Risperidone


Generic Medicine Info
Indications and Dosage
Intramuscular
Bipolar disorder
Adult: Patient naive to risperidone use must receive oral risperidone 1st to establish tolerability before initiation of inj. As monotherapy or adjunctive therapy to lithium or valproate for maintenance treatment: Initially, 25 mg every 2 weeks. Dose may be increased, if necessary, in increments of 12.5 mg at intervals of at least 4 weeks. Max: 50 mg every 2 weeks. Continue oral supplementation for 3 weeks after the 1st inj.

Intramuscular
Schizophrenia
Adult: Patient naive to risperidone use must receive oral risperidone 1st to establish tolerability before initiation of inj. Initially, 25 mg every 2 weeks. For patients on fixed dose of oral risperidone treated with >4 mg daily for ≥2 weeks: Initially, 37.5 mg every 2 weeks. Doses may be increased in increments of 12.5 mg at intervals of at least 4 weeks. Max: 50 mg every 2 weeks. Continue oral supplementation for 3 weeks after the 1st inj.

Oral
Schizophrenia
Adult: Initially, 2 mg daily, may be increased to 4 mg on the 2nd day. Subsequent dosage may be maintained or adjusted further if needed in increments of 1-2 mg, as tolerated, at intervals of at least 24 hours. Usual dose range: 4-6 mg daily. Doses may be given once or twice daily. Max: 16 mg daily.
Child: 13-17 years Initially, 0.5 mg once daily, may be increased in increments of 0.5-1 mg daily at intervals of at least 24 hours, as tolerated, to a target dose of 3 mg daily. Dose range: 1-6 mg daily.
Elderly: Initially, 0.5 mg bid, gradually increased in 0.5 mg bid increments to 1-2 mg bid.

Oral
Persistent aggression associated with dementia in Alzheimer’s disease
Adult: Short-term treatment in patients with moderate to severe dementia who are unresponsive to non-pharmacological intervention, and when there is a risk of harm to self or others: Initially, 0.25 mg bid. Adjusted individually in increments of 0.25 mg bid on alternate days, if required. Usual dose: 0.5 mg bid (up to 1 mg bid, if needed). Max treatment duration: 6 weeks.

Oral
Acute manic episodes of bipolar disorder, Acute mixed episodes of bipolar disorder
Adult: As monotherapy or adjunctive therapy with lithium or valproate: Initially, 2-3 mg once daily. Dosage may be increased in increments of 1 mg daily at intervals of at least 24 hours. Max: 6 mg daily.
Child: 10-17 years As monotherapy: Initially, 0.5 mg once daily, may be increased in increments of 0.5-1 mg daily at intervals of at least 24 hours, as tolerated, to a target dose of 1-2.5 mg daily. Max: 6 mg daily.
Elderly: Initially, 0.5 mg bid, gradually increased in 0.5 mg bid increments to 1-2 mg bid.

Oral
Conduct disorder
Child: Short-term symptomatic treatment (up to 6 weeks) of persistent aggression in patients with subaverage intellectual functioning or mental retardation, in whom the severity of condition requires pharmacologic treatment: 5-18 years <50 kg: Initially, 0.25 mg once daily. Adjusted individually in increments of 0.25 mg once daily on alternate days, if required. Usual dose: 0.5 mg once daily; some may require up to 0.75 mg once daily. ≥50 kg: Initially, 0.5 mg once daily. Adjusted individually in increments of 0.5 mg once daily on alternate days, if required. Usual dose: 1 mg once daily; some may require up to 1.5 mg once daily.

Oral
Irritability associated with autistic disorder
Child: 5-17 years Dosage is individualised according to patient response and tolerability. 15-<20 kg: Initially, 0.25 mg daily, may be increased to 0.5 mg daily after at least 4 days; maintain dose for at least 14 days. If response is insufficient, dose may be increased in increments of 0.25 mg daily at intervals of ≥2 weeks. ≥20 kg: Initially, 0.5 mg daily, may be increased to 1 mg daily after at least 4 days; maintain dose for at least 14 days. If response is insufficient, dose may be increased in increments of 0.5 mg daily at intervals of ≥2 weeks. All doses may be given as single or in 2 divided doses. Max: 3 mg daily. Consider gradually reducing the dose to lowest effective dose once sufficient response has been achieved.

