution is recommended when treating patients with epilepsy.

Patients may be advised to refrain from excessive eating in view of the possiblity of weight gain.

Interactions
The risk of using risperidone (Risperdal^TM) in combination with other drugs have not been systemically evaluated. Given the primary CNS effects of risperidone (Risperdal^TM) it should be used with caution in combination with other centrally acting drugs.

Risperidone (Risperdal^TM) may antagonize the effect of levodopa and other dopamine-agonists.

Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone (Risperdal^TM). Similar effects may be observed with other hepatic enzyme inducers. On discontinuation of carbamazepine or other hepatic enzyme inducers the dosage of risperidone (Risperdal^TM) should be re-evaluated and, if necessary, decreased.

Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentrations of risperidone but not those of the antipsychotic fraction. Fluoxetine may increase the plasma concentration of risperidone but less so of the antipsychotic fraction. When risperidone (Risperdal^TM) is taken together with other highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.

Pregnancy and lactation
The safety of risperidone (Risperdal^TM) for use during human pregnancy has not been established. Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed. No teratogenic effect of risperidone was noted in any study. Therefore, risperidone (Risperdal^TM) should only be used during pregnancy if the benefits outweigh the risks.

It is not known whether risperidone (Risperdal*) is excreted in human milk. In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. Therefore, women receiving risperidone (Risperdal^TM) should not breast feed.

Effects on driving ability and use of machinery
Risperidone (Risperdal^TM) may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

Dosage and administration
Switching from other antipsychotics.
When medically appropriate, gradual discontinuation of the previous treatment while risperidone (Risperdal^TM) therapy is initiated is recommended. Also if medically appropriate, when switching patients from depot antipsychotics, initiate risperidone (Risperdal^TM) therapy in place of the next scheduled injection. The need for continuing existing anti-parkinson medications should be re-evaluated periodically.

Adults
Risperidone (Risperdal^TM) may be given once daily or twice daily.

Patients should start with 2 mg/day risperidone (Risperdal^TM). The dosage may be increased on the second day to 4 mg. From then on the dosage can be maintained unchanged, or further individualized, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients a slower titration phase and a lower starting and maintenance dose may be appropriate.

Alternative titration scheme: When medically appropriate, a slower titration phase could be used: 4 mg gradually over 7 days - all patients, whether acute or chronic should start with 2 mg/day risperidone (Risperdal^TM). The dose should be increased to 3 mg on the 4th day and 4 mg on the 7th day.

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

A benzodiazepine may be added to risperidone (Risperdal^TM) when additional sedation is required.

Elderly
A starting dose of 0.5 mg b.i.d. is recommended. This dosage can be individually adjusted with 0.5 mg b.i.d. increments to 1 to 2 mg b.i.d.

Risperidone (Risperdal^TM) is well tolerated by the elderly.

Children
Experience is lacking in children aged less than 15 years.

Renal and liver disease
A starting dose of 0.5 mg b.i.d. is recommended. This dosage can be individually adjusted with 0.5 mg b.i.d. increments to 1 to 2 mg b.i.d.

Risperidone (Risperdal^TM) should be used with caution in this group of patients until further experience is gained.

Adverse reactions
Based on extensive clinical experience including long term use, risperidone (Risperdal^TM) is generally well tolerated. In many instances it has been difficult to differentiate adverse events from symptoms of the underlying disease. Adverse events observed in association with the use of risperidone (Risperdal^TM) are listed below:

Common:
insomnia, agitation, anxiety, headache

Less common:
somnolence, fatigue, dizziness, impaired concentration, constipation, dyspepsia, nausea/vomiting, abdominal pain, blurred vision, priapism, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, urinary incontinence, rhinitis, rash and other allergic reactions.

Risperidone (Risperdal^TM) has a lower propensity to induce extrapyramidal symptoms than classical neuroleptics. However, in some cases the following extrapyramidal symptoms may occur: tremor, rigidity, hypersalivation, bradykinesia, akathisia, acute dystonia. These are usually mild and are reversible upon dose reduction and/or administration of antiparkinson medication, if necessary.

Occasionally, (orthostatic) hypotension, and (reflex) tachycardia or hypertension have been observed following administration of risperidone (Risperdal^TM). See Precautions. A mild fall in neutrophil and/or thrombocyte count has been reported.

Risperidone (Risperdal^TM) can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhea, gynecomastia, disturbances of the menstrual cycle and amenorrhea. Weight gain (see Precautions), edema and increased hepatic enzyme levels have been observed during treatment with risperidone (Risperdal^TM).

As with classical neuroleptics, the following have occasionally been reported in psychotic patients: water intoxication due to either polydipsia or the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), tardive dyskinesia, neuroleptic malignant syndrome, body temperature disregulation and seizures.

Overdosage
Symptoms
In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. Overdosages of up to 360 mg have been reported. The available evidence suggests a wide safety margin. In a patient with concomitant hypokalemia who had ingested 360 mg, a prolonged QT was reported.

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

Treatment
Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to risperidone (Risperdal^TM). Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

How supplied
Risperidone (Risperdal^TM) is available as tablets of the following strength:

• 1mg risperidone as white, film-coated, half-scored oblong tablets (marked RIS 1); 100 tablets per box, i.e. 10 blisters of 10 tablets each.

• 2 mg risperidone as orange, film-coated, half-scored oblong tablets (marked RIS 2): 100 tablets per box, i.e. 10 blisters of 10 tablet each.

• 3 mg risperidone as yellow, film-coated, half-scored oblong tablets (marked RIS 3); 100 tablets per box, i.e. 10 blisters of 10 tablets each.

• 4 mg risperidone as green, film-coated, half-scored oblong tablets (marked RIS 4); 100 tablets per box, i.e. 10 blisters of 10 tablets each.

Storage conditions
Risperidone (Risperdal^TM) tablets should be stored between 15ºC and 30ºC.
Keep out of reach of children.

CAUTION: Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

Manufactured by:
JANSSEN PHARMACEUTICA
Beerse, Belgium
Repacked by:
INTERPHIL LABORATORIES, INC.
Canlubang Industrial Estate
Bo. Pittland, Cabuyao, Laguna
for: Johnson & Johnson (Philippines), Inc.
Edison Road, Bo. Ibayo
Parañaque, Metro Manila
Exclusively distributed by:
ZUELLIG PHARMA CORPORATION
Sen. Gil Puyat Avenue
Makati City