DESCRIPTION
RISPERDAL® (risperidone) is 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. Inactive ingredients are colloidal silicon dioxide,
hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl
sulfate, and starch (corn). Tablets of 0.25, 0.5, 2, 3, and 4 mg 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. The inactive ingredients for this solution are
tartaric acid, benzoic acid, sodium hydroxide, and purified water.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg, 1 mg, and 2 mg strengths and
are light coral in color.
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.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL® (risperidone), 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.
Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of RISPERDAL®.
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), 1 and 2 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 ß1 and ß2 adrenergic receptors.
Pharmacokinetics
Absorption
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The
relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.
Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and
RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.
Plasma concentrations of risperidone, its major metabolite, 9–hydroxyrisperidone, and risperidone plus
9–hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg BID).
Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone
occurred at about 1 hour. Peak concentrations of 9–hydroxyrisperidone occurred at about 3 hours in
extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are
reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days
in poor metabolizers. Steady-state concentrations of 9–hydroxyrisperidone are reached in 5-6 days
(measured in extensive metabolizers).
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given
with or without meals.
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to
albumin and 1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major
metabolite, 9–hydroxyrisperidone, is 77%. Neither risperidone nor 9–hydroxyrisperidone displaces each
other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin
(10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of
risperidone at 10 ng/mL and 9–hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of
risperidone to 9–hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through
N-dealkylation. The main metabolite, 9–hydroxyrisperidone, has similar pharmacological activity as
risperidone. Consequently, the clinical effect of the drug (e.g., the active moiety) results from the combined
concentrations of risperidone plus 9–hydroxyrisperidone.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many
neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic
polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity
and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably
quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9–hydroxyrisperidone, whereas
poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower
risperidone and higher 9–hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics
of the active moiety, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone could be subject to two kinds of drug-drug interactions (see PRECAUTIONS - Drug
Interactions). First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9–hydroxyrisperidone.
This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of
poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving
quinidine have not been evaluated, but observations in a modest number (n70) of poor metabolizers
given risperidone do not suggest important differences between poor and extensive metabolizers. Second,
co-administration of known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with
risperidone may cause a decrease in the combined plasma concentrations of risperidone and
9–hydroxyrisperidone. It would also be possible for risperidone to interfere with metabolism of other drugs
metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to 6 mg/day
for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During
co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite,
9–hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not
appear to be affected. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and
phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of
risperidone and 9–hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment
(see PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION – Co-Administration of
RISPERDAL® with Certain Other Medications).
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) 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
an average of 13% (see PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION –
Co-Administration of RISPERDAL® with Certain Other Medications).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS – Drug Interactions).
Repeated oral doses of risperidone (4 mg QD) 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 risperidone (see PRECAUTIONS – Drug Interactions).
There were no significant interactions between risperidone (1 mg QD) and erythromycin (500 mg QID)
(see PRECAUTIONS – Drug Interactions).
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As
illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution
to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the
urine and 14% in the feces.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours
(CV=40%) in poor metabolizers. The apparent half-life of 9–hydroxyrisperidone was about 21 hours
(CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics
of the active moiety, after single and multiple doses, were similar in extensive and poor metabolizers, with
an overall mean elimination half-life of about 20 hours.
Special Populations
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active
metabolite decreased by 60% compared to young healthy subjects. RISPERDAL® doses should be reduced
in patients with renal disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young
healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the
diminished concentration of both albumin and 1-acid glycoprotein. RISPERDAL® doses should be reduced in
patients with liver disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Elderly
In healthy elderly subjects, renal clearance of both risperidone and 9–hydroxyrisperidone was decreased,
and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified
accordingly in the elderly patients (see DOSAGE AND ADMINISTRATION).
Race and Gender Effects
No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population
pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to
gender (whether corrected for body weight or not) or race.
CLINICAL TRIALS
Schizophrenia
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
(BID 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, 6, 10, and
16 mg/day, on a BID 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, 4, 8, 12, and
16 mg/day, on a BID 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 QD 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.
Bipolar Mania
Monotherapy
The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was established in 2
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 (Y-MRS), 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 Y-MRS 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 Y-MRS 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 Y-MRS total score.
Combination Therapy
The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed
episodes was established in one controlled trial in 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
Y-MRS total score.