Subcutaneous
Schizophrenia
Adult: Patient naive to risperidone use must receive oral risperidone 1st to establish tolerability before initiation of inj. Usual dose: 90 mg or 120 mg once monthly. Patients on stable oral risperidone doses of <3 mg daily or >4 mg daily may not be eligible for this route.
Special Patient Group
Oral:
Patients receiving enzyme inducers (e.g. carbamazepine): Increase up to double of the usual dose.
Patients receiving CYP2D6 inhibitors (fluoxetine or paroxetine): Dose reduction may be required. Titrate risperidone dose slowly during initial therapy. Max: 8 mg daily.

IM:
Patients receiving enzyme inducers (e.g. carbamazepine): Dose increase or additional oral risperidone may be required (refer to specific product guideline).
Patients receiving CYP2D6 inhibitors (fluoxetine or paroxetine): Dose reduction may be required (refer to specific product guideline).

SC:
Patients receiving enzyme inducers (e.g. carbamazepine): Dose increase or additional oral risperidone may be required (refer to specific product guideline).
Patients receiving strong CYP2D6 inhibitors (fluoxetine or paroxetine): May give the lowest dose of 90 mg once monthly (refer to specific product guideline).

Pharmacogenomics:

Risperidone is well absorbed and is extensively metabolised via hydroxylation by CYP2D6 isoenzyme into the primary active metabolite 9-hydroxyrisperidone. The combination of the concentrations of these two entities comprises the total active moiety. CYP2D6 is subject to genetic polymorphism and to inhibition by a variety of substrates and some non-substrates.

CYP2D6 poor metabolisers convert risperidone more slowly into its active metabolite. The prevalence of poor metabolisers is approx 6-8% of Caucasians and a very low percentage of Asians. CYP2D6 ultrarapid metabolisers and poor metabolisers had a higher rate of treatment failure (37% and 26%, respectively), defined as switching to an alternative agent within 1 year as compared to extensive metabolisers.

Several published studies have various data on the significance of CYP2D6 phenotype in response to risperidone. Currently, there are insufficient evidences to recommend genetic testing prior to initial treatment. Local treatment guidelines or protocols must be considered.

Royal Dutch Pharmacists Association - Pharmacogenetics Working Group (DPWG) Guideline as of May 2020:

 Phenotype  Implications  Recommendations
CYP2D6 ultrarapid metabolisers High ratio of 9-hydroxyrisperidone as compared to risperidone. Choose an alternative agent or titrate dose according to Max dose of the active metabolite (Oral: Adults and children ≥15 years ≥51 kg: 12 mg daily; children ≥15 years <51 kg: 6 mg daily. IM: 75 mg per 2 weeks).
CYP2D6 poor metabolisers Increased plasma concentration of active moiety (risperidone plus 9-hydroxyrisperidone) and increases the proportion of risperidone in this ratio. Use 67% of standard dose; if problematic CNS adverse effects occur, reduce dose further to 50% of standard dose.

In contrast, the FDA drug label annotation for risperidone states that although extensive metabolisers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolisers, the concentration of the active moiety does not substantially differ by CYP2D6 status therefore no dosing adjustment is needed.
Renal Impairment
Oral:
Schizophrenia; Acute manic or mixed episodes of bipolar disorder:
Initial and subsequent doses must be halved. Dose titration must be slower.

 CrCl (mL/min)  Dosage
 <30 Initially, 0.5 mg bid, may be increased gradually in increments of 0.5 mg (or less) bid, if necessary; for doses >1.5 mg bid, dose increase must be done at intervals of at least 1 week.

