Brand name: RisperDAL
Drug class: Atypical Antipsychotics
VA class: CN709
Chemical name: 3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8, 9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
Molecular formula: C₂₃H₂₇FN₄O₂
CAS number: 106266-06-2

Medically reviewed by Drugs.com on Nov 15, 2023. Written by ASHP.

Introduction

Benzisothiazol-derivative; atypical or second-generation antipsychotic agent.^{1 2 3 5 6 7 8 9 10 11 12 13 60}

Uses for Risperidone

Schizophrenia

Orally and IM (as extended-release injection) for the treatment of schizophrenia.^{1 3 4 5 6 8 12 23 28 29 60 103 118 119 120}

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).⁶⁰

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.^{18 60 126 127}

Bipolar Disorder

Orally for the treatment (alone or in combination with lithium or valproate) of acute manic or mixed episodes associated with bipolar I disorder (bipolar mania).^{1 99 100 101 121}

IM (as extended-release injection) for the maintenance treatment (alone or in combination with lithium or valproate) of bipolar I disorder.^{103 122 123}

Autistic Disorder

Orally for the management of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.^{1 31 33 105 106 107 108 124}

Risperidone Dosage and Administration

Administration

Administer orally or IM.^{1 103}

Oral Administration

Administer orally once or twice (in equally divided doses) daily without regard to meals.^{1 14}

Twice-daily administration may be helpful in pediatric patients with schizophrenia or bipolar mania who experience persistent somnolence.¹

Twice-daily administration also may minimize risk of orthostatic hypotension and syncope in geriatric patients and in patients with renal or hepatic impairment.¹

Do not remove orally disintegrating tablets from the blister until just prior to administration.¹ With dry hands, peel back the blister foil backing to expose the tablet.¹ Do not push the tablet through the foil, since this may damage the tablet.¹ Gently remove the tablet and immediately place on tongue, where it rapidly disintegrates in saliva, and then swallow with or without liquid.¹ Do not chew or divide orally disintegrating tablet.¹

Risperidone oral solution may be administered directly from the calibrated pipette provided by the manufacturer or mixed with a compatible beverage prior to administration.¹ (See Compatibility under Stability.)

IM Administration

Must be administered by a health care professional.¹⁰³

In patients who have never received oral risperidone, manufacturer recommends establishing tolerability with oral risperidone prior to initiating IM therapy with extended-release risperidone (Risperdal Consta).¹⁰³

Administer by deep IM injection into the deltoid (using the 1-inch needle supplied by the manufacturer) or the upper outer quadrant of the gluteal area (using the 2-inch needle supplied by the manufacturer) every 2 weeks, alternating arms or buttocks.¹⁰³ IM injections into the deltoid and gluteal areas are bioequivalent and, therefore, interchangeable.¹⁰³ Do not administer IV.¹⁰³ Take care to avoid inadvertent injection into a blood vessel.¹⁰³

Administer only with needle and other components of dose pack supplied by manufacturer.¹⁰³

Do not combine 2 different strengths of IM risperidone in a single administration.¹⁰³

Reconstitution

Consult manufacturer’s labeling for instructions for using components of dose pack for reconstitution.¹⁰³

Allow the risperidone dose pack to sit at room temperature for ≥30 minutes before reconstituting; do not warm any other way.¹⁰³

Reconstitute vial containing risperidone extended-release microspheres only with diluent in prefilled syringe supplied by manufacturer.¹⁰³ Inject entire contents of prefilled syringe and shake vial vigorously while holding plunger rod down with thumb for ≥10 seconds to ensure a homogeneous suspension (appears uniform, thick, milky).¹⁰³

Upon suspension in diluent, immediate use is necessary because suspension will settle over time.¹⁰³ Once reconstituted suspension is transferred to syringe and appropriate needle attached, shake syringe vigorously to resuspend drug just prior to administration.¹⁰³

Dosage

If risperidone is used concurrently with a CYP enzyme inducer or CYP2D6 inhibitor, dosage adjustment may be required.^{1 103} (See Interactions.)

