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Risperidone

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish):

Synonyms: R-64766; Risperidon; Risperidona; Risperidonas; Risperidoni; Risperidonum; Riszperidon
BAN: Risperidone
USAN: Risperidone
INN: Risperidone [rINN (en)]
INN: Risperidona [rINN (es)]
INN: Rispéridone [rINN (fr)]
INN: Risperidonum [rINN (la)]
INN: Рисперидон [rINN (ru)]
Chemical name: 3-{2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl}-6,7,8,9-tetrahydro-2-methylpyrido[1,2-a]pyrimidin-4-one
Molecular formula: C23H27FN4O2 =410.5
CAS: 106266-06-2
ATC code: N05AX08
Read code: y022W

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Risperidone). A white or almost white powder. It exhibits polymorphism. Practically insoluble in water sparingly soluble in alcohol freely soluble in dichloromethane dissolves in dilute acid solutions. Protect from light.

The United States Pharmacopeia 31, 2008 (Risperidone). A white or almost white powder. Practically insoluble in water sparingly soluble in alcohol soluble in dichloromethane.

Adverse Effects, Treatment, and Precautions

Although risperidone may share some of the adverse effects seen with the classical antipsychotics (see Chlorpromazine), the incidence and severity of such effects may vary. Risperidone is reported to be less likely to cause sedation or extrapyramidal effects (see also Uses and Administration, below) but agitation may occur more frequently. Other common adverse effects include insomnia, anxiety, and headache. Dyspepsia, nausea and vomiting, abdominal pain, constipation, blurred vision, sexual dysfunction including priapism, urinary incontinence, rash and other allergic reactions, drowsiness, concentration difficulties, dizziness, fatigue, and rhinitis have been reported less commonly. In addition to orthostatic hypotension, hypertension has been reported infrequently. Other adverse effects with risperidone include cerebrovascular accidents, tachycardia, weight gain, oedema, increased liver enzyme values, and decreases in neutrophil or thrombocyte counts. Risperidone may cause dose-dependent increases in prolactin levels. In rare cases, hyperglycaemia and exacerbation of pre-existing diabetes mellitus have also been reported. Clinical monitoring for hyperglycaemia has been recommended, especially in patients with or at risk of developing diabetes. Other rare effects include seizures, body temperature dysregulation, hyponatraemia, neuroleptic malignant syndrome, and tardive dyskinesia.

Risperidone should be used with caution in patients with cardiovascular disease, including conditions associated with QT prolongation, or conditions predisposing to hypotension. Caution is also recommended in patients with a history of or at risk of developing cerebrovascular disease, in patients with Parkinson’s disease or epilepsy, and in patients with hepatic or renal impairment.

Risperidone may affect the performance of skilled tasks such as driving.

Gradual withdrawal of risperidone is recommended because of the risk of withdrawal symptoms, including sweating, nausea and vomiting, and rebound psychosis, with abrupt cessation.
Risperidone 4 mg film-coated tablets

Breast feeding. From the study of concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in the breast milk of a mother receiving 6 mg daily by mouth, it was estimated that a breast-fed infant would ingest the daily equivalent of 4.3% (as risperidone equivalents) of the weight-adjusted maternal dose. Later case reports of 3 women receiving risperidone 3 mg daily, 4 mg daily, and 1.5 mg daily, by mouth, estimated that a breast-fed infant would receive the daily equivalent of 2.3%, 2.8%, and 4.7%, respectively, of the weight-adjusted maternal dose. Where breast feeding occurred, in the latter 2 cases, no adverse effects were reported in the breast-fed infants risperidone and 9-hydroxyrisperidone were not detected in the plasma of either infant.

Licensed product information states that patients receiving risperidone should not breast feed the US information also recommends that patients should not breast feed for at least 12 weeks after intramuscular injection.

Dementia. After analysis of data from controlled studies there was evidence that the use of risperidone in elderly patients with dementia appeared to be associated with an increased risk of cerebrovascular adverse effects such as stroke and transient ischaemic attacks. In 4 studies, involving 764 such patients treated with risperidone, there were 29 cases of cerebrovascular adverse events (4 fatal) versus 7 cases (1 fatal) in 466 patients given placebo. Postmarketing data for elderly dementia patients, representing over 2.4 million patient-years of exposure, included 37 cases, of which 16 were fatal.