1
RISPERDAL® M-TAB®
(RISPERIDONE)
ORALLY DISINTEGRATING TABLETS
Increased Mortality in Elderly Patients with Dementia –Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic
drugs are at an increased risk of death compared to placebo. Analyses of seventeen
placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk
of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebotreated
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. RISPERDAL® (risperidone) is not approved for the treatment of patients with
Dementia-Related Psychosis.
7503230
12/05
O1-RS-1720
(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 Y-MRS 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.
INDICATIONS AND USAGE
Schizophrenia
RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia.
The efficacy of RISPERDAL® in schizophrenia was established in short-term (6- to 8-weeks) controlled
trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY).
The efficacy of RISPERDAL® in delaying relapse was demonstrated in schizophrenic patients who had
been clinically stable for at least 4 weeks before initiation of treatment with RISPERDAL® or an active
comparator and who were then observed for relapse during a period of 1 to 2 years (see CLINICAL
PHARMACOLOGY – Clinical Trials). Nevertheless, the physician who elects to use RISPERDAL® for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
Bipolar Mania
Monotherapy
RISPERDAL® is indicated for the short-term treatment of acute manic or mixed episodes associated with
Bipolar I Disorder.
The efficacy of RISPERDAL® was established in two placebo-controlled trials (3-week) with patients
meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode
with or without psychotic features (see CLINICAL PHARMACOLOGY).
Combination Therapy
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.
The efficacy of RISPERDAL® in combination with lithium or valproate was established in one placebocontrolled
(3-week) trial with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed
an acute manic or mixed episode with or without psychotic features (see CLINICAL PHARMACOLOGY).
The effectiveness of RISPERDAL® for longer-term use, that is, for more than 3 weeks of treatment of an
acute episode, and for prophylactic use in mania, has not been systematically evaluated in controlled
clinical trials. Therefore, physicians who elect to use RISPERDAL® for extended periods should periodically
re-evaluate the long-term risks and benefits of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
CONTRAINDICATIONS
RISPERDAL® (risperidone) is contraindicated in patients with a known hypersensitivity to the product.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at
an increased risk of death compared to placebo. RISPERDAL® (risperidone) is not approved for the
treatment of dementia-related psychosis (see Boxed Warning).
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 creatinine 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.
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® (risperidone) 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.
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 WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-
Related Psychosis.)
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 treatmentemergent
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.
PRECAUTIONS
General
Orthostatic Hypotension
RISPERDAL® (risperidone) 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. The risk of orthostatic hypotension and syncope may be minimized by
limiting the initial dose to 2 mg total (either QD or 1 mg BID) in normal adults and 0.5 mg BID in the elderly
and patients with renal or hepatic impairment (see DOSAGE AND ADMINISTRATION). 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.
Seizures
During premarketing testing, 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.
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, WARNINGS: Increased Mortality in Elderly Patients with
Dementia-Related Psychosis.)
Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the
elevation persists during chronic administration. Tissue culture experiments indicate that approximately onethird
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. Although
disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with
prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most
patients. As is common with compounds which increase prolactin release, an increase in pituitary gland,
mammary gland, and pancreatic islet cell hyperplasia and/or neoplasia was observed in the risperidone
carcinogenicity studies conducted in mice and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis,
Impairment of Fertility). However, 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.
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.
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.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving 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.
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.
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.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia, 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.
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®, may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased
sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion,
obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.
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).
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
RISPERDAL®:
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose
titration.
Interference With Cognitive and Motor Performance
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.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant
during therapy.
Nursing
Patients should be advised not to breast-feed an infant if they are taking RISPERDAL®.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or
over-the-counter drugs, since there is a potential for interactions.
Alcohol
Patients should be advised to avoid alcohol while taking RISPERDAL®.
2
Phenylketonurics
Phenylalanine is a component of aspartame. Each 2 mg RISPERDAL® M-TAB® Orally Disintegrating
Tablet contains 0.56 mg phenylalanine; each 1 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet
contains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet
contains 0.14 mg phenylalanine.
Laboratory Tests
No specific laboratory tests are recommended.
Drug Interactions
The interactions of RISPERDAL® and other drugs have not been systematically evaluated. Given the
primary CNS effects of risperidone, caution should be used when RISPERDAL® is taken in combination
with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive effects of
other therapeutic agents with this potential.