Dosing recommendation may vary among countries and individual products, refer to local treatment or specific product guidelines.

Persistent aggression associated with dementia in Alzheimer’s disease:
Initial and subsequent doses must be halved. Dose titration must be slower.

Conduct disorder; Irritability associated with autistic disorder:
Dosing adjustment may be required.

IM:
Initiate 1st with oral risperidone (0.5 mg bid for the 1st week followed by 1 mg bid or 2 mg once daily for the 2nd week). If total daily dose of at least 2 mg oral risperidone is well tolerated, dose of 25 mg inj every 2 weeks may be given. Continue oral supplementation for 3 weeks after the 1st inj until the main release from the inj site has begun.

SC:
Initiate 1st with oral risperidone and carefully titrate up to at least 3 mg daily. If tolerated and patient is psychiatrically stable, dose of 90 mg inj once monthly may be considered.
Hepatic Impairment
Oral:
Schizophrenia; Acute manic or mixed episodes of bipolar disorder:
Initial and subsequent doses must be halved. Dose titration must be slower. Severe (Child-Pugh class C): Initially, 0.5 mg bid, may be increased gradually in increments of 0.5 mg (or less) bid, if necessary; for doses >1.5 mg bid, dose increase must be done at intervals of at least 1 week. Dosing recommendation may vary among countries and individual products, refer to local treatment or specific product guidelines.

Persistent aggression associated with dementia in Alzheimer’s disease:
Initial and subsequent doses must be halved. Dose titration must be slower.

Conduct disorder; Irritability associated with autistic disorder:
Dosing adjustment may be required.

IM:
Initiate 1st with oral risperidone (0.5 mg bid for the 1st week followed by 1 mg bid or 2 mg once daily for the 2nd week). If total daily dose of at least 2 mg oral risperidone is well tolerated, dose of 25 mg inj every 2 weeks may be given. Continue oral supplementation for 3 weeks after the 1st inj until the main release from the inj site has begun.

SC:
Initiate 1st with oral risperidone and carefully titrate up to at least 3 mg daily. If tolerated and patient is psychiatrically stable, dose of 90 mg inj once monthly may be considered.
Administration
May be taken with or without food.
Special Precautions
Patient with known CV disease (e.g. conduction abnormalities, heart failure, prior MI or ischaemic heart disease), cerebrovascular diseases, risk factors for stroke, family history of QT prolongation; history of clinically significant low WBC or drug-induced leucopenia or neutropenia; Lewy body dementia, Parkinson’s disease, history of seizures or at risk of seizures (e.g. head trauma, brain damage, alcoholism); diabetes mellitus or its risk factors (e.g. obesity, family history), other disorders of glucose regulation; pre-existing hyperprolactinaemia, possible prolactin-dependent tumours; at risk of orthostatic hypotension, suicidal ideation (during initiation of therapy), or aspiration pneumonia. Patient subjected to dehydration or strenuous exercise, exposed to extreme heat, receiving drugs with anticholinergic effects, or undergoing cataract surgery. Avoid abrupt withdrawal. Renal and hepatic impairment. Children, elderly (particularly those with dementia). Pregnancy and lactation. CYP2D6 ultrarapid or poor metabolisers. Concomitant use with enzyme inhibitors or inducers.
Adverse Reactions
Significant: Altered cardiac conduction, prolonged QT interval; oesophageal dysmotility and aspiration; venous thromboembolism, neutropenia, leucopenia, extrapyramidal symptoms (e.g. parkinsonism, acute dystonic reactions, akathisia, tardive dyskinesia); falls, hyperglycaemia, diabetes mellitus or exacerbation of pre-existing diabetes, hyperprolactinaemia, hypersensitivity reactions, intraoperative floppy iris syndrome (in patients undergoing cataract surgery), orthostatic hypotension, priapism, impaired core body temperature regulation, weight gain.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Tachycardia.
Ear and labyrinth disorders: Ear infection, tinnitus, ear pain.
Eye disorders: Blurred vision, conjunctivitis.
Gastrointestinal disorders: Abdominal pain or discomfort, vomiting, nausea, diarrhoea, dyspepsia, dry mouth, toothache.
General disorders and administration site conditions: Oedema, pyrexia, chest pain, asthenia, fatigue; injection site reaction (e.g. pain, induration, swelling).
Infections and infestations: Influenza.
Investigations: Decreased weight, increased transaminases and gamma-glutamyltransferase.
Metabolism and nutrition disorders: Increased or decreased appetite.
Musculoskeletal and connective tissue disorders: Muscle spasms, musculoskeletal pain, back pain, arthralgia.
Nervous system disorders: Headache, sedation or somnolence, dizziness, tremor.
Psychiatric disorders: Insomnia, sleep disorder, agitation, depression, anxiety.
Renal and urinary disorders: Urinary incontinence, UTI, urinary retention.
Reproductive system and breast disorders: Amenorrhoea, galactorrhoea, decreased libido.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion, pneumonia, bronchitis, upper respiratory tract infection, sinusitis.
Skin and subcutaneous tissue disorders: Rash, erythema.
Vascular disorders: Hypertension.
Potentially Fatal: Cerebrovascular events (e.g. TIA, stroke), neuroleptic malignant syndrome, agranulocytosis.
Patient Counseling Information
This drug may cause somnolence, impaired judgment, thinking, or motor skills; if affected, do not drive or operate machinery.
Monitoring Parameters
Assess for personal and family history of obesity, diabetes, dyslipidaemia, hypertension, or CV disease. Monitor blood pressure (at baseline; repeat after 3 months then annually); weight, height, BMI, waist circumference; CBC, electrolytes, renal and liver function (as clinically indicated); fasting plasma glucose level/HbA1c and fasting lipid panel (at baseline; repeat after 3 months then as required). Evaluate mental status for depression, psychosis, and suicidal ideation. Assess any changes in menstruation, libido, development of galactorrhoea, erectile and ejaculatory function. Observe for signs of neuroleptic malignant syndrome, tardive dyskinesia, abnormal involuntary movements or parkinsonian signs. Perform ocular examination yearly in patients >40 years or every 2 years in younger patients.
Overdosage
Oral: Symptoms: Drowsiness, sedation, tachycardia, hypotension, extrapyramidal symptoms, QT prolongation, convulsions. Management: Supportive and symptomatic treatment. Establish and maintain clear airway, ensure adequate oxygenation and ventilation. If intake is less than 1 hour before, consider gastric lavage (after intubation, if the patient is unconscious) and administration of activated charcoal with laxative. Perform CV monitoring immediately including continuous ECG monitoring. Treat hypotension and circulatory collapse with IV fluids and/or sympathomimetic agents. Administer an anticholinergic agent in case of severe extrapyramidal symptoms.
Drug Interactions
May enhance effects of antihypertensives and CNS depressants. Increased risk of QT prolongation with antiarrhythmics (e.g. quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), TCAs (e.g. amitriptyline), tetracyclic antidepressants (e.g. maprotiline), certain antihistamines, certain antimalarials (e.g. quinine, mefloquine), other antipsychotics, and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesaemia) or bradycardia. May antagonise the actions of levodopa and other dopamine agonists. Plasma concentrations of the active antipsychotic fraction (risperidone plus 9-hydroxyrisperidone) may be decreased with carbamazepine and other CYP3A4 enzyme inducers (e.g. rifampicin, phenytoin, phenobarbital). Increased bioavailability with cimetidine, ranitidine. Increased plasma concentration with strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine), phenothiazines, verapamil; increased plasma concentrations of active antipsychotic fraction with strong CYP3A4 inhibitors (e.g. itraconazole). Concomitant use with psychostimulants (e.g. methylphenidate) may lead to extrapyramidal symptoms when adjusting one or both drugs.
Potentially Fatal: Increased risk of mortality with concomitant use of furosemide in elderly patients with dementia.
Food Interaction
May enhance CNS depressant effect of alcohol.
Action
Description: Risperidone is a benzisoxazole atypical antipsychotic and a selective monoaminergic antagonist that has high affinity for serotoninergic 5-HT2, dopaminergic D2, adrenergic (α1 and α2), and histaminergic H1 receptors. It has no affinity for cholinergic receptors.
Pharmacokinetics:
Absorption: Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: 70% (oral). Time to peak plasma concentration: Risperidone: Oral: Within 1-2 hours. SC: 4-6 hours (1st peak); 10-14 days (2nd peak).
Distribution: Rapidly distributed. Enters breast milk (small amounts). Volume of distribution: 1-2 L/kg. Plasma protein binding: Approx 90% (risperidone), 77% (9-hydroxyrisperidone); mainly to albumin and α1-acid glycoprotein (risperidone).
Metabolism: Extensively metabolised in the liver via hydroxylation mediated by CYP2D6 isoenzyme to 9-hydroxyrisperidone (main active metabolite); oxidative N-dealkylation is a minor metabolic pathway.
Excretion: Via urine (70%; 35-45% risperidone and 9-hydroxyrisperidone); faeces (14%). Elimination half-life: Risperidone: Approx 3 hours (oral); 9-11 days (SC). Active antipsychotic fraction: Approx 20 hours (oral); 3-6 days (IM).
Chemical Structure