The UK CSM have therefore recommended that risperidone should not be used to treat behavioural problems in elderly patients with dementia. Similarly, the CSM and the EMEA have recommended that olanzapine should not be used to treat behavioural problems or dementia-related psychosis in elderly patients with dementia after analysis of placebo-controlled studies revealed a threefold increase in cerebrovascular adverse effects including stroke and a twofold increase in all-cause mortality. It was considered that the risk may not be confined to use in dementia and should be considered relevant to any patient with a history of stroke or transient ischaemic attack or other risk factors for cerebrovascular disease, including hypertension, diabetes, current smoking, or atrial fibrillation. The FDA has also issued advice against the use of all atypical antipsychotics in the treatment of behavioural problems in elderly patients with dementia. Their advice was based on an unpublished analysis of 17 placebo-controlled studies involving aripiprazole, olanzapine, quetiapine, or risperidone use in elderly demented patients with behavioral disorders: the analysis found that 15 studies showed an increase in the mortality rate in the drug-treated group compared to the placebo-treated patients. A total of 5106 patients were included in these studies, and a 1.6- to 1.7-fold increase in mortality was seen most of the deaths appeared due to cardiovascular events or infection. Another published meta-analysis of placebo-controlled studies also had similar findings.

However, 2 large retrospective population-based studies in the elderly (1 involving 10 385 patients given atypicals and 1015 given classical antipsychotics, the other involving 17 845 given atypicals and 14 865 given classical antipsychotics), suggested that use of atypical antipsychotics was not associated with a statistically significant increased risk of stroke compared with the classical drugs.

For further discussion of the problems associated with the use of antipsychotics in disturbed behaviour in the elderly.

Effects on body-weight. The increased risk of weight gain with some atypical antipsychotics is discussed under Adverse Effects of Clozapine.

Effects on carbohydrate metabolism. The increased risk of glucose intolerance and diabetes mellitus with some atypical antipsychotics, including risperidone, and recommendations for monitoring, are discussed under Adverse Effects of Clozapine.

Effects on lipid metabolism. The increased risk of hyperlipidaemia with some atypical antipsychotics is discussed under Adverse Effects of Chlorpromazine. See also Effects on Carbohydrate Metabolism under Adverse Effects of Clozapine.

Effects on the liver. There has been a report of 2 cases of hepatotoxicity associated with risperidone. An idiosyncratic reaction to risperidone was suspected in another patient who developed hepatotoxicity after receiving only 2 doses of risperidone.

Effects on the skin. A patient developed facial and periorbital oedema 2 weeks after her dose of risperidone reached 6 mg daily. The oedema subsided when the dose was halved but recurred shortly after it was again increased to 6 mg. She had previously had a similar reaction to lithium and there was also a family history of angioedema.

Extrapyramidal disorders. In reports of 3 cases of tardive dystonia associated with oral risperidone therapy,lt onset ranged from 3 to 8 months after starting the drug. Dyskinesia has also been reported 5 days after the withdrawal of oral risperidone and citalopram therapy. In another report, three patients receiving risperidone orally developed early-onset tardive dyskinesia despite the addition of antimuscarinic therapy with biperiden or trihexyphenidyl. Extrapyramidal adverse effects have also been reported within 24 hours of intramuscular risperidone injection.

However, the incidence of extrapyramidal effects is generally lower with atypical than classical antipsychotics.

Mania. Although it is used in the treatment of bipolar disorder, risperidone has been associated with reports of mania in both schizophrenic and bipolar patients.

Neuroleptic malignant syndrome. Neuroleptic malignant syndrome has occasionally been associated with risperidone.

Overdosage. A 3/-year-old child developed extrapyramidal symptoms after accidental ingestion of a single 4-mg tablet of risperidone. The child was initially treated with gastric lavage, activated charcoal, and sorbitol extrapyramidal symptoms responded to treatment with diphenhydramine and the child recovered completely. The need to monitor for and treat hypotension after overdosage with risperidone was highlighted in a report of a 15-year-old girl who took 40 mg of risperidone. A 72-year-old woman receiving risperidone 6 mg daily was found unconscious, hypotensive, and hypothermia Other reported symptoms include first-degree heart block, prolonged QT interval, and respiratory arrest she recovered after supportive treatment.