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
Cimetidine and ranitidine increased the bioavailability of risperidone, but only marginally increased the
plasma concentration of the active antipsychotic fraction.
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to 6 mg/day
for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During
co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite,
9–hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not
appear to be affected. The dose of risperidone 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 risperidone may cause
similar decreases in the combined plasma concentrations of risperidone and 9–hydroxyrisperidone, which
could lead to decreased efficacy of risperidone treatment.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) 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 an
average of 13%. 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.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma
concentrations (Cmax) of lithium (n=13).
Valproate
Repeated oral doses of risperidone (4 mg QD) 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 risperidone.
Digoxin
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.
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). 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 (n70)
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.
There were no significant interactions between risperidone and erythromycin (see CLINICAL
PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitrostudies 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, risperidone did not significantly affect the pharmacokinetics of donepezil and
galantamine, which are metabolized by CYP 2D6.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was
administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to
rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose
(MRHD) (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times
the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were
statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and
mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a
mg/m2 (mg/kg) basis at which these tumors occurred.
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin
levels were not measured during the risperidone carcinogenicity studies; however, measurements during
subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats
at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine
pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs
and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactinmediated
endocrine tumors in rodents is unknown (see PRECAUTIONS, General - Hyperprolactinemia).
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test, mouse
lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in mice, the sexlinked
recessive lethal test in Drosophila, or the chromosomal aberration test in human lymphocytes or
Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive
studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended
human dose (MRHD) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior
was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in
which risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were
decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in
serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but
remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog.
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 crossfostering
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 risperidone
during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
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 risperidone
should not breast-feed.
Pediatric Use
Safety and effectiveness in children have not been established.
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 and DOSAGE AND ADMINISTRATION). 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 BID followed by careful titration (see PRECAUTIONS). 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).
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of
mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years,
range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years,
range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in
patients treated with furosemide plus risperidone was observed in two of the four clinical trials.
No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern
for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this
combination should be considered prior to the decision to use. There was no increased incidence of
mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective
of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided
in elderly patients with dementia-related psychosis. RISPERDAL® is not approved for the treatment of
patients with dementia-related psychosis. (See also Boxed WARNING, WARNINGS: Increased
Mortality in Elderly Patients with Dementia-Related Psychosis.)
ADVERSE REACTIONS
The following findings are based on the short-term, placebo-controlled, North American, premarketing
trials for schizophrenia and acute bipolar mania. In patients with Bipolar I Disorder, treatment-emergent
adverse events are presented separately for risperidone as monotherapy and as adjunctive therapy to
mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety parameters, namely dosedependent
adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are
derived from studies in patients with schizophrenia. However, this information is also generally applicable
to bipolar mania.
Associated With Discontinuation of Treatment
Schizophrenia
Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated patients in Phase 2 and 3 studies
discontinued treatment due to an adverse event, compared with about 7% on placebo and 10% on active
control drugs. The more common events (≥0.3%) associated with discontinuation and considered to be
possibly or probably drug-related included:
Adverse Event RISPERDAL® Placebo
Extrapyramidal symptoms 2.1% 0%
Dizziness 0.7% 0%
Hyperkinesia 0.6% 0%
Somnolence 0.5% 0%
Nausea 0.3% 0%
Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL®-treated patients compared
to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in RISPERDAL®
compared to placebo patients, it is unlikely that suicide attempt is a RISPERDAL®-related adverse event
(see PRECAUTIONS). Discontinuation for extrapyramidal symptoms was 0% in placebo patients, but
3.8% in active-control patients in the Phase 2 and 3 trials.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, approximately 8% (10/134) of
RISPERDAL®-treated patients discontinued treatment due to an adverse event, compared with
approximately 6% (7/125) of placebo-treated patients. The adverse events associated with discontinuation
and considered to be possibly, probably, or very likely drug-related included paroniria, somnolence,
dizziness, extrapyramidal disorder, and muscle contractions involuntary. Each of these events occurred in
one RISPERDAL®-treated patient (0.7%) and in no placebo-treated patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, there was no
overall difference in the incidence of discontinuation due to adverse events (4% for RISPERDAL® vs. 4%
for placebo).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia
In two 6- to 8-week placebo-controlled trials, spontaneously-reported, treatment-emergent adverse events
with an incidence of 5% or greater in at least one of the RISPERDAL® groups and at least twice that of
placebo were anxiety, somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia,
rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial comparing RISPERDAL®
at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for detecting adverse events, a method
that is more sensitive than spontaneous reporting. By this method, the following additional common and drugrelated
adverse events occurred at an incidence of at least 5% and twice the rate of placebo: increased dream
activity, increased duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances,
diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory dysfunction,
and orgastic dysfunction.
