INFORMATION FOR HEALTH PROFESSIONALS
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0.5 mg Tablets: A red, round tablet engraved with "R" on one face and a breakline on the other
1 mg Tablets: A white oblong tablet engraved with "R", a breakline and "l" on one face and plain on the other
2 mg Tablets: An orange, oblong tablet engraved with "R", a breakline and "2" on one face and plain on the other
3 mg Tablets: A yellow, oblong tablet engraved with "R", a breakline and "3" on one face and plain on the other
4 mg Tablets: A green, oblong tablet engraved with "R", a breakline and "4" on one face and plain on the other
6 mg Tablets: A yellow, oblong tablet engraved with "R", a breakline and "6" on one face and plain on the other.
Risperidone is a compound which belongs to a new class of antipsychotic agents, the benzisoxazole derivatives.
Risperidone is a selective monoaminergic antagonist having a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to alpha1-adrenergic receptors and, with lower affinity, to H1-histamine and alpha2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Risperidone, as a potent D2 antagonist, improves the positive symptoms of schizophrenia but 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.
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 may be given with or without meals.
Risperidone is partly metabolised by CYP2D6 to 9-hydroxyrisperidone which has similar pharmacological activity to risperidone. Risperidone plus 9-hydroxyrisperidone form the active antipsychotic fraction. Another metabolic pathway 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 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%, while that of 9-hydroxy-risperidone is 77%. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces.
In urine, risperidone plus 9-hydroxy-risperidone represents 35-45% of the dose.
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.
Risperidone is indicated for the treatment of schizophrenia and other psychotic disorders. These include 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 effect, emotional and social withdrawal, poverty of speech) are prominent.
Risperidone also alleviates affective symptoms (such as depression, guilt-feelings, anxiety) associated with schizophrenia. In addition, risperidone also appears effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial response to treatment with this agent.
Risperidone is also indicated for the treatment of behavioural and psychological symptoms of dementia such as aggressiveness (verbal outburst, physical violence), activity disturbance (agitation, wandering) or psychotic symptoms.
Risperidone is also indicated for the treatment of conduct and other disruptive disorders in children, adolescents and adults with subaverage intellectual functioning or mental retardation in whom destructive behaviours (e.g. aggression, impulsivity and self-injurious behaviours) are prominent.
When medically appropriate, gradual discontinuation of the previous treatment while risperidone therapy is initiated is recommended. Also if medically appropriate, when switching patients from depot antipsychotics, initiate risperidone therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medications should be re-evaluated periodically.
Adults
Risperidone may be given once daily or twice daily. Patients should start with 2 mg/day risperidone. The dose may be increased on the second day to 4 mg. From then on the dosage can be maintained unchanged, or further individualised, 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.
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 when additional sedation is required.
A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 - 2 mg twice daily. Risperidone is well tolerated in the elderly.
A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 - 2 mg twice daily risperidone should be used with caution in this group of patients until further experience is gained.
Experience is lacking in children aged less than 15 years.
A starting dose of 0.25 mg twice daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5 mg twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily
Once patients have reached their target dose, a once daily dosing regimen can be considered. As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an on-going basis.
A starting dose of 0.5mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5mg once daily not more frequently than every other day, if needed. The optimum dose is 1mg once daily for most patients. Some patients, however, may benefit from 0.5mg once daily while others may require 1.5mg once daily.
A starting dose of 0.25mg once daily is recommended, which can be individually adjusted by increments of 0.25mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5mg once daily for most patients, although some patients may benefit from 0.25mg once daily while others may require 0.75mg once daily.
As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an on-going basis
Risperidone is contraindicated in patients with a known hypersensitivity to the product.
Risperidone may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.
Due to the alpha-blocking activity of risperidone, orthostatic hypotension can occur, especially during the initial dose-titration period. RISPERIDONE should be used with caution in patients with known cardiovascular disease (eg. heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolaemia, 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.
In placebo controlled trials in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events, including cerebrovascular accidents and transient ischaemic attacks, in patients treated with risperidone compared to patients treated with placebo (mean age 85 years, range 73-97).
Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised 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 has a lower potential to induce extrapyramidal symptoms than classic neuroleptics, it should have a reduced risk of inducing tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotic medicines should be considered.
The Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated creatine phosphokinase (CPK) levels has been reported to occur with classical neuroleptics. In this event, all antipsychotic medicines, including risperidone, should be discontinued.
Physicians should weigh the risks versus benefits when prescribing antipsychotics including risperidone to patients with Lewy Body Dementia or Parkinson's disease since these patients may be at increased risk of neuroleptic malignant syndrome or a worsening of Parkinson-like symptoms.
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 possibility of weight gain.
Use in the elderly: It is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients.
It is recommended to halve both the starting dose and the subsequent dose increments in patients with renal insufficiency.
It is recommended to halve both the starting dose and the subsequent dose increments in patients with hepatic insufficiency.
The safety of risperidone 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 should only be used during pregnancy if the benefits outweigh the risks.
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in the milk. It has been demonstrated that this excretion also occurs in human breast milk. Therefore, women receiving risperidone should not breast feed.
Experience of risperidone treatment in children aged less than 15 years is lacking.
Hepatic reactions.
Based on extensive clinical experience including long term use, risperidone is generally well tolerated, and, in many instances, it has been difficult to differentiate adverse events from the symptoms of the underlying disease. Adverse events observed in association with the use of risperidone are listed below.
Common:
Insomnia, agitation, anxiety, headache.
Uncommon:
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 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 anti-Parkinson medication, if necessary.
Cerebrovascular accidents have occurred in patients taking risperidone.
Occasionally, (orthostatic) hypotension, (reflex) tachycardia or hypertension have been observed following administration of risperidone. A decrease in neutrophil and/or thrombocyte count has been reported.
Risperidone can induce a dose-dependent increase in plasma prolactin concentration. Possible associated manifestations are: galactorrhoea, gynaecomastia, disturbances of the menstrual cycle and amenorrhoea.
Weight gain (see WARNINGS AND PRECAUTIONS), oedema and increased hepatic enzyme levels have been reported during treatment with risperidone. As with neuroleptics of the butyrophenone group 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, body temperature dysregulation neuroleptic malignant syndrome and seizures.
Hyperglycaemia and exacerbation of pre-existing diabetes have been reported in very rare cases during risperidone treatment.
The risks of using risperidone in combination with other medicines have not been systemically evaluated. Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally-acting medicines.
Risperidone may antagonise the effects of levodopa and other dopamine agonists.
Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone. Similar effects may be observed with other hepatic enzyme inducers. On discontinuation of carbamazepine or other hepatic enzyme inducers the dosage of risperidone 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 is taken together with other highly protein-bound medicines, there is no clinically relevant displacement of either medicine from the plasma proteins.
Food does not affect the absorption of risperidone.
In general, reported signs and symptoms have been those resulting from an exaggeration of the known pharmacological effects of risperidone. 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 overdose, rare cases of QT-prolongation have been reported.
In case of acute overdosage, the possibility of multiple medicine involvement should be considered.
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. 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.
Risperidone tablets have a shelf of 36 months in blisters and 24 months in bottles. Store below 25°C. Protect from light and moisture.
Prescription Medicine
0.5 mg Tablets: Packaging blisters and bottles, 15, 20, 30, 60 and 100 tablets
1 mg, 2 mg, 3 mg, 4 mg and 6 mg Tablets: Packaging blisters and bottles, 60 tablets
All the tablets contain as excipients: lactose, microcrystalline cellulose, maize starch, colloidal anhydrous silica, magnesium stearate and Opadry white Y-1-7000 (hypromellose, titanium dioxide CI77891, macrogol). The 0.5 mg tablets also contain: red iron oxide CI77491. The 1 mg tablets contain no other ingredients other than those listed. The 2 mg tablets also contain: red iron oxide CI77491 and Quinoline yellow CI 47005. The 3 mg and 6 mg tablets contain: Quinoline yellow CI 47005. The 4 mg tablets contain: Eurolake Indigo Carmine CI 73015 and Quinoline yellow CI 47005.
Douglas Pharmaceuticals Ltd
P O Box 45 027
Auckland 8
New Zealand
Phone:(09) 835 0660
Fax: (09) 835 0665
15 December 2005