Pregnancy. For comments on the use of some atypical antipsychotics, including risperidone, during pregnancy, see under Precautions of Clozapine.

Risperidone 3 mg film-coated tablets

Interactions

The central effects of other CNS depressants, including alcohol, may be enhanced by risperidone. Risperidone may also enhance the effects of antihypertensives. There may be an increased risk of QT prolongation when risperidone is given with other drugs that are known to cause this effect. Risperidone may antagonise the actions of levodopa and other dopaminergics. Carbamazepine has been shown to decrease the antipsychotic fraction (risperidone plus 9-hydroxyrisperidone) of risperidone and a similar effect may be seen with other enzyme inducers. Fluoxetine may increase the plasma concentrations of the antipsychotic fraction by raising the concentration of risperidone. Dose adjustment of risperidone may be necessary in such situations.

Antiepileptics. For the effect of risperidone on valproate.

Antipsychotics. For a report suggesting that risperidone might increase plasma concentrations of clozapine. For a report of asymptomatic QT prolongation associated with quetiapine in a patient also receiving risperidone, see under Overdosage of Quetiapine.

Antivirals. Dystonia and worsening of tremors were reported 1 week after adding indinavir and ritonavir to treatment with risperidone in a patient with AIDS he recovered once all 3 drugs were withdrawn and following treatment with clonazepam. An early exposure to risperidone, indinavir, and ritonavir had not resulted in any extrapyramidal adverse effects. The authors considered this to reflect the patient’s relatively short exposure to risperidone at the time.

Pharmacokinetics

Risperidone is readily absorbed after oral doses, peak plasma concentrations being reached within 1 to 2 hours. It is extensively metabolised in the liver by hydroxylation to its main active metabolite, 9-hydroxyrisperidone (paliperidone) oxidative N-dealkylation is a minor metabolic pathway. Hydroxylation is mediated by the cytochrome P450 isoenzyme CYP2D6 and is the subject of genetic polymorphism. Excretion is mainly in the urine and, to a lesser extent, in the faeces. Risperidone and 9-hydroxyrisperidone are about 90% and 77% bound to plasma proteins, respectively. Both are distributed into breast milk.

Metabolism. Although the hydroxylation of risperidone is subject to genetic polymorphism, the pharmacokinetics and effects of the active antipsychotic fraction (risperidone plus 9-hydroxyrisperidone) have been reported to vary little between extensive and poor metabolisers. A mean value of 19.5 hours has been reported for the terminal elimination half-life of the active fraction following oral doses of risperidone.

Uses and Administration

Risperidone is a benzisoxazole atypical antipsychotic, reported to be an antagonist at dopamine D2, serotonin (5-HT2), adrenergic (a1 and alpha2), and histamine (H1) receptors. It is given orally for the treatment of schizophrenia and other psychoses and in the short-term treatment of acute manic or mixed episodes associated with bipolar disorder. In the USA, risperidone is used similarly in children and also for the treatment of irritability associated with autistic disorder for further details see Administration in Children and Disturbed Behaviour, below. Risperidone may also be given by deep intramuscular injection for maintenance therapy in patients with schizophrenia or other psychoses tolerant to oral antipsychotics.

For schizophrenia, the usual initial oral dose of risperidone is 2 mg daily this may be increased to 4 mg daily on the second day, and subsequently adjusted as required in steps of 1 or 2 mg according to tolerance, at intervals of not less than 24 hours. Most patients benefit from doses of 4 to 6 mg daily. Risperidone may be given once daily or in 2 divided doses. Extrapyramidal symptoms maybe more likely with doses above 10 mg daily US licensed product information does not recommend daily doses above 6 mg if divided into 2 doses, although higher doses are permitted if given as a single dose. The maximum recommended dose is 16 mg daily.

An initial oral dose of 500 micrograms twice daily slowly increased in steps of 500 micrograms twice daily, if necessary, to a dose of 1 to 2 mg twice daily is recommended for elderly or debilitated patients. Above doses of 1.5 mg twice daily, increases should be made at intervals of at least 1 week.

The long-acting formulation of risperidone should be given by deep intramuscular injection every 2 weeks. Patients with no history of risperidone use should be given risperidone orally for several days to assess tolerability. Treatment may then be started as follows:

• patients not stabilised on oral risperidone: 25 mg every 2 weeks

• patients stabilised on oral risperidone for at least 2 weeks in doses of 4 mg daily or less: 25 mg every 2 weeks

• patients stabilised on oral risperidone for at least 2 weeks in doses above 4 mg daily: 37.5 mg every 2 weeks

• elderly patients should be given a maximum of 25 mg every 2 weeks

Oral risperidone should be continued for the first 3 weeks after the first injection.

Dose increases of 12.5 mg may be considered at least 4 weeks after the previous adjustment up to a maximum of 50 mg every 2 weeks the clinical effects of a dose adjustment may not be seen for at least 3 weeks after the change.

For the treatment of mania in bipolar disorder, a recommended initial oral dose is 2 to 3 mg once daily. Dosage adjustments of 1 mg daily may be made at intervals of not less than 24 hours up to a total of 6 mg daily. The initial dosage regimen in elderly or debilitated patients should be reduced as for schizophrenia (see above).

Reduced doses are recommended in patients with hepatic or renal impairment, see below.

Action. Risperidone is described as an atypical antipsychotic although it has a lower propensity to produce parkinsonism, dys-tonias and akathisias have been reported. (See also Extrapyramidal Disorders, above.) The traditional hypothesis is that antipsychotics work through inhibition of dopamine D2 receptors and that extrapyramidal adverse effects result from blockade of D2 receptors in the striatum. Like clozapine, risperidone has a high affinity for 5-HT2 receptors and, like haloperidol, it has a high affinity for dopamine D2 receptors. Risperidone also binds to alpha-adrenergic and histamine H: sites. It is unclear whether risperidone’s antipsychotic effect is due to activity at dopamine D2 receptors or at another site. It has been suggested that other potent effects of risperidone may be counterbalancing the D2 activity to produce its atypicality.

Risperidone 0.5 mg film-coated tablets

Administration in children. In the USA, risperidone is licensed for the treatment of schizophrenia in adolescents aged 13 to 17 years, for the short-term treatment of acute manic or mixed episodes associated with bipolar disorder in children and adolescents aged 10 to 17 years, and for the treatment of irritability associated with autistic disorder in those aged 5 to 16 years.

For schizophrenia or mania, an initial oral dose of 500 micrograms is given once daily in the morning or in the evening. This may be increased in steps of 0.5 or 1 mg according to tolerance, at intervals of not less than 24 hours, to a dose of 3 mg daily for schizophrenia or 2.5 mg daily for mania. The maximum recommended dose for both indications is 6 mg daily. The total daily dose may be given in 2 divided doses to those who experience persistent somnolence.

For the treatment of irritability associated with autistic disorder, the following oral doses are given once daily or in 2 divided doses according to body-weight:

• under 20 kg: the usual initial daily dose is 250 micrograms this may be increased to 500 micrograms daily after at least 4 days and subsequently adjusted as required in steps of 250 micrograms, generally at intervals of no less than 2 weeks. The maximum recommended dose is 1 mg daily. Caution should be exercised with dosage for children who weigh less than 15 kg

• 20 kg and over: the usual initial daily dose is 500 micrograms this may be increased to 1 mg daily after at least 4 days and subsequently adjusted as required in steps of 500 micrograms, generally at intervals of no less than 2 weeks. The maximum recommended dose is 2.5 mg daily in those weighing over 20 kg and 3 mg daily in those over 45 kg

• For those who experience persistent somnolence, the total daily dose may be given as a single dose at bedtime, or in 2 divided doses, or in a reduced dose

For further details on the use of risperidone in children with autism see Disturbed Behaviour, below.

Risperidone is not licensed in the UK for use in children aged under 15 years however, the BNFC suggests that it may be used in those aged 12 years and over for the oral treatment of acute and chronic psychoses. Doses are similar to those used in the treatment of schizophrenia in adults (see above). The BNFC also suggests that risperidone may be used, under specialist supervision, in children over 5 years of age for the short-term treatment of severe aggression in autism doses are similar to those licensed for autistic disorders in the USA.