3
Tumor Type Species Sex
Multiples of Maximum Human Dose
in mg/m2 (mg/kg)
Lowest Highest
Effect No-Effect
Level Level
Pituitary adenomas mouse female 0.75 (9.4) 0.2 (2.4)
Endocrine pancreas rat male 1.5 (9.4) 0.4 (2.4)
adenomas
Mammary gland mouse female 0.2 (2.4) none
adenocarcinomas rat female 0.4 (2.4) none
rat male 6.0 (37.5) 1.5 (9.4)
Mammary gland rat male 1.5 (9.4) 0.4 (2.4)
neoplasm, Total
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy, the most commonly observed adverse
events associated with the use of RISPERDAL® (incidence of 5% or greater and at least twice that of
placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and
saliva increased. In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers,
the most commonly observed adverse events associated with the use of RISPERDAL® were somnolence,
dizziness, parkinsonism, saliva increased, akathisia, abdominal pain, and urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL®-Treated Patients -
Schizophrenia
The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were
more frequent among RISPERDAL®-treated patients treated at doses of ≤10 mg/day than among placebotreated
patients in the pooled results of two 6- to 8-week controlled trials. Patients received RISPERDAL®
doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or up to a maximum dose of 10 mg/day in the
titration study. This table shows the percentage of patients in each dose group (≤ 10 mg/day or 16 mg/day)
who spontaneously reported at least one episode of an event at some time during their treatment. Patients
given doses of 2, 6, or 10 mg did not differ materially in these rates. Reported adverse events were
classified using the World Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects
in the course of usual medical practice where patient characteristics and other factors differ from those
which prevailed in this clinical trial. Similarly, the cited frequencies cannot be compared with figures
obtained from other clinical investigations involving different treatments, uses, and investigators. The
cited figures, however, do provide the prescribing physician with some basis for estimating the relative
contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
Table 1. Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
Body System/ RISPERDAL®
Preferred Term ≤10 mg/day 16 mg/day Placebo
(N=324) (N=77) (N=142)
Psychiatric
Insomnia 26% 23% 19%
Agitation 22% 26% 20%
Anxiety 12% 20% 9%
Somnolence 3% 8% 1%
Aggressive reaction 1% 3% 1%
Central & peripheral nervous system
Extrapyramidal symptoms2 17% 34% 16%
Headache 14% 12% 12%
Dizziness 4% 7% 1%
Gastrointestinal
Constipation 7% 13% 3%
Nausea 6% 4% 3%
Dyspepsia 5% 10% 4%
Vomiting 5% 7% 4%
Abdominal pain 4% 1% 0%
Saliva increased 2% 0% 1%
Toothache 2% 0% 0%
Respiratory system
Rhinitis 10% 8% 4%
Coughing 3% 3% 1%
Sinusitis 2% 1% 1%
Pharyngitis 2% 3% 0%
Dyspnea 1% 0% 0%
Body as a whole - general
Back pain 2% 0% 1%
Chest pain 2% 3% 1%
Fever 2% 3% 0%
Dermatological
Rash 2% 5% 1%
Dry skin 2% 4% 0%
Seborrhea 1% 0% 0%
Infections
Upper respiratory 3% 3% 1%
Visual
Abnormal vision 2% 1% 1%
Musculo-Skeletal
Arthralgia 2% 3% 0%
Cardiovascular
Tachycardia 3% 5% 0%
1 Events reported by at least 1% of patients treated with RISPERDAL® ≤ 10 mg/day are included,
and are rounded to the nearest %. Comparative rates for RISPERDAL® 16 mg/day and placebo are
provided as well. Events for which the RISPERDAL® incidence (in both dose groups) was equal to
or less than placebo are not listed in the table, but included the following: nervousness, injury,
and fungal infection.
