Generic Name: RISPERIDONE
Brand Name: RISPERDAL
- Substance Name(s):
- RISPERIDONE
DRUG INTERACTIONS
7 Due to CNS effects, use caution when administering with other centrally-acting drugs.
Avoid alcohol.
(7.1) Due to hypotensive effects, hypotensive effects of other drugs with this potential may be enhanced.
(7.2) Effects of levodopa and dopamine agonists may be antagonized.
(7.3) Cimetidine and ranitidine increase the bioavailability of risperidone.
(7.5) Clozapine may decrease clearance of risperidone.
(7.6) Fluoxetine and paroxetine increase plasma concentrations of risperidone.
(7.10) Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone.
(7.11) 7.1 Centrally-Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively.
However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.
7.6 Clozapine Chronic administration of clozapine with RISPERDAL® may decrease the clearance of risperidone.
7.7 Lithium Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21).
However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERDAL®.
7.9 Digoxin RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.
7.10 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology (12.3)].
Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone.
Analysis of clinical studies involving a modest number of poor metabolizers (n≅70) does not suggest that poor and extensive metabolizers have different rates of adverse effects.
No comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold, respectively.
Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.
Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%.
When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL®.
The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin There were no significant interactions between RISPERDAL® and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers Carbamazepine co-administration decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%.
Plasma concentrations of carbamazepine did not appear to be affected.
The dose of RISPERDAL® may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy.
Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® treatment.
7.12 Drugs Metabolized by CYP 2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6.
Therefore, RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway.
In drug interaction studies, RISPERDAL® did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
OVERDOSAGE
10 10.1 Human Experience Premarketing experience included eight reports of acute RISPERDAL® overdosage with estimated doses ranging from 20 to 300 mg and no fatalities.
In general, reported signs and symptoms were those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS.
Another case, involving an estimated overdose of 36 mg, was associated with a seizure.
Postmarketing experience includes reports of acute RISPERDAL® overdosage, with estimated doses of up to 360 mg.
In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug’s known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms.
Other adverse reactions reported since market introduction related to RISPERDAL® overdose include prolonged QT interval and convulsions.
Torsade de pointes has been reported in association with combined overdose of RISPERDAL® and paroxetine.
10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation.
Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
Because of the rapid disintegration of RISPERDAL® M-TAB®Orally Disintegrating Tablets, pill fragments may not appear in gastric contents obtained with lavage.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects that might be additive to those of risperidone.
Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.
There is no specific antidote to RISPERDAL®.
Therefore, appropriate supportive measures should be instituted.
The possibility of multiple drug involvement should be considered.
Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade).
In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.
Close medical supervision and monitoring should continue until the patient recovers.
DESCRIPTION
11 RISPERDAL® contains risperidone, a psychotropic agent belonging to the chemical class of benzisoxazole derivatives.
The chemical designation is 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.
Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49.
The structural formula is: Risperidone is a white to slightly beige powder.
It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.
RISPERDAL® Tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths.
RISPERDAL® tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn).
The 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg tablets also contain talc and titanium dioxide.
The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No.
6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No.
10; the 4 mg tablets contain FD&C Blue No.
2 Aluminum Lake.
RISPERDAL® is also available as a 1 mg/mL oral solution.
RISPERDAL® Oral Solution contains the following inactive ingredients: tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (coral), 3 mg (coral), and 4 mg (coral) strengths.
RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil.
In addition, the 2 mg, 3 mg, and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.
Chemical Structure
CLINICAL STUDIES
14 14.1 Schizophrenia Adults Short-Term Efficacy The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia.
The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients.
A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.
In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed.
The results of the trials follow: (1)In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL® in doses up to 10 mg/day (twice-daily schedule), RISPERDAL® was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.
(2)In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL® (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 RISPERDAL® groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest RISPERDAL® dose groups were generally superior to placebo on the PANSS negative subscale.
The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses.
(3)In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL® (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest RISPERDAL® dose groups were generally superior to the 1 mg RISPERDAL® dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score.
None of the dose groups were superior to the 1 mg group on the PANSS negative subscale.
The most consistently positive responses were seen for the 4 mg dose group.
(4)In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of RISPERDAL® (4 and 8 mg/day on a once-daily schedule), both RISPERDAL® dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS).