Chemical Structure Image
Risperidone

Source: National Center for Biotechnology Information. PubChem Database. Risperidone, CID=5073, https://pubchem.ncbi.nlm.nih.gov/compound/Risperidone (accessed on Jan. 23, 2020)

Storage
Tab/oral solution: Store between 15-25°C. Protect from light and moisture. IM inj: Store between 2-8°C or below 25°C for <7 days before administration. Protect from light. SC inj: Store between 2-8°C or between 20-25°C for up to 7 days before administration. Storage recommendations for oral preparations may vary among countries or individual products. Refer to specific product guidelines.
MIMS Class
Antipsychotics
ATC Classification
N05AX08 - risperidone ; Belongs to the class of other antipsychotics.
References
Annotation of DPWG Guideline for Risperidone and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 22/01/2021.

Annotation of FDA Label for Risperidone and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 22/01/2021.

Anon. CYP2D6 - Risperidone (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 22/01/2021.

Anon. Risperidone. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 08/07/2020.

Anon. Risperidone. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 08/07/2020.

Buckingham R (ed). Risperidone. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/07/2020.

Janssen-Cilag (New Zealand) Ltd. Risperdal Consta Suspension for Injection data sheet 29 June 2020. Medsafe. http://www.medsafe.govt.nz. Accessed 20/01/2021.

Joint Formulary Committee. Risperidone. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 08/07/2020.

Perseris (Indivior Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/07/2020.

Risperdal 0.5 mg Film-coated Tablet (Janssen-Cilag Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/07/2020.

Risperdal 1mg/mL Oral Solution (Janssen-Cilag Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/07/2020.

Risperdal Consta (Janssen Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/07/2020.

Risperdal Consta 25 mg Powder and Solvent for Prolonged-release Suspension (Janssen-Cilag Ltd). MHRA. https://products.mhra.gov.uk. Accessed 08/07/2020.

Risperdal M-Tab Tablet, Orally Disintegrating, Solution (Janssen Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 08/07/2020.

Risperdal Tablet; Oral Solution (Johnson & Johnson Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 20/01/2021.

Risperidone 0.5 mg Orodispersible Tablets (Krka, d.d., Novo mesto). MHRA. https://products.mhra.gov.uk. Accessed 08/07/2020.

Risperidone 2 mg Tablets (Sandoz Limited). MHRA. https://products.mhra.gov.uk. Accessed 20/01/2021.

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Disclaimer: This information is independently developed by MIMS based on Risperidone from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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