If risperidone is reinitiated after a drug-free period, titrate oral dosage as with initial therapy.¹

Pediatric Patients

Schizophrenia

Oral

Adolescents ≥13 years of age: Initially, 0.5 mg once daily in the morning or evening.¹

Adjust dosage, if indicated, in increments of 0.5–1 mg daily at intervals of ≥24 hours to target dosage of 3 mg daily.¹

Dosages >3 mg daily did not result in greater efficacy and were associated with increased adverse effects.¹ Antipsychotic efficacy demonstrated in dosage range of 1–6 mg daily in clinical trials; dosages >6 mg daily not studied.¹

Twice-daily administration may be helpful in pediatric patients experiencing persistent somnolence.¹

Efficacy maintained for up to 2 years in adults, but optimum duration of therapy currently not known.^{1 23} In responding patients, continue therapy at the effective dosage; periodically reassess need for continued therapy.¹

Bipolar Disorder

Oral

Children and adolescents 10–17 years of age: Initially, 0.5 mg once daily in the morning or evening.¹

Adjust dosage, if indicated, in increments of 0.5–1 mg daily at intervals of ≥24 hours to target dosage of 1–2.5 mg daily.¹

Dosages >2.5 mg daily did not result in greater efficacy, but were associated with increased adverse effects.¹

Antimanic efficacy demonstrated in dosage range of 0.5–6 mg daily in clinical trials; dosages >6 mg daily not studied.¹

Twice-daily administration may be helpful in pediatric patients experiencing persistent somnolence.¹

If used for extended periods (i.e., >3 weeks), periodically reevaluate long-term risks and benefits for the individual patient.¹

Irritability associated with Autistic Disorder

Oral

Children ≥5 years of age and adolescents weighing <20 kg: Initially, 0.25 mg daily; may administer once daily or in divided doses twice daily.^{1 31 105} May increase dosage to 0.5 mg daily after ≥4 days; maintain this dosage for ≥14 days.¹ In patients not responding adequately, may increase dosage in increments of 0.25 mg daily in ≥2-week intervals.¹ Individualize dosage based on clinical response and tolerability; once adequate clinical response achieved and maintained, consider gradually reducing dosage.¹

Children ≥5 years of age and adolescents weighing ≥20 kg: Initially, 0.5 mg daily; may administer once daily or in divided doses twice daily.^{1 31 105} May increase dosage to 1 mg daily after ≥4 days; maintain this dosage for ≥14 days.¹ In patients not responding adequately, may increase dosage in increments of 0.5 mg daily in ≥2-week intervals.¹ Individualize dosage based on clinical response and tolerability; once adequate clinical response achieved and maintained, consider gradually reducing dosage.¹

Overall efficacy demonstrated in dosage range of 0.5–3 mg daily.^{1 31 105} In the main clinical trials, 90% of patients who responded to therapy received dosages from 0.5–2.5 mg daily.^{31 105} Maximum daily dosage (i.e., when therapeutic effect reached a plateau) in one trial was 1 mg in patients weighing <20 kg, 2.5 mg in patients weighing ≥20 kg, and 3 mg in patients weighing >45 kg.³¹

Dosing data not available for children weighing <15 kg.¹

Patients experiencing persistent somnolence may benefit from a once-daily dosage administered at bedtime, administering half the daily dosage twice daily, or a reduction in dosage.¹

If used for extended periods, periodically reevaluate long-term risks and benefits for the individual patient.^{1 115}

Adults

Schizophrenia

Oral

Initially, 2 mg daily (as 2 mg once daily or 1 mg twice daily), with increases in increments of 1–2 mg daily at intervals of ≥24 hours, as tolerated, to target dosage of 4–8 mg daily (once daily or in 2 equally divided doses) recommended by manufacturers.^{1 115} The manufacturers state that slower dosage titration may be appropriate in certain patients.^{1 115}

Alternatively, an initial dosage of 1–2 mg daily, with increases in increments of 0.5–1 mg daily titrated over 6–7 days, as tolerated, to target dosage of 4 mg daily may be more appropriate in most otherwise healthy adults.³⁰

Lower initial dosages (e.g., 1 mg daily) and slower dosage titrations to an initial target dosage of 2 mg daily may be appropriate for younger patients and those being treated for their first psychotic episode.³⁰ Titrate dosage up to 4 mg daily depending on clinical response and adverse neurologic effects; 1–3 mg daily may be optimal.³⁰

Efficacy generally observed in dosage range of 4–16 mg daily; dosages >6 mg daily (given twice daily) did not result in greater efficacy, but were associated with increased adverse effects (e.g., extrapyramidal symptoms) and are generally not recommended.^{1 15 30} In a study of once-daily dosing, efficacy of 8-mg dosage generally was better than for 4-mg dosage.¹

Efficacy maintained for up to 2 years in adults, but optimum duration of therapy currently not known.^{1 23} In responding patients, continue therapy at their effective dosage; periodically reassess need for continued therapy.¹

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.⁶⁰ Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.⁶⁰ Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.⁶⁰

IM

Usual initial and maintenance dosage: 25 mg IM every 2 weeks.¹⁰³

Some patients not responding to the usual dosage may benefit from an increased dosage of 37.5 or 50 mg IM every 2 weeks, although dose response for efficacy not established.¹⁰³ Dosages >50 mg IM every 2 weeks did not demonstrate greater efficacy, but were associated with increased adverse effects.¹⁰³

Increase dosage at intervals of ≥4 weeks.¹⁰³ Clinical effects of the increased dosage generally occur ≥3 weeks after the first injection at the higher dosage.¹⁰³

Consider lower initial dosage of 12.5 mg IM every 2 weeks and maintenance dosages ≥12.5 mg every 2 weeks when clinical factors warrant (e.g., hepatic or renal impairment, concurrent use of drugs that increase plasma risperidone concentrations, history of poor tolerability to psychotropic drugs).¹⁰³ However, efficacy of the 12.5-mg IM dosage not evaluated in clinical trials.¹⁰³ (See Special Populations under Dosage and Administration and also see Interactions.)

Administer oral risperidone (or another antipsychotic agent) with the first IM risperidone injection and continue oral therapy for 3 weeks thereafter to ensure adequate therapeutic plasma concentrations are maintained prior to main release of risperidone from injection site.¹⁰³ (See Bioavailability and Plasma Concentrations under Pharmacokinetics.)

Periodically reevaluate need for continuing any concomitant therapy for managing extrapyramidal manifestations.¹⁰³

If reinitiating IM risperidone after a drug-free period, administration of oral risperidone (or another antipsychotic agent) initially for supplementation will be needed.¹⁰³

Bipolar Disorder

Acute Manic or Mixed Episodes

Oral

As monotherapy or adjunctive therapy with lithium or valproate, initially 2–3 mg once daily.^{1 99 100 101}

Adjust dosage, if indicated, in increments or decrements of 1 mg daily at intervals of ≥24 hours.^{1 99}

Antimanic efficacy demonstrated in dosage range of 1–6 mg daily; dosages >6 mg daily not studied.^{1 99}

If used for extended periods (i.e., >3 weeks), periodically reevaluate long-term risks and benefits for the individual patient.^{1 115}

Maintenance Treatment

IM

As monotherapy or adjunctive therapy with lithium or valproate, 25 mg IM every 2 weeks.¹⁰³

Lower initial dosage of 12.5 mg IM every 2 weeks may be appropriate in certain patients (e.g., renal or hepatic impairment, concurrent use of drugs that can increase risperidone plasma concentrations); however, efficacy of this dosage not systematically evaluated in clinical trials.¹⁰³ (See Hepatic Impairment and Renal Impairment under Dosage and Administration, and also see Interactions.)

Administer oral risperidone (or another antipsychotic agent) with the first IM risperidone injection and continue oral therapy for 3 weeks thereafter to ensure adequate therapeutic plasma concentrations are maintained prior to main release of risperidone from injection site.¹⁰³ (See Bioavailability and Plasma Concentrations under Pharmacokinetics.)

Some patients not responding to 25 mg may benefit from dosages of 37.5 or 50 mg IM every 2 weeks, although dose response for efficacy not established.¹⁰³

Dosages >50 mg IM every 2 weeks not studied.¹⁰³

Increase dosage at intervals of ≥4 weeks.¹⁰³ Clinical effects of the increased dosage generally occur ≥3 weeks after the first injection at the higher dosage.¹⁰³

If reinitiating IM risperidone after a drug-free period, administration of oral risperidone (or another antipsychotic agent) initially for supplementation will be needed.¹⁰³

If used for extended periods, periodically reevaluate long-term risks and benefits for the individual patient.¹⁰³

Prescribing Limits

Pediatric Patients

Schizophrenia

Oral

Adolescents ≥13 years of age: Dosages >3 mg daily generally not recommended; safety and efficacy of dosages >6 mg daily not established.¹

Bipolar Disorder

Acute Manic or Mixed Episodes

Oral

Children and adolescents 10–17 years of age: Dosages >2.5 mg daily generally not recommended; safety and efficacy of dosages >6 mg daily not established.¹

Irritability associated with Autistic Disorder

Oral

Children ≥5 years of age and adolescents: Safety and efficacy of dosages >3 mg daily not established.^{1 31 105}

Adults

Schizophrenia

Oral

Dosages >6 mg daily (given in 2 divided doses) generally not recommended; safety of dosages >16 mg daily not established.¹

IM

Maximum 50 mg every 2 weeks.¹⁰³

Bipolar Disorder

Acute Manic or Mixed Episodes

Oral

Safety and efficacy of dosages >6 mg daily not established.¹

Maintenance Treatment

IM

Maximum 50 mg every 2 weeks.¹⁰³

Special Populations

Hepatic Impairment

Oral: Initially, 0.5 mg twice daily in patients with severe hepatic impairment (Child-Pugh score 10–15); increase dosage in increments of ≤0.5 mg, administered twice daily.¹ If increase in dosage beyond 1.5 mg twice daily is planned, adjust at intervals of ≥1 week.¹