Administration in hepatic or renal impairment. The recommended initial oral dose of risperidone in patients with renal or hepatic impairment is 500 micrograms twice daily this may be slowly increased in steps of 500 micrograms twice daily, if necessary, to a dose of 1 to 2 mg twice daily. Above doses of 1.5 mg twice daily, increases should be made at intervals of at least 1 week.

Patients with schizophrenia who tolerate an oral dose of risperidone of at least 2 mg daily may be switched to the long-acting formulation of risperidone a dose of 25 mg by deep intramuscular injection every 2 weeks is recommended. Alternatively, an initial dose of 12.5 mg by deep intramuscular injection may be given.

AIDS. Risperidone was used successfully to control HIV- or AIDS-related psychosis in 21 patients, some of whom also had manic symptoms. No extrapyramidal symptoms were reported during treatment. However, for reports suggesting that risperidone can induce or exacerbate manic symptoms in patients with schizoaffective disorders, see under Mania in Adverse Effects, above. For an interaction between risperidone and antiretroviral therapy in a patient with AIDS, see under Interactions, above.

Anxiety disorders. Although there have been anecdotal reports of improvement after the addition of risperidone to treatment in patients with obsessive-compulsive disorder refractory to conventional treatment, there has also been a report of a patient whose obsessive-compulsive behaviour recurred when he was treated with risperidone for tardive dyskinesia.

Bipolar disorder. Risperidone is of benefit for the treatment of mania, including in patients with bipolar disorder, and the use of atypical antipsychotics in the management of such patients is increasing. However, there have been individual case reports of risperidone-induced mania (see above).

Disturbed behaviour. Although risperidone has been used for the management of behavioural disturbances’ in elderly patients with dementia, such use is no longer recommended, see Dementia, under Adverse Effects, above. Furthermore, despite anecdotal reports of efficacy in patients with Lewy-body dementia, other reports suggest that these patients are likely to be just as sensitive to risperidone as to classical antipsychotics (see the Elderly in Precautions for Chlorpromazine).

There is evidence that risperidone may be effective in reducing behavioural disturbances in children with autism (see Disturbed Behaviour), but it appears to have little effect on core symptoms, and it has been pointed out that the marked hyperprolactinaemia induced by risperidone could lead to hypogonadism, and deleterious effects on adolescent bones. A systematic review concluded that risperidone may be of some benefit for symptoms such as hyperactivity, irritability, repetition, and social withdrawal although this must be weighed against the risk of adverse effects, notably weight gain. The authors noted that only 3 studies were analysed, including 1 that was carried out in adults, and the data available were limited further studies were considered warranted. Nonetheless, in some countries, including the USA, risperidone is licensed for the treatment of irritability associated with autistic disorder in children and adolescents aged 5 to 16 years for details of doses see Administration in Children, above.

Dystonias. Antipsychotics are sometimes useful in the treatment of idiopathic dystonia in patients who have failed to respond to treatment with levodopa or antimuscarinics, but, as with classical antipsychotics, there is the risk of adding drug-induced extrapyramidal effects to the dystonia. Risperidone has been reported to be of benefit in a few patients with idiopathic segmental dystonia partly insensitive to haloperidol.

Parkinsonism. There have been conflicting reports of the use of risperidone as an antipsychotic in a small number of patients with Parkinson’s disease (see also Disturbed Behaviour). While some patients found that risperidone ameliorated levodopa-induced hallucinations without worsening extrapyramidal symptoms, others reported that risperidone produced a substantial worsening of symptoms.