The results were generally stronger for the 8 mg than for the 4 mg dose group.
Long-Term Efficacy In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL® (2–8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse.
Patients receiving RISPERDAL® experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.
Pediatrics The efficacy of RISPERDAL® in the treatment of schizophrenia in adolescents aged 13–17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials.
All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment.
In the first trial (study #1), patients were randomized into one of three treatment groups: RISPERDAL® 1–3 mg/day (n = 55, mean modal dose = 2.6 mg), RISPERDAL® 4–6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54).
In the second trial (study #2), patients were randomized to either RISPERDAL® 0.15–0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or RISPERDAL® 1.5–6 mg/day (n = 125, mean modal dose = 4 mg).
In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15–0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7.
Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14.
The primary efficacy variable in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of RISPERDAL® in all dose groups from 1–6 mg/day compared to placebo, as measured by significant reduction of total PANSS score.
The efficacy on the primary parameter in the 1–3 mg/day group was comparable to the 4–6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day group in study #2.
In study #2, the efficacy in the 1.5–6 mg/day group was statistically significantly greater than that in the 0.15–0.6 mg/day group.
Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.
14.2 Bipolar Mania – Monotherapy Adults The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes.
These trials included patients with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).
The primary outcome in these trials was change from baseline in the YMRS total score.
The results of the trials follow: (1)In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of RISPERDAL® 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), RISPERDAL® was superior to placebo in the reduction of YMRS total score.
(2)In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL® was superior to placebo in the reduction of YMRS total score.
Pediatrics The efficacy of RISPERDAL® in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder.
Patients were randomized into one of three treatment groups: RISPERDAL® 0.5–2.5 mg/day (n = 50, mean modal dose = 1.9 mg), RISPERDAL® 3–6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58).
In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10.
The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of RISPERDAL® in both dose groups compared with placebo, as measured by significant reduction of total YMRS score.
The efficacy on the primary parameter in the 3–6 mg/day dose group was comparable to the 0.5–2.5 mg/day dose group.
Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania – Combination Therapy The efficacy of RISPERDAL® with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder.
This trial included patients with or without psychotic features and with or without a rapid-cycling course.
(1)In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL®, placebo, or an active comparator, in combination with their original therapy.
RISPERDAL®, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.
(2)In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL® or placebo, in combination with their original therapy.
RISPERDAL®, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4–12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score.
A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder Short-Term Efficacy The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder.
Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16–104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression – Change (CGI-C) scale.
The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I).
The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.
The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows: (1)In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL® 0.5–3.5 mg/day on a weight-adjusted basis.
RISPERDAL®, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo.
(2)In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, RISPERDAL® 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.
Long-Term Efficacy Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with RISPERDAL® for 4 or 6 months (depending on whether they received RISPERDAL® or placebo in the double-blind study).
During this open-label treatment period, patients were maintained on a mean modal dose of RISPERDAL® of 1.8–2.1 mg/day (equivalent to 0.05 – 0.07 mg/kg/day).
Patients who maintained their positive response to RISPERDAL® (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of ‘much improved’ or ‘very much improved’) during the 4–6 month open-label treatment phase for about 140 days, on average, were randomized to receive RISPERDAL® or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients).
A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the RISPERDAL® group compared with the placebo group.
Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention.
Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).
HOW SUPPLIED
16 /STORAGE AND HANDLING RISPERDAL® (risperidone) Tablets RISPERDAL® (risperidone) Tablets are imprinted “JANSSEN” on one side and either “R1”, or “R3” according to their respective strengths.
1 mg white, capsule-shaped tablets: bottles of 15 NDC 21695-113-15 3 mg yellow, capsule-shaped tablets: bottles of 30 NDC 21695-115-30 and bottles of 60 NDC 21695-113-60.
Storage and Handling RISPERDAL® Tablets should be stored at controlled room temperature 15°–25°C (59°–77°F).
Protect from light and moisture.
Keep out of reach of children.
RECENT MAJOR CHANGES
Warnings and Precautions, Leukopenia, Neutropenia, and Agranulocytosis (5.8) 07/2009
GERIATRIC USE
8.5 Geriatric Use Clinical studies of RISPERDAL® in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients.
Other reported clinical experience has not identified differences in responses between elderly and younger patients.