2 Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculogyric crisis, ataxia, abnormal
gait, involuntary muscle contractions, hyporeflexia, akathisia, and extrapyramidal disorders. Although
the incidence of 'extrapyramidal symptoms' does not appear to differ for the '10 mg/day' group and
placebo, the data for individual dose groups in fixed dose trials do suggest a dose/response
relationship (see ADVERSE REACTIONS – Dose Dependency of Adverse Events).
Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL®-Treated Patients -
Bipolar Mania
Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were more
frequent among patients treated with flexible doses of RISPERDAL® (1-6 mg daily as monotherapy and as
adjunctive therapy to mood stabilizers, respectively) than among patients treated with placebo. Reported
adverse events were classified using the World Health Organization preferred terms.
Table 2. Incidence of Treatment-Emergent Adverse Events
in a 3-Week, Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/ RISPERDAL® Placebo
Preferred Term (N=134) (N=125)
Central & peripheral nervous system
Dystonia 18% 6%
Akathisia 16% 6%
Dizziness 11% 9%
Parkinsonism 6% 3%
Hypoaesthesia 2% 1%
Psychiatric
Somnolence 28% 7%
Agitation 8% 6%
Manic reaction 8% 6%
Anxiety 4% 2%
Concentration impaired 2% 1%
Gastrointestinal system
Dyspepsia 11% 6%
Nausea 11% 2%
Saliva increased 5% 1%
Mouth dry 3% 2%
Body as a whole - general
Pain 5% 3%
Fatigue 4% 2%
Injury 2% 0%
Table 2. Incidence of Treatment-Emergent Adverse Events
in a 3-Week, Placebo-Controlled Trial - Monotherapy in Bipolar Mania1 (continued)
Body System/ RISPERDAL® Placebo
Preferred Term (N=134) (N=125)
Respiratory system
Sinusitis 4% 1%
Rhinitis 3% 2%
Coughing 2% 2%
Skin and appendages
Acne 2% 0%
Pruritus 2% 1%
Musculo-Skeletal
Myalgia 5% 2%
Skeletal pain 2% 1%
Metabolic and nutritional
Weight increase 2% 0%
Vision disorders
Vision abnormal 6% 2%
Cardiovascular, general
Hypertension 3% 1%
Hypotension 2% 0%
Heart rate and rhythm
Tachycardia 3% 2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are rounded
to the nearest %. Events reported by at least 2% of patients treated with RISPERDAL® that were less
than the incidence reported by patients treated with placebo are not listed in the table, but included
the following: headache, tremor, insomnia, constipation, back pain, upper respiratory tract infection,
pharyngitis, and arthralgia.
Table 3. Incidence of Treatment-Emergent Adverse Events
in a 3-Week, Placebo-Controlled Trial - Adjunctive Therapy in Bipolar Mania1
RISPERDAL® Placebo
Body System/ + Mood Stabilizer + Mood Stabilizer
Preferred Term (N=52) (N=51)
Gastrointestinal system
Saliva increased 10% 0%
Diarrhea 8% 4%
Abdominal pain 6% 0%
Constipation 6% 4%
Mouth dry 6% 4%
Tooth ache 4% 0%
Tooth disorder 4% 0%
Central & peripheral nervous system
Dizziness 14% 2%
Parkinsonism 14% 4%
Akathisia 8% 0%
Dystonia 6% 4%
Psychiatric
Somnolence 25% 12%
Anxiety 6% 4%
Confusion 4% 0%
Respiratory system
Rhinitis 8% 4%
Pharyngitis 6% 4%
Coughing 4% 0%
Body as a whole - general
Asthenia 4% 2%
Urinary system
Urinary incontinence 6% 2%
Heart rate and rhythm
Tachycardia 4% 2%
Metabolic and nutritional
Weight increase 4% 2%
Skin and appendages
Rash 4% 2%
1 Events reported by at least 2% of patients treated with RISPERDAL® are included and are rounded to the
nearest %. Events reported by at least 2% of patients treated with RISPERDAL® that were less than the
incidence reported by patients treated with placebo are not listed in the table, but included the following:
dyspepsia, nausea, vomiting, headache, tremor, insomnia, chest pain, fatigue, pain, skeletal pain,
hypertension, and vision abnormal.
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness for extrapyramidal symptoms
associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4
fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a parkinsonism score (mean change
from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous
complaints of EPS:
Other Adverse Events
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of
RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-
Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse events:
sleepiness, increased duration of sleep, accommodation disturbances, orthostatic dizziness, palpitations,
weight gain, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, asthenia/lassitude/increased
fatigability, and increased pigmentation.
Vital Sign Changes
RISPERDAL® is associated with orthostatic hypotension and tachycardia (see PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL® and placebo-treated patients meeting a weight gain criterion of ≥7% of
body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically
significantly greater incidence of weight gain for RISPERDAL® (18%) compared to placebo (9%).
Laboratory Changes
A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically significant
RISPERDAL®/placebo differences in the proportions of patients experiencing potentially important
4
Dose Groups Placebo Ris 2 Ris 6 Ris 10 Ris 16
Parkinsonism 1.2 0.9 1.8 2.4 2.6
EPS Incidence 13% 13% 16% 20% 31%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing
5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups Ris 1 Ris 4 Ris 8 Ris 12 Ris 16
Parkinsonism 0.6 1.7 2.4 2.9 4.1
EPS Incidence 7% 12% 18% 18% 21%
changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no
RISPERDAL®/placebo differences in the incidence of discontinuations for changes in serum chemistry,
hematology, or urinalysis. However, RISPERDAL® administration was associated with increases in serum
prolactin (see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant
differences between risperidone and placebo in mean changes from baseline in ECG parameters,
including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL® doses were pooled from
randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per
minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of
risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to
placebo (4-6 beats per minute).
Other Events Observed During the Premarketing Evaluation of RISPERDAL®
During its premarketing assessment, multiple doses of RISPERDAL® were administered to 2607 patients
in Phase 2 and 3 studies. The conditions and duration of exposure to RISPERDAL® varied greatly, and
included (in overlapping categories) open-label and double-blind studies, uncontrolled and controlled
studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term
exposure. In most studies, untoward events associated with this exposure were obtained by spontaneous
report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is
not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of untoward events into a smaller number of standardized event
categories. In two large studies, adverse events were also elicited utilizing the UKU (direct questioning)
side effect rating scale, and these events were not further categorized using standard terminology. (Note:
These events are marked with an asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified using World Health
Organization (WHO) preferred terms. The frequencies presented, therefore, represent the proportion of
the 2607 patients exposed to multiple doses of RISPERDAL® who experienced an event of the type cited
on at least one occasion while receiving RISPERDAL®. All reported events are included, except those
already listed in Table 1, those events for which a drug cause was remote, and those event terms which
were so general as to be uninformative. It is important to emphasize that, although the events reported
occurred during treatment with RISPERDAL®, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to
the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those
not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent
adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer
than 1/1000 patients.
Psychiatric Disorders
Frequent: increased dream activity*, diminished sexual desire*, nervousness. Infrequent: impaired
concentration, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia. Rare:
emotional lability, nightmares, delirium, withdrawal syndrome, yawning.
Central and Peripheral Nervous System Disorders
Frequent:increased sleep duration*. Infrequent:dysarthria, vertigo, stupor, paraesthesia, confusion. Rare:
aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma,
migraine, hyperreflexia, choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation*. Infrequent: flatulence, diarrhea, increased appetite, stomatitis,
melena, dysphagia, hemorrhoids, gastritis. Rare:fecal incontinence, eructation, gastroesophageal reflux,
gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue edema, diverticulitis, gingivitis,
discolored feces, GI hemorrhage, hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms. Rare: pallor, enlarged
abdomen, allergic reaction, ascites, sarcoidosis, flushing.
Respiratory System Disorders
Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma, increased sputum,
aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation*, photosensitivity*. Infrequent: increased sweating, acne, decreased
sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare: bullous eruption, skin ulceration,
aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction. Rare: ventricular
tachycardia, angina pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles,
ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain, blepharitis, photopsia,
photophobia, abnormal lacrimation.
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight decrease,
diabetes mellitus. Rare: decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia,
hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia.
Urinary System Disorders
Frequent: polyuria/polydipsia*. Infrequent: urinary incontinence, hematuria, dysuria. Rare: urinary
retention, cystitis, renal insufficiency.