IM: Titrate oral therapy prior to initiation of IM therapy in patients with hepatic impairment.¹⁰³ Initially, 0.5 mg twice daily during the first week; may increase to 1 mg twice daily or 2 mg once daily during the second week.¹⁰³ If an oral dosage of ≥2 mg daily is well tolerated, administer 25 mg IM every 2 weeks.¹⁰³ In some patients, slower titration may be medically appropriate.¹⁰³ Alternatively, initial dosage of 12.5 mg IM every 2 weeks; however, efficacy of this dosage not evaluated in clinical trials.¹⁰³ Administer oral risperidone with the first IM risperidone injection and continue oral supplementation for 3 weeks thereafter.¹⁰³

Renal Impairment

Oral: Initially, 0.5 mg twice daily in patients with severe renal impairment (Cl_cr <30 mL/minute); increase dosage in increments of ≤0.5 mg, administered twice daily.¹ If increase in dosage beyond 1.5 mg twice daily is planned, adjust at intervals of ≥1 week.¹

IM: Titrate oral therapy prior to initiation of IM therapy in patients with renal impairment.¹⁰³ Initially, 0.5 mg twice daily during the first week; may increase to 1 mg twice daily or 2 mg once daily during the second week.¹⁰³ If an oral dosage of ≥2 mg daily is well tolerated, administer 25 mg IM every 2 weeks.¹⁰³ In some patients, slower titration may be medically appropriate.¹⁰³ Alternatively, initial dosage of 12.5 mg IM every 2 weeks; however, efficacy of this dosage not evaluated in clinical trials.¹⁰³ Administer oral risperidone with the first IM risperidone injection and continue oral supplementation for 3 weeks thereafter.¹⁰³

Geriatric Patients and Others at Risk of Orthostatic Hypotension

Oral: Initially, 0.5 mg twice daily to minimize risk of orthostatic hypotension in geriatric and other patients at risk of orthostatic hypotension.¹

Alternatively, in geriatric patients, initially give 0.25 mg orally daily; gradually increase dosage as tolerated.³⁰

In otherwise healthy adults, may reduce risk of orthostatic hypotension and syncope by limiting initial oral dosage to 2 mg daily (given once or twice daily).¹

IM: 25 mg every 2 weeks in otherwise healthy geriatric patients.¹⁰³ Administer oral risperidone with the first IM risperidone injection and continue oral supplementation for 3 weeks thereafter.¹⁰³

Cautions for Risperidone

Contraindications

• Known hypersensitivity to risperidone.^{1 103}

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.^{1 98 103 125}

Antipsychotic agents, including risperidone, are not approved for the treatment of dementia-related psychosis.^{1 98 103 125} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and also see Dysphagia under Cautions.)

Sensitivity Reactions

Hypersensitivity reactions, including anaphylactic reactions and angioedema, reported.¹

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with risperidone in placebo-controlled studies.^{1 14 38 103} Risperidone is not approved for the treatment of patients with dementia-related psychosis.^{1 103} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including risperidone.^{1 103}

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs.^{1 103} Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.^{1 103}

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including risperidone.^{1 21}

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.¹ In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.¹

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.⁶⁰ Consider discontinuance of risperidone if signs and symptoms of tardive dyskinesia appear.¹ However, some patients may require treatment despite presence of the syndrome.¹

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).^{1 103} While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.^{1 103} (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including risperidone.^{1 44 45 46 47 48 49 50 51 52 53 54 55 56 57 71 72 73 74 78 97 103}

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).^{1 45 46 47 48 49 50 51 52 53 54 55 56 103} If manifestations of hyperglycemia occur in any risperidone-treated patient, perform fasting blood glucose testing.^{1 45 46 47 48 49 50 51 52 53 54 55 56 103} (See Advice to Patients.)

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.^{1 45 46 47 48 49 50 51 52 53 54 55 56 78 103}

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with atypical antipsychotics.^{1 103}

Weight Gain

Weight gain observed with atypical antipsychotic therapy, including risperidone.^{1 103 115}

In clinical studies in adults with schizophrenia or bipolar mania, 8.7 and 20.9% of patients treated with 1–8 mg and >8–16 mg daily of oral risperidone, respectively, gained ≥7% of their baseline body weight compared with 2.9% of patients who received placebo.¹

In pediatric clinical studies, approximately 33% of children and adolescents treated with risperidone gained ≥7% of their baseline body weight compared with approximately 7% of pediatric patients who received placebo.¹ (See Pediatric Use under Cautions.)

The manufacturers recommend monitoring of weight during risperidone therapy.^{1 103 115} (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Hyperprolactinemia

May cause elevated serum prolactin concentrations in children, adolescents, and adults, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence).^{1 103} (See Pediatric Use under Cautions.) Chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both females and males.^{1 103}

Risperidone appears to be associated with higher levels of prolactin elevation than other antipsychotic agents.^{1 103}

If contemplating risperidone therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro.^{1 103}

Orthostatic Hypotension

Orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period with oral risperidone, reported, probably reflecting the drug’s α-adrenergic antagonistic properties.^{1 103} Syncope reported in 0.2 and 0.8% of patients receiving oral and extended-release IM risperidone, respectively, in clinical studies.^{1 103}

Use with particular caution in patients with known cardiovascular disease (e.g., history of MI or ischemic heart disease, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that predispose patients to hypotension (e.g., dehydration, hypovolemia).^{1 103}

Clinically important hypotension observed with concomitant use of oral risperidone and antihypertensive therapy.^{1 103}

May reduce risk of orthostatic hypotension and syncope by limiting initial oral dosage to 2 mg daily (given as 2 mg once daily or 1 mg twice daily) in otherwise healthy adults and to 0.5 mg twice daily in geriatric patients and patients with renal or hepatic impairment.¹ (See Special Populations under Dosage and Administration.)

Consider monitoring orthostatic vital signs in patients at risk of orthostatic hypotension and reducing oral or extended-release IM risperidone dosage if hypotension occurs.^{1 103} (See Advice to Patients.)

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including risperidone, reported during clinical trial and/or postmarketing experience.^{1 103 116 117} Agranulocytosis also reported.^{1 103}

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.^{1 103 116} Monitor CBC frequently during the first few months of therapy in patients with such risk factors.^{1 103} Discontinue risperidone at the first sign of a decline in WBC count in the absence of other causative factors.^{1 103}

Carefully monitor patients with clinically important neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.^{1 103} Discontinue risperidone if severe neutropenia (ANC <1000/mm³) occurs; monitor WBC until recovery occurs.^{1 103}

Cognitive and Motor Impairment

Dose-related somnolence commonly occurs with oral risperidone (reported in 41% of patients receiving risperidone 16 mg daily in one study).¹ In patients receiving extended-release IM risperidone in multiple-dose studies, somnolence reported in 5% of patients.¹⁰³

Judgment, thinking, or motor skills may be impaired.^{1 103} (See Specific Drugs under Interactions and also see Advice to Patients.)

Seizures

Seizures reported in 0.3% of risperidone-treated patients in clinical trials.^{1 103} Use with caution in patients with a history of seizures.^{1 103}

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.^{1 103}

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer’s dementia.^{1 103} Use with caution in patients at risk for aspiration pneumonia.^{1 103} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Priapism

Priapism reported; may require surgical intervention in severe cases.^{1 103 111}

Body Temperature Regulation

Disruption of ability to regulate body temperature possible with antipsychotic agents; both hyperthermia and hypothermia reported with oral and extended-release IM risperidone therapy.^{1 103} Use with caution in patients who may be exposed to temperature extremes.^{1 103}

Thrombotic Thrombocytopenic Purpura (TTP)

TTP reported in at least one patient; relationship to risperidone not established.¹⁰³

Antiemetic Effect

Antiemetic effect demonstrated in animals; also may occur in humans and mask manifestations of overdosage with certain drugs or of underlying conditions (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).¹⁰³

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients.¹⁰³

Phenylketonuria

Orally disintegrating tablets contain aspartame (e.g., NutraSweet), which is metabolized in the GI tract to provide phenylalanine; consult manufacturer's labeling for specific information regarding phenylalanine content of individual preparations and dosage strengths.^{1 39 40 41 42 43 115} (See Advice to Patients.)

Osteodystrophy and Tumors in Animals

Osteodystrophy, renal tubular tumors, and adrenomedullary pheochromocytomas demonstrated in rats following IM administration of extended-release risperidone; not observed previously with oral risperidone.¹⁰³ Relevance to humans currently not known.¹⁰³

Concomitant Illnesses

Experience in patients with certain concomitant diseases is limited.¹⁰³

Patients with parkinsonian syndrome or dementia with Lewy bodies reportedly have an increased sensitivity to antipsychotic agents.^{1 103} Clinical manifestations of increased sensitivity reportedly include confusion, obtundation, postural instability with frequent falls, extrapyramidal adverse effects, and clinical features consistent with NMS.^{1 103}

Patients with recent history of MI or unstable heart disease generally were excluded from premarketing clinical studies.¹⁰³ Use with caution in patients with altered metabolism or hemodynamics.¹⁰³

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarities in both the trade (brand) and generic (nonproprietary) names, similarities in container labels and carton packaging, illegible handwriting on prescriptions, overlapping product characteristics (e.g., drug strengths, dosage forms, dosage intervals) between risperidone (Risperdal) and ropinirole hydrochloride (Requip, a dopamine receptor agonist used in the treatment of parkinsonian syndrome and restless legs syndrome), and stocking close to one another on pharmacy shelves may result in medication errors.¹¹⁰ These errors have required hospitalization in some cases.¹¹⁰

Specific Populations

Pregnancy

Category C.^{1 103}

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.^{1 103 112 113 114} Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.^{1 103 112 113 114}

Lactation

Risperidone and an active metabolite (9-hydroxyrisperidone) are distributed into milk.^{1 103 115} Discontinue nursing or the drug.^{1 115} Women receiving extended-release IM risperidone should not breast-feed during and for at least 12 weeks after the last injection.¹⁰³

Pediatric Use

Oral: Safety and efficacy not established in pediatric patients <13 years of age with schizophrenia or <10 years of age with bipolar mania.¹ Safety and efficacy not established in pediatric patients <5 years of age for the treatment of irritability associated with autistic disorder.^{1 31 33 105 124}

IM: Safety and efficacy not established in pediatric patients <18 years of age.¹⁰³

Somnolence frequently occurred in controlled trials of oral risperidone in pediatric patients; most cases were mild to moderate in severity, occurred early (i.e., within first 2 weeks) during therapy, and were transient.¹ Pediatric patients experiencing persistent somnolence may benefit from a change in dosage regimen.¹ (See Administration under Dosage and Administration.)

Dose-dependent prolactin elevations reported in 49–87% of pediatric patients receiving oral risperidone in clinical studies compared with 2–7% of placebo recipients; galactorrhea (0.8%) and gynecomastia (2.3%) also reported.¹ Long-term effects on growth and sexual maturation unknown.¹ (See Hyperprolactinemia under Cautions.)

Weight gain ≥7% from baseline occurred in approximately 33% of pediatric patients in short-term clinical trials, and in longer-term schizophrenia trials, a mean weight gain of 9 kg after 8 months was reported.¹ The manufacturers recommend assessing weight gain against that expected with normal growth when treating pediatric patients with risperidone for any indication.^{1 115} (See Weight Gain under Cautions.)

Geriatric Use

Insufficient experience with oral risperidone in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Use with caution due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.¹

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;^{1 98 103 125} increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents.^{1 103} Risperidone is not approved for the treatment of patients with dementia-related psychosis.^{1 98 103 125} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and also see Dysphagia under Cautions.)

Minimize risk of orthostatic hypotension with lower initial oral dosage and careful dosage titration; monitor orthostatic vital signs in patients receiving oral or IM risperidone for whom hypotension is a concern.^{1 103} (See Special Populations under Dosage and Administration and see Orthostatic Hypotension under Cautions.)

No differences in tolerability of extended-release IM risperidone were observed in one study in patients ≥65 years of age with schizophrenia or schizoaffective disorder; no dosage adjustment recommended for otherwise healthy geriatric patients.¹⁰³

Increased mortality reported in geriatric patients receiving oral risperidone concomitantly with furosemide (but not other diuretics) for the management of dementia-related psychosis.^{1 103}

Hepatic Impairment

Possible increases in risperidone free fraction, resulting in enhanced effect; dosage adjustment recommended.^{1 103} (See Special Populations under Dosage and Administration.)

Renal Impairment

Possible decreased elimination compared with healthy adults; dosage adjustment recommended.^{1 103} (See Special Populations under Dosage and Administration.)

Common Adverse Effects

Oral risperidone therapy in adults with schizophrenia: Nausea,¹ parkinsonism,¹ akathisia,¹ sedation,¹ dizziness.¹

Oral risperidone therapy in pediatric patients with schizophrenia: Salivary hypersecretion,^{1 118} sedation,^{1 118} parkinsonism,^{1 118} akathisia,^{1 118} dizziness,^{1 118} dystonia,^{1 118} anxiety.^{1 118}

Oral risperidone therapy for manic or mixed episodes associated with bipolar disorder in adults (as monotherapy or adjunctive therapy with mood stabilizers [e.g., lithium, valproate]): Nausea,¹ parkinsonism,¹ sedation,¹ akathisia,¹ tremor,¹ dystonia,¹ dizziness,¹ pharyngolaryngeal pain.¹

Oral risperidone therapy for manic or mixed episodes associated with bipolar disorder in pediatric patients (as monotherapy): Blurred vision,¹ upper abdominal pain,¹ nausea,¹ vomiting,¹ diarrhea,¹ dyspepsia,¹ stomach discomfort,¹ fatigue,¹ increased appetite,¹ sedation,¹ dizziness,¹ parkinsonism,¹ dystonia,¹ akathisia,¹ anxiety,¹ pharyngolaryngeal pain,¹ rash.¹