In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.4, 2.5)].
While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions (5.7)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.
This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus RISPERDAL® when compared to patients treated with RISPERDAL® alone or with placebo plus furosemide.
No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed.
An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of RISPERDAL® regardless of concomitant use with furosemide.
RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis.
[See Boxed Warning and Warnings and Precautions (5.1)]
DOSAGE FORMS AND STRENGTHS
3 RISPERDAL® Tablets are available in the following strengths and colors: 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green).
All are capsule shaped, and imprinted with “JANSSEN” on one side and either “Ris 0.25”, “Ris 0.5”, “R1”, “R2”, “R3”, or “R4” on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square), 3 mg (coral, round), and 4 mg (coral, round).
All are biconvex and etched on one side with “R0.5”, “R1”, “R2”, “R3”, or “R4” according to their respective strengths.
Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3) Oral solution: 1 mg/mL (3) Orally disintegrating tablets: 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (3)
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of RISPERDAL®, as with other drugs used to treat schizophrenia, is unknown.
However, it has been proposed that the drug’s therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors.
RISPERDAL® acts as an antagonist at other receptors, but with lower potency.
RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or β1 and β2 adrenergic receptors.
INDICATIONS AND USAGE
1 RISPERDAL® is an atypical antipsychotic agent indicated for: Treatment of schizophrenia in adults and adolescents aged 13–17 years (1.1) Alone, or in combination with lithium or valproate, for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults, and alone in children and adolescents aged 10–17 years (1.2) Treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years (1.3) 1.1 Schizophrenia Adults RISPERDAL® (risperidone) is indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)].
Adolescents RISPERDAL® is indicated for the treatment of schizophrenia in adolescents aged 13–17 years [see Clinical Studies (14.1)].
1.2 Bipolar Mania Monotherapy – Adults and Pediatrics RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10–17 years [see Clinical Studies (14.2)].
Combination Therapy – Adults The combination of RISPERDAL® with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder Pediatrics RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies (14.4)].
PEDIATRIC USE
8.4 Pediatric Use The efficacy and safety of RISPERDAL® in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-blind controlled trials [see Indications and Usage (1.1) , Adverse Reactions (6.1) , and Clinical Studies (14.1)].
Additional safety and efficacy information was also assessed in one long-term (6-month) open-label extension study in 284 of these adolescent patients with schizophrenia.
Safety and effectiveness of RISPERDAL® in children less than 13 years of age with schizophrenia have not been established.
The efficacy and safety of RISPERDAL® in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2) , Adverse Reactions (6.2) , and Clinical Studies (14.2)].
Safety and effectiveness of RISPERDAL® in children less than 10 years of age with bipolar disorder have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3) , Adverse Reactions (6.3) and Clinical Studies (14.4)].
Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of RISPERDAL® as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients less than 5 years of age with autistic disorder have not been established.
Tardive Dyskinesia In clinical trials in 1885 children and adolescents treated with RISPERDAL®, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of RISPERDAL® treatment [see also Warnings and Precautions (5.4)].
Weight Gain In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients.
In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of RISPERDAL® treatment.
The majority of that increase was observed within the first 6 months.
The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data).
The majority of that increase occurred within the first 6 months of exposure to RISPERDAL®.
The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL® groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5–2.5 mg group, 1.44 kg in the RISPERDAL® 3–6 mg group, and 0.65 kg in the placebo group).
A similar trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be assessed against that expected with normal growth.
[See also Adverse Reactions (6.7)] Somnolence Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder.
Most cases were mild or moderate in severity.
These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days.
Somnolence was the most commonly observed adverse event in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents.
As was seen in the autistic disorder trials, these events were most often of early onset and transient in duration.
[See also Adverse Reactions (6.1 , 6.2 , 6.3)] Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration (2.1 , 2.2 , 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation RISPERDAL® has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)].
In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received RISPERDAL® had elevated prolactin levels compared to 2% of patients who received placebo.
Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received RISPERDAL® had elevated levels of prolactin compared to 3–7% of patients on placebo.
Increases were dose-dependent and generally greater in females than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL®-treated patients and gynecomastia was reported in 2.3% of RISPERDAL®-treated patients.
The long-term effects of RISPERDAL® on growth and sexual maturation have not been fully evaluated.
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63–10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31–5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis).
The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m2 basis.
In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16–5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis.
It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.
There was no no-effect dose for increased rat pup mortality.
In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis.
In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed.
In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered.
Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams.
These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.
Placental transfer of risperidone occurs in rat pups.
There are no adequate and well-controlled studies in pregnant women.
However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero.
The causal relationship to RISPERDAL® therapy is unknown.
Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of RISPERDAL® during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
8.3 Nursing Mothers In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk.
Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk.
Therefore, women receiving RISPERDAL® should not breast-feed.
BOXED WARNING
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients.
Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality.
The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
RISPERDAL® (risperidone) is not approved for the treatment of patients with dementia-related psychosis.
[See Warnings and Precautions (5.1)] WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
RISPERDAL® is not approved for use in patients with dementia-related psychosis.
(5.1)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis.
RISPERDAL® is not approved for use in patients with dementia-related psychosis (5.2) Neuroleptic Malignant Syndrome (5.3) Tardive dyskinesia (5.4) Hyperglycemia and diabetes mellitus (5.5) Hyperprolactinemia (5.6) Orthostatic hypotension (5.7) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including risperidone.
Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
(5.8) Potential for cognitive and motor impairment (5.9) Seizures (5.10) Dysphagia (5.11) Priapism (5.12) Thrombotic Thrombocytopenic Purpura (TTP) (5.13) Disruption of body temperature regulation (5.14) Antiemetic Effect (5.15) Suicide (5.16) Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies (5.17) Diseases or conditions that could affect metabolism or hemodynamic responses (5.17) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
RISPERDAL® (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis.
In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo.
RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis.
[See also Boxed Warnings and Warnings and Precautions (5.1)] 5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs.
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated.
In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).
Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available.
There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs.
Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.
Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.
However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.
Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.
The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.
Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.
In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought.
The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug discontinuation should be considered.
However, some patients may require treatment with RISPERDAL® despite the presence of the syndrome.
5.5 Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including RISPERDAL®.
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.
Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood.
However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.
Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment.
Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.
Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing.
In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin levels and the elevation persists during chronic administration.
RISPERDAL® is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.
This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.
Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds.
Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer.
An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology (13.1)].
Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
5.7 Orthostatic Hypotension RISPERDAL® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties.
Syncope was reported in 0.2% (6/2607) of RISPERDAL®-treated patients in Phase 2 and 3 studies in adults with schizophrenia.
The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration (2.1 , 2.4)].
Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.
A dose reduction should be considered if hypotension occurs.
RISPERDAL® should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia.
Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERDAL®.
Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia.
Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERDAL® should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur.
Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERDAL® and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event associated with RISPERDAL® treatment, especially when ascertained by direct questioning of patients.
This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERDAL® 16 mg/day) reported somnolence compared to 16% of placebo patients.
Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event.
Since RISPERDAL® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that RISPERDAL® therapy does not affect them adversely.
5.10 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia.
RISPERDAL® should be used cautiously in patients with a history of seizures.
5.11 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia.
RISPERDAL® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
[See also Boxed Warning and Warnings and Precautions (5.1)] 5.12 Priapism Rare cases of priapism have been reported.
While the relationship of the events to RISPERDAL® use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that RISPERDAL® may share this capacity.
Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP) A single case of TTP was reported in a 28 year-old female patient receiving oral RISPERDAL® in a large, open premarketing experience (approximately 1300 patients).
She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis.
The relationship to RISPERDAL® therapy is unknown.
5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents.
Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use.
Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor.
5.16 Suicide The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy.
Prescriptions for RISPERDAL® should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.
5.17 Use in Patients with Concomitant Illness Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is limited.
Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to antipsychotic medications.
Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
RISPERDAL® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.
Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment.
A lower starting dose should be used in such patients [see Dosage and Administration (2.4)].
5.18 Monitoring: Laboratory Tests No specific laboratory tests are recommended.
DOSAGE AND ADMINISTRATION
2 Initial Dose Titration Target Dose Effective Dose Range Schizophrenia- adults (2.1) 2 mg/day 1–2 mg daily 4–8 mg daily 4–16 mg/day Schizophrenia – adolescents (2.1) 0.5mg/day 0.5– 1 mg daily 3mg/day 1–6 mg/day Bipolar mania – adults (2.2) 2–3 mg/day 1mg daily 1–6mg/day 1–6 mg/day Bipolar mania in children/adolescents (2.2) 0.5 mg/day 0.5–1mg daily 2.5mg/day 0.5–6 mg/day Irritability associated with autistic disorder (2.3) 0.25 mg/day (<20 kg) 0.5 mg/day (≥20 kg) 0.25–0.5 mg at ≥ 2 weeks 0.5 mg/day (<20 kg) 1 mg/day (≥20 kg) 0.5–3 mg/day 2.1 Schizophrenia Adults Usual Initial Dose RISPERDAL® can be administered once or twice daily.
Initial dosing is generally 2 mg/day.
Dose increases should then occur at intervals not less than 24 hours, in increments of 1–2 mg/day, as tolerated, to a recommended dose of 4–8 mg/day.
In some patients, slower titration may be appropriate.
Efficacy has been demonstrated in a range of 4–16 mg/day [see Clinical Studies (14.1)].
However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended.
In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg.
The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the effectiveness of RISPERDAL® 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)].
Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening.
Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day.
Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events.
Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
There are no controlled data to support the longer term use of RISPERDAL® beyond 8 weeks in adolescents with schizophrenia.
The physician who elects to use RISPERDAL® for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off RISPERDAL®, the initial titration schedule should be followed.
Switching From Other Antipsychotics There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL®, or treating patients with concomitant antipsychotics.
While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others.
The period of overlapping antipsychotic administration should be minimized.
When switching schizophrenic patients from depot antipsychotics, initiate RISPERDAL® therapy in place of the next scheduled injection.
The need for continuing existing EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania Usual Dose Adults RISPERDAL® should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day.
Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials.
In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1–6 mg per day [see Clinical Studies (14.2 , 14.3)].
RISPERDAL® doses higher than 6 mg per day were not studied.
Pediatrics The dosage of RISPERDAL® should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening.
Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day.
Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events.
Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
Maintenance Therapy There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with RISPERDAL®.
While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks).
The physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents) The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less than 5 years of age have not been established.
The dosage of RISPERDAL® should be individualized according to the response and tolerability of the patient.
The total daily dose of RISPERDAL® can be administered once daily, or half the total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients ≥ 20 kg.
After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients ≥ 20 kg.
This dose should be maintained for a minimum of 14 days.
In patients not achieving sufficient clinical response, dose increases may be considered at ≥ 2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg.
Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see Clinical Studies (14.4)]) received doses of RISPERDAL® between 0.5 mg and 2.5 mg per day.
The maximum daily dose of RISPERDAL® in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients 45 kg.
No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety.
The physician who elects to use RISPERDAL® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk.
Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily.
Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week.
In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate RISPERDAL® than normal adults.
Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3)].
Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see Warnings and Precautions (5.2 , 5.7 , 5.17)].
If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2–3 days at the target dose.
Subsequent switches to a once-daily dosing regimen can be done thereafter.
2.5 Co-Administration of RISPERDAL® with Certain Other Medications Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with RISPERDAL® would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of RISPERDAL® treatment.
The dose of RISPERDAL® needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold, respectively.
Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.
Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%.
The dose of RISPERDAL® needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see Drug Interactions (7.10)].
2.6 Administration of RISPERDAL® Oral Solution RISPERDAL® Oral Solution can be administered directly from the calibrated pipette, or can be mixed with a beverage prior to administration.
RISPERDAL® Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets Tablet Accessing RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each.
Do not open the blister until ready to administer.
For single tablet removal, separate one of the four blister units by tearing apart at the perforations.
Bend the corner where indicated.
Peel back foil to expose the tablet.
DO NOT push the tablet through the foil because this could damage the tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister.
Do not open the blister until ready to administer.
Peel back foil from the side to expose the tablet.
DO NOT push the tablet through the foil, because this could damage the tablet.
Tablet Administration Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue.
The RISPERDAL® M-TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit.
RISPERDAL® M-TAB® Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid.
Patients should not attempt to split or to chew the tablet.