Musculo-Skeletal System Disorders
Infrequent:myalgia. Rare:arthrosis, synostosis, bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia*, orgastic dysfunction*, dry vagina*. Infrequent: nonpuerperal lactation,
amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual
bleeding, vaginal hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic hepatitis, cholecystitis,
cholelithiasis, hepatitis, hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent:epistaxis, purpura. Rare:hemorrhage, superficial phlebitis, thrombophlebitis, thrombocytopenia.
Hearing and Vestibular Disorders
Rare:tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent:anemia, hypochromic anemia. Rare:normocytic anemia.
Reproductive Disorders, Male
Frequent:erectile dysfunction*. Infrequent:ejaculation failure.
White Cell and Resistance Disorders
Rare:leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly.
Endocrine Disorders
Rare:gynecomastia, male breast pain, antidiuretic hormone disorder.
Special Senses
Rare:bitter taste.
* Incidence based on elicited reports.
Postintroduction Reports
Adverse events reported since market introduction which were temporally (but not necessarily causally)
related to RISPERDAL® therapy, include the following: anaphylactic reaction, angioedema, apnea, atrial
fibrillation, benign pituitary adenomas, cerebrovascular disorder, including cerebrovascular accident,
diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction,
jaundice, mania, pancreatitis, Parkinson’s disease aggravated, pulmonary embolism. There have been
rare reports of sudden death and/or cardiopulmonary arrest in patients receiving RISPERDAL®. A causal
relationship with RISPERDAL® has not been established. It is important to note that sudden and
unexpected death may occur in psychotic patients whether they remain untreated or whether they are
treated with other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL® (risperidone) is not a controlled substance.
Physical and Psychological Dependence
RISPERDAL® has not been systematically studied in animals or humans for its potential for abuse,
tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drugseeking
behavior, these observations were not systematic and it is not possible to predict on the basis of
this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused
once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such
patients should be observed closely for signs of RISPERDAL® misuse or abuse (e.g., development of
tolerance, increases in dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
Premarketing experience included eight reports of acute RISPERDAL® (risperidone) 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 events reported since market introduction
which were temporally (but not necessarily causally) related to RISPERDAL® overdose, include torsade de
pointes, prolonged QT interval, convulsions, cardiopulmonary arrest, and rare fatality associated with
multiple drug overdose.
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.
DOSAGE AND ADMINISTRATION
Schizophrenia
Usual Initial Dose
RISPERDAL® (risperidone) can be administered on either a BID or a QD schedule. In early clinical trials,
RISPERDAL® was generally administered at 1 mg BID initially, with increases in increments of 1 mg BID on
the second and third day, as tolerated, to a target dose of 3 mg BID by the third day. Subsequent controlled
trials have indicated that total daily risperidone doses of up to 8 mg on a QD regimen are also safe and
effective. However, regardless of which regimen is employed, in some patients a slower titration may be
medically appropriate. Further dosage adjustments, if indicated, should generally occur at intervals of not less
than 1 week, since steady state for the active metabolite would not be achieved for approximately 1 week in
the typical patient. When dosage adjustments are necessary, small dose increments/decrements of 1-2 mg
are recommended.
Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the clinical trials supporting
effectiveness of RISPERDAL®; however, maximal effect was generally seen in a range of 4 to 8 mg/day.
Doses above 6 mg/day for BID dosing were not demonstrated to be more efficacious than lower doses, were
associated with more extrapyramidal symptoms and other adverse effects, and are not generally
recommended. In a single study supporting QD 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 there is no body of evidence available to answer the question of how long the schizophrenic patient
treated with RISPERDAL® should remain on it, 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. In this trial, RISPERDAL® was
administered on a QD schedule, at 1 mg QD initially, with increases to 2 mg QD on the second day, and to
a target dose of 4 mg QD on the third day (see CLINICAL PHARMACOLOGY – Clinical Trials).
Nevertheless, patients should be periodically reassessed to determine the need for maintenance
treatment with an appropriate dose.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended that when
restarting patients who have had 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 concerning concomitant administration with other 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. In all cases, the
period of overlapping antipsychotic administration should be minimized. When switching schizophrenic
patients from depot antipsychotics, if medically appropriate, initiate RISPERDAL® therapy in place of
the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated
periodically.
