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JANSSEN
PHARMACEUTICA
PRODUCTS, L.P.
RISPERDAL
(RISPERIDONE)
TABLETS/ORAL SOLUTION
RISPERDAL M-TAB
(RISPERIDONE)
ORALLY DISINTEGRATING TABLETS

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.
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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), 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.
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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 a1-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 (10mcg/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.
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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
(n@70) 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).
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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).
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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 a1-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.
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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
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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.
(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
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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.
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The efficacy of RISPERDAL in combination with lithium or valproate was
established in one placebo-controlled (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 dementiarelated
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.
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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.
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If signs and symptoms of tardive dyskinesia appear in a patient treated on
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 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;
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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 one-third of human breast cancers are
prolactin dependent in vitro, a factor of potential importance if the prescription of
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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.
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.
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:
16
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.
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.
17
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.
Amytriptyline 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).
18
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
(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.
There were no significant interactions between risperidone and erythromycin
(see CLINICAL PHARMACOLOGY).
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, 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
19
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.
Multiples of Maximum
Human Dose in mg/m2
(mg/kg)
Tumor Type Species Sex Lowest
Effect Level
Highest No-
Effect Level
Pituitary adenomas mouse female 0.75 (9.4) 0.2 (2.4)
Endocrine pancreas adenomas rat male 1.5 (9.4) 0.4 (2.4)
Mammary gland adenocarcinomas mouse female 0.2 (2.4) None
rat female 0.4 (2.4) none
rat male 6.0 (37.5) 1.5 (9.4)
Mammary gland neoplasm, Total rat male 1.5 (9.4) 0.4 (2.4)
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
prolactin-mediated 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 sex-linked 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
20
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 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 wellcontrolled
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.
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.
21
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
22
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 dose-dependent 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
(³0.3%) 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.
23
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
drug-related 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.
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
24
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 placebo-treated 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.
25
Table 1. Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(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%
(continued)
26
Table 1. Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
RISPERDAL
Body System/
Preferred Term
<10mg/day
(N=324)
16 mg/day
(N=77)
Placebo
(N=142)
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/
Preferred Term
RISPERDAL
(N=134)
Placebo
(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%
(continued)
27
Table 2. Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL
(N=134)
Placebo
(N=125)
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%
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%
1Events 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.
28
Table 3. Incidence of Treatment-Emergent Adverse Events in a 3-Week,
Placebo-Controlled Trial - Adjunctive Therapy in Bipolar Mania1
Body System/
Preferred Term
RISPERDAL
+ Mood Stabilizer
(N=52)
Placebo
Mood Stabilizer
(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%
1Events 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:
29
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%
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 ³7% 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 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
30
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.
31
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.
32
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.
33
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, cerebrovascular disorder,
including cerebrovascular accident, hyperglycemia, diabetes mellitus aggravated,
including diabetic ketoacidosis, 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 drug-seeking 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,
34
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.
35
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.
36
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.
37
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). 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.
38
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.
39
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
15o-25oC (59o-77oF). Protect from light and moisture.
Keep out of reach of children.
RISPERDAL 1 mg/mL oral solution should be stored at controlled room
temperature 15o-25oC (59o-77oF). Protect from light and freezing.
Keep out of reach of children.
RISPERDAL M-TAB Orally Disintegrating Tablets should be stored at controlled
room temperature 15o-25oC (59o-77oF).
Keep out of reach of children.
7503228
US Patent 4,804,663
Revised February 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
40
RISPERDAL tablets, RISPERDAL M-TAB Orally Disintegrating Tablets, and
oral solution are distributed by:
Janssen Pharmaceutica Products, L.P.
Titusville, NJ 08560

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