Oral risperidone therapy for irritability associated with autistic disorder in children and adolescents: Constipation,¹ dry mouth,¹ salivary hypersecretion,¹ fatigue,¹ nasopharyngitis,¹ upper respiratory tract infection,¹ weight gain,¹ increased appetite,¹ sedation,¹ drooling,¹ tremor,¹ dizziness,¹ parkinsonism,¹ nasal congestion.¹

Extended-release IM therapy in adults with schizophrenia: Headache,¹⁰³ parkinsonism,¹⁰³ dizziness,¹⁰³ akathisia,¹⁰³ fatigue,¹⁰³ constipation,¹⁰³ dyspepsia,¹⁰³ sedation,¹⁰³ weight gain,¹⁰³ pain in extremities,¹⁰³ dry mouth.¹⁰³

Extended-release IM therapy in adults with bipolar disorder: Weight gain (5% in monotherapy trial),¹⁰³ tremor (≥10% in adjunctive therapy trial),¹⁰³ parkinsonism (≥10% in adjunctive therapy trial).¹⁰³

Drug Interactions

Metabolized by CYP2D6 to 9-hydroxyrisperidone, which has similar pharmacologic activity.^{1 103} May weakly inhibit CYP2D6.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacokinetic interaction (altered risperidone metabolism and plasma concentrations of the active moiety [risperidone plus 9-hydroxyrisperidone]; increased plasma concentrations of risperidone likely).¹ Adjust oral risperidone dosage during concurrent use.¹ (See Specific Drugs under Interactions and see Metabolism under Pharmacokinetics.)

Inducers of CYP enzymes: Potential pharmacokinetic interaction (decreased plasma concentrations of risperidone).^{1 103} Increase oral risperidone dosage up to twice original dosage when administered concurrently with enzyme inducers (e.g., CYP3A inducers); a reduction in oral risperidone dosage may be necessary when the enzyme inducer is discontinued.¹ Patients receiving IM risperidone may need dosage increase or supplemental oral risperidone when therapy with an enzyme inducer is initiated; consider reducing IM risperidone dosage 2–4 weeks before discontinuance of the enzyme inducer.¹⁰³ (See Specific Drugs under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP2D6: Substantial pharmacokinetic interaction unlikely.¹

In vitro, drugs metabolized by CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 only weakly inhibit risperidone metabolism.¹

Specific Drugs1 103

Risperidone Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration, with peak plasma concentrations of risperidone attained in approximately 1 hour.¹

Mean peak plasma concentrations of the major active metabolite, 9-hydroxyrisperidone, occur at about 3 and 17 hours in patients who are extensive and poor metabolizers of CYP2D6, respectively.¹ Steady state of risperidone reached in 1 day in extensive metabolizers and expected in 5 days in poor metabolizers; 9-hydroxyrisperidone steady state reached in 5–6 days in extensive metabolizers.¹

Absolute bioavailability is 70%; relative oral bioavailability from a tablet is 94% compared with a solution.¹

Commercially available conventional and orally disintegrating tablets and oral solution are bioequivalent.¹

After IM administration, there is a small initial release of the drug (<1% of dose) followed by a 3-week lag time; main drug release starts from 3 weeks onward and is maintained for 4–6 weeks and then subsides by 7 weeks after the injection.¹⁰³

IM injections into the deltoid and gluteal areas are bioequivalent.¹⁰³

Food

Food does not affect rate or extent of absorption.¹

Plasma Concentrations

With IM administration of extended-release risperidone injection every 2 weeks, steady-state plasma concentrations achieved after 4 doses and are maintained 4–6 weeks after the last injection.¹⁰³

Distribution

Extent

Rapidly distributed.^{1 103} Crosses the placenta in rats; not known if crosses the placenta in humans.¹ Risperidone and its active metabolite distribute into milk.^{1 103 115}

Plasma Protein Binding

Approximately 90% (mainly albumin and α₁-acid glycoprotein); major active metabolite (9-hydroxyrisperidone) is 77% protein bound.^{1 103}

Elimination

Metabolism

Extensively metabolized, principally in the liver via CYP2D6, to an active metabolite (9-hydroxyrisperidone); N-dealkylation is minor metabolic pathway.^{1 128}

9-Hydroxyrisperidone has similar pharmacologic activity to parent drug and is commercially available as paliperidone (another atypical antipsychotic agent); clinical effects result from combined concentrations of risperidone and 9-hydroxyrisperidone (active antipsychotic moiety).^{1 103 128}

Elimination Route

Excreted principally in urine (70%) and to much lesser extent, in feces (14%).¹

Half-life

After oral administration, overall mean elimination half-life for active moiety (risperidone plus 9-hydroxyrisperidone) is about 20 hours.¹

After IM administration, apparent half-life of active moiety is 3–6 days.¹⁰³ Elimination phase is complete approximately 7–8 weeks after last injection.¹⁰³

Special Populations

In patients with moderate to severe renal impairment (Cl_cr 15–59 mL/minute), total active moiety clearance (risperidone plus 9-hydroxyrisperidone) is decreased by 60% compared with that of young healthy adults.^{1 103} (See Special Populations under Dosage and Administration.)