Bipolar Mania
Usual Dose
Risperidone 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 PHARMACOLOGY – Clinical Trials). RISPERDAL® doses higher than 6 mg per day
were not studied.
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 risperidone.
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 risperidone in such longer-term treatment (i.e.,
beyond 3 weeks).
Pediatric Use
Safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia or acute mania
associated with Bipolar I Disorder have not been established.
Dosage in Special Populations
The recommended initial dose is 0.5 mg BID 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
BID. Increases to dosages above 1.5 mg BID 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).
5
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 PRECAUTIONS). If a once-a-day
dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient
be titrated on a twice-a-day regimen for 2-3 days at the target dose. Subsequent switches to a once-a-day
dosing regimen can be done thereafter.
Co-Administration of RISPERDAL® with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital)
with risperidone would be expected to cause decreases in the plasma concentrations of active moiety (the
sum of risperidone and 9–hydroxyrisperidone), which could lead to decreased efficacy of risperidone
treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme
inducers, especially during initiation or discontinuation of therapy with these inducers (see CLINICAL
PHARMACOLOGY and PRECAUTIONS).
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 an average of 13%. The dose of risperidone
needs to be titrated accordingly when fluoxetine or paroxetine is co-administered (see CLINICAL
PHARMACOLOGY and PRECAUTIONS).
Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
RISPERDAL® M-TAB® Orally Disintegrating Tablets are supplied in blister packs of 4 tablet units each.
Tablet Accessing
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.
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.
HOW SUPPLIED
RISPERDAL® (risperidone) tablets are imprinted “JANSSEN”, and either “Ris” and the strength “0.25”,
“0.5”, or “R” and the strength “1”, “2”, “3”, or “4”.
0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-50, hospital
unit dose packs of 100 NDC 50458-301-01.
0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50, hospital
unit dose packs of 100 NDC 50458-302-01.
1 mg white tablet: bottles of 60 NDC 50458-300-06, blister pack of 100 NDC 50458-300-01, bottles of 500
NDC 50458-300-50.
2 mg orange tablet: bottles of 60 NDC 50458-320-06, blister pack of 100 NDC 50458-320-01, bottles of
500 NDC 50458-320-50.
3 mg yellow tablet: bottles of 60 NDC 50458-330-06, blister pack of 100 NDC 50458-330-01, bottles of
500 NDC 50458-330-50.
4 mg green tablet: bottles of 60 NDC 50458-350-06, blister pack of 100 NDC 50458-350-01.
RISPERDAL® (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied in 30 mL bottles with a
calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume is 0.25 mL, while the
maximum calibrated volume is 3 mL.
Tests indicate that RISPERDAL® (risperidone) 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, however.
RISPERDAL® M-TAB® (risperidone) Orally Disintegrating Tablets are etched on one side with “R0.5”, “R1”,
and “R2”, respectively, and are packaged in blister packs of 4 (2 X 2) tablets.
0.5 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-395-28, long-term care
packaging of 30 tablets NDC 50458-395-30.
1 mg light coral, square, biconvex tablets: 7 blister packages per box, NDC 50458-315-28, long-term care
packaging of 30 tablets NDC 50458-315-30.
2 mg light coral, round, biconvex tablets: 7 blister packages per box, NDC 50458-325-28.
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.
RISPERDAL® 1 mg/mL oral solution should be stored at controlled room temperature 15°-25°C (59°-
77°F). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL® M-TAB® Orally Disintegrating Tablets should be stored at controlled room temperature
15°-25°C (59°-77°F).
Keep out of reach of children.
7503230
US Patent 4,804,663
Revised November 2005
© Janssen 2003
RISPERDAL® tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico or
Janssen-Cilag, SpA, Latina, Italy
RISPERDAL® oral solution is manufactured by:
Janssen Pharmaceutica N.V.
Beerse, Belgium
RISPERDAL® M-TAB® Orally Disintegrating Tablets are manufactured by:
JOLLC, Gurabo, Puerto Rico
RISPERDAL® tablets, RISPERDAL® M-TAB® Orally Disintegrating Tablets,
and oral solution are distributed by:
Janssen, L.P.
Titusville, NJ 08560
6
O1-RS-1720

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