Schizophrenia. Risperidone is claimed to produce a relatively low incidence of extrapyramidal effects and to have efficacy against both positive and negative symptoms of schizophrenia. Most of the earlier studies compared risperidone with haloperidol but, of these, some of the major studies were criticised for potential methodological flaws and it was difficult to determine any difference in efficacy including effect on negative symptoms. A later systematic review suggested that risperidone’s benefits over haloperidol or other classical antipsychotics were marginal although it did appear to reduce the risk of extrapyramidal effects compared with haloperidol, the latter produces a relatively high incidence of such effects. Furthermore, the risk of extrapyramidal effects with risperidone appears to be dose-dependent: although similar to that for placebo overall, at doses of more than 10 mg the risk appears to approach that associated with haloperidol. In a more recent double-blind randomised study the relapse rate after at least 2 years of treatment in patients with first-episode psychosis, who had initially responded to relatively small daily doses of risperidone (mean modal 3.3 mg) or haloperidol (2.9 mg), was 42% (82 of 197 patients) and 55% (111 of 203), respectively. The median time to relapse was also longer for risperidone (466 days) when compared with haloperidol (205 days). In the few comparative studies with other atypical antipsychotics, risperidone has appeared to be of similar efficacy to clozapine. However, another systematic review concluded that such equivalence with clozapine cannot be assumed. For a systematic review of studies comparing risperidone with olanzapine, see p. 1013. There is insufficient evidence to indicate whether risperidone is effective for treatment-resistant or poorly responsive patients but there is some evidence that patients stabilised on risperidone may be less likely to relapse. A systematic review of the use of the long-acting injectable formulation of risperidone in schizophrenia considered that, although it might offer the advantage of better compliance, there was little evidence of benefit over oral use.

Stuttering. Risperidone 0.5 to 2 mg daily was found to be of benefit in the management of stuttering in a placebo-controlled study involving 16 patients but there has also been a case report of a patient whose stuttering returned during treatment with risperidone.

Tourette’s syndrome. When drug treatment is required for tics and behavioural disturbances in Tourette’s syndrome (see Tics) haloperidol or pimozide are commonly used but atypical antipsychotics, especially risperidone, are being increasingly tried.

Preparations

The United States Pharmacopeia 31, 2008: Risperidone Tablets.

Proprietary Preparations

Argentina: Dozic Dropicine Edalen Restelea Riatul Risper Risperdal Risperin Rispex Sequinan

Australia: Risperdal

Austria: Belivorv Risperdal Rispolin

Belgium: Risperdal

Brazil: Respidon Risperdal Viverdal Zargus

Canada: Risperdal

Chile: Dagotil Goval Radigen Risperdal Spiron

Czech Republic: Apo-Risper Medorisper Ridoner Rigenin Rileptid Ripetomar Risepro Rispadim Rispedep Rispedolet Rispedospes Rispemar Rispen Rispera Risperdal Risperinin Risperit Rispimed Rispolux Risset Rorendo

Denmark: Risperdal

Finland: Risperdal

France: Risperdal

Germany: Risperdal

Greece: Adovia Axelabron Depolan Depredon Dixine Helposper Isipredon Lassen Lucipral Nerve Novoris Preridon Rifocus Ripepral Risenar Risgal Risidral Rispalm Rispefar Risperascol Risperdal Risperom Risperoprol Rispogen Wisperdon Zafitral

Hong Kong: Risperdal

Hungary: Hunperdal Perdox Ripedon Risperdal Rispolux Rispons Ronkal Rosipin Torendo Ziperid

India: Respidon Risnia Risperdal Rispidl Rozidal Sizorisp

Indonesia: Neripros Persidal Risperdal Rizodal Zofredal

Ireland: Risperdal

Israel: Risperdal

Italy: Belivon Risperdal

Japan: Risperdal

Malaysia: Risperdal

Mexico: Risperdal

The Netherlands: Belivon Risperdal Rispimed Rispimedica

Norway: Risperdal

New Zealand: Ridal Risperdal

Philippines: Risperdal

Poland: Lioxam Mepharis Rispen Risperatio Risperiwin Risperon Rispolept Rispolux Risset Ryspolit Speridan Ziperid

Portugal: Belivonf Perdin Risperdal

Russia: Rileptid Risclonal Rispolept Risset Speridan

South Africa: Risperdal

Singapore: Risperdal

Spain: Arketin Diaforin Risfarmal Risperdal

Sweden: Risperdal

Switzerland: Risperdal

Thailand: Risperdal

Turkey: Risperdal

UK: Risperdal

USA: Risperdal

Venezuela: Ridal Risperdal Risperid.

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