In patients with hepatic impairment, pharmacokinetics were similar to those in young healthy adults; however, the mean free-fraction of risperidone in plasma was increased by about 35% due to diminished albumin and α₁-acid glycoprotein concentrations.¹ Dosage adjustment recommended.¹ (See Special Populations under Dosage and Administration.)

In geriatric patients receiving oral risperidone, renal clearance was decreased and half-lives were prolonged for both risperidone and its active metabolite compared with younger adults.¹ Adjust dosage accordingly.¹ However, in otherwise healthy patients ≥65 years of age treated with IM risperidone for up to 12 months, pharmacokinetics were similar to younger adults; no dosage adjustment recommended in such patients.¹⁰³

CYP2D6 is subject to genetic polymorphism; extensive metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, while poor metabolizers convert it much more slowly.¹ Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations, the pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) are similar after single and multiple doses in extensive and poor metabolizers.¹

Stability

Storage

Oral

Conventional Tablets

15–25°C.¹ Protect from light and moisture.¹

Orally Disintegrating Tablets

15–25°C.¹ Store in original sealed blister.¹

Solution

15–25°C.¹ Protect from light and freezing.¹

Parenteral

Extended-release Injection

Store entire dose pack at 2–8°C; protect from light.¹⁰³ If refrigeration unavailable, store at temperatures not >25°C for ≤7 days prior to administration.¹⁰³ Do not expose unrefrigerated product to temperatures >25°C.¹⁰³

After mixing with diluent, use within 6 hours of suspension; do not expose to temperatures >25°C.¹⁰³

Compatibility

Oral

Solution

May be mixed with water, coffee, orange juice, or low-fat milk.¹ Not compatible with cola or tea.¹

Actions

• Exact mechanism of antipsychotic action has not been fully elucidated; may involve antagonism of central type 2 serotonergic (5-HT₂) receptors and central dopamine D₂ receptors.^{1 2 3 8 10 12 13 15 103}

• Antagonism at other receptors (e.g., α₁- and α₂-adrenergic receptors, histamine H₁ receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).^{1 103}

• Exhibits low to moderate affinity for other serotonin receptor subtypes (e.g., 5HT_1C, 5HT_1A, 5HT_1D), and weak affinity for dopamine D₁ receptors and the haloperidol-sensitive sigma site.^{1 103} Possesses no affinity for cholinergic muscarinic or β₁- and β₂-adrenergic receptors.^{1 103}

Advice to Patients

• Importance of advising patients and caregivers that elderly patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.^{1 60 98 125} Inform patients and caregivers that risperidone is not approved for treating elderly patients with dementia-related psychosis.^{1 98 103 125}

• Risk of somnolence.^{1 103} Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with drug’s effects.^{1 103}

• Risk of orthostatic hypotension.^{1 103} Importance of using nonpharmacologic methods (e.g., sitting on edge of bed for several minutes upon waking, slowly rising from sitting to standing position) to minimize effects.¹⁰³

• Risk of leukopenia/neutropenia.^{1 103} Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia of the need for CBC monitoring during risperidone therapy.^{1 103}

• Importance of avoiding alcohol during risperidone therapy.^{1 103}

• Importance of using caution if patients are exposed to extreme temperatures.^{1 103}

• Importance of informing patients with phenylketonuria and their caregivers that risperidone orally disintegrating tablets contain aspartame.^{1 39 40 41 42 43}

• Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain).¹

• Importance of informing patients and caregivers of risk of tardive dyskinesia.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (see Interactions) or OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular or cerebrovascular disease, diabetes mellitus, seizures, dementia).^{1 103}

• Importance of women informing clinicians if they are or plan to become pregnant during oral or IM risperidone therapy or within 12 weeks after last long-acting IM injection of risperidone.^{1 103}

• Breast-feeding not recommended.^{1 103} Importance of women informing clinicians if they are or plan to breast-feed during oral or IM risperidone therapy or within 12 weeks after last long-acting IM injection of risperidone.^{1 103}

• Importance of informing patients of other important precautionary information.^{1 103 115} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Frequently asked questions

• What is the difference between Perseris and Risperdal Consta?

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