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Risperdal
RISPERDAL
(RISPERIDONE)
RISPERDAL M_TAB
(RISPERIDONE)
If
you are taking Risperdal or thinking of taking Risperdal and you are wondering about side effects or the potential of side
effects with using Risperdal, there is something you need to know. There is a way
to predict adverse reactions with a very simple test.
Dr. Lester M. Crawford, Acting FDA
Commissioner had this to say about this test on
Dec. 24, 2004. “Physicians can use the genetic information from this test to
prevent harmful drug interactions and to assure drugs are used optimally, which
in some cases will enable patients to avoid less effective or potentially
harmful treatment choices,”
TABLETS/ORAL SOLUTION ORALLY
DISINTEGRATING TABLETS
If you or your child have been harmed by taking Risperdal, been
prescribed Risperdal off label or had adverse reactions to the medication, you
may wish to file a lawsuit before the statute of limitations runs out. Having a
law firm which understands this medication and most importantly one which has
the resources to see the case through is vital. If you would like for us to send
your information to a law firm handling Risperdal claims,
click here and fill
out the short form.
DESCRIPTION
The mechanism of action of RISPERDAL (risperidone), as with
other drugs used to treat schizophrenia, is unknown.
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.
CYP2D6, also called debrisoquin hydrozylase, is the enzyme
responsible for metabolism of many neuroleptics, antidepressants,
antiarrhythimics, 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 phenobarbitital) 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 suggest this is unlikely.
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In a drug interaction study in schizophrenic patients, 11
subjects received risperidone titrated to 6mg/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 carbanazepine 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 ADMINISTRATION – Co-Administration of RISPERDAL with
Certain Other Medications).Fluoxetine (20mg QD) and paroxetine (20 mg QD) have
been shown to increase the plasma concentration of risperidone 2.5-238 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).
Special Populations
Renal Impairment.
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In patients with moderate to severe renal disease,
clearance of the sume 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 or, -acid glycoprotien. Risperdal
doses should be reduced in patients with liver disease (see PRECAUTIONS and
DOSAGE AND ADMINISTRATION).
Race and Gender Effects
No specific pharmadokintetic 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.
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to
as Neuroleptic Malignant Syndrome (NMS) has been reported in association with
antipshychotic 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 antipshychotic 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 antipshychotic drug treatment after
recover 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.
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Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary,
dyskinesia movements may develop in patients treated with antipshychotic 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 antipshychotic treatment, which patients are likely
to develop the syndrome. Whether antipshychotic 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 antipshychotic 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 my remit, partially or completely, if
antipshychotic 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 antipshychotic treatment should generally be
reserved for patients who suffer from a chronic illness that (1) is known to
respond to antipshychotic 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 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
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.
Hyperglycemia, in some cases extreme and associated with
detoacidosis or hyperosmolar coma or death, has been reported in patients
treated with atypical antipsychotics including RISPERDAL. Assessment of the
relationship between atypical antipshychotic use and glucose abnormalities is
complicated by the possibility of an increased background fisk 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 antipshychotic use and hyperglycemia-related adverse events is
not completely understood. However, epidemiological studies suggest an increased
risk of treatment-emergent hyperglycemia-related adverse events in patients
treated with the atypical antipsychotics. Precise risk estimates for
hyperglycemia-related adverse events in patients treated with atypical
antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus
who are started on atypical antipsychotics should be monitored regularly for
worsening of glucose control. Patients with risk factors for diabetes mellitus
(e.g., obesity, family history of diabetes) who are starting treatment with
atypical antipsychotics should undergo fasting blood glucose testing at the
beginning of treatment and periodically during treatment. Any patient treated
with atypical antipsychotics should be monitored for symptoms of hyperglycemia
including polydipsia, polyuria, polyphagia, and weakness. Patients who develop
symptoms of hyperglycemia during treatment with atypical antipsychotics should
undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved
when the atypical antipsychotic was discontinued; however, some patients
required continuation of anti-diabetic treatment despite discontinuation of the
suspect drug.
PRECAUTIONS
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General
Orthostatic Hypotension
RISPERDAL (risperidone) may induce orthostatic hypotension
associated with dizziness, tychycardia, and in some patients, syncope,
especially during the initial dose-titration period, probably reflection 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 1mg 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 infraction or ischemia, heart
failure, or condition 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.
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.
As with other drugs that antagonize dopamine D2 receptors,
resperiodone 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 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 glend, 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 Cognative and Motor Impairment
Somnolence was 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 16mg/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.
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.
Disruption of body temperature regulation has been
attributed to antipsychotic agents. Both hyperthermia and hypothermia have been
reported in association with oral RISPERDAL us. Caution is advised when
prescribing for pactients who will be exposed to temperature extremes.
Suicide
The possibility of 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. Caution is advisable in using
RISPERDAL in patients with disease of 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
(seeDOSAGE AND ADMINISTRATION).
Physicians are advised to discuss the following issues with
patients for whom they prescribe RISPERDAL.
Orthostatic HypotensionPatients 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.
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 0.56mg phenylalanine; each
1mgRISPERDAL 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
The interactions of RISPERDAL and other drugs have not been
systematically evaluated. Given the primary CNS effect 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. Amtripyline does not affect the pharmacokinetics of
risperidone of the active antipsychotic fraction. Cimetidine and ranitidine
increased the bioavaiability 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 scizophrenic 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 does 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 (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 (AUD) or peak plasma concentrations (C
max) 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
(1000mg/day in three divided doses) compared to placebo (n+12). However, there
was a 20% increase in valproate peak plasma concentration (C
max) after concomitant administration of
risperidone.
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-hydroxyrisperidoneby 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).
In vitro studies indicate that risperidone is a
relatively week 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, and37.5 times the maximum recommended human dose (MRHD)
(16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3times 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 the mg/m2
(mg/mk) basis at which these tumors occurred.
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
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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 neoplasm 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 1
and a muligenerational 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 1 study in which 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 Category C
The teratogenic potential of risperidone was studied in
three Segment 11 studies in Sprague-Dawley and Wistar rats (0.63-10mg/kg or 0.4
to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in
one Segment 11 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 111
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 111 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 by 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.
RISPERDAL should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
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.
Clinical studies of RISPERDAL did not include sufficient
numbers of patients aged 65 and over to determine whether or not thy 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
ADMINISTATION). 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 ,a and it may be useful to
monitor renal function (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The following findings are based on the short-term,
placebo-controlled, North American, premarketing trial for schizophrenia and
acute bipolar mania, In patients with Bipolar 1 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
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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%
Somonlence
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 RIPERDAL 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 2
trials.
Bipolar Mania
In the US placebo-controlled trail 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 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
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In tow 6-to 8-week placebo-controlled trials,
spontaneously-reproted, 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, extra-pyramidal symptoms, dizziness,
constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two
trails. (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
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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 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 10mg/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. Back to top of page
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 Trials (1)
Body System RISPERDAL
Preferred Term ≤10
mg/day 16 mg/day Placebo
(N=324) (N=77) (N=142)
______________________________________________________________________
Psychiatric
26% 23% 19%
Insomnia
22% 26% 20%
Agitation
22% 26% 20%
Anxiety 12%
20% 20%
Somnolence 3%
8% 1%
Aggressive reaction
1% 3% 1%
Central &peripheral nervous system
Extapyramidal Symptoms 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%
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%
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
fugal infection.
(2)
Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesias,
oculogyriccrisis, ataxia, abnormal gait, involuntary muscle contractions,
hyporeglexia, 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). Back to top of page
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 Mania (1)
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%
Mounth dry
3% 2%
Body as a whole – general
Pain
5% 3%
Fatigue
4% 2%
Injury
2% 0%
Respitory system
Sinusitis
4% 1%
Rhinitis
3% 2%
Coughing
2% 2%
Skin appendage
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.
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Table 3. Incidence of
Treatment-Emergent Adverse Events
In a 3-Week, Placebo-Controlled Trial – adjunctive
Therapy In Bipolar Mania (1)
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%
Mount
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
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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), in parkinsonism score (mean change from
baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of
spontaneous complaints of EPS.
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%
Simialr 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 .06
1.7 2.4 2.9 4.1
EPS Incidence 7%
12% 18% 18% 21%
Other Adverse Events
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Adverse event data elicited by a checklist for
side effect from a large study comparing 5 fixed doses of RISPERDAL (1, 4, 8,
12, 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
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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. Simiarly, there were no RISPERDAL/placebo differences in
the incidence of discontinuations for chages 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 an 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
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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, gerorrhoids, gastritis. Rare: fecal incontinence, eructation,
gastroesophageal reflux. Gastroentertits, esophagitis, tongue discoloration,
cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, GI
hemorrhage, hematemesis.
Body
as a Whole/General Disorders
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Frequent: fatigue. Infrequent: edema, rigors,
malaise, influenza-like symptoms. Rare: pallor, enlarged abdomen, allergic
reaction, ascites, sarcoidosis, flushing.
Respirator System Disorders
Infrequent: hyperventilation, bronchospasm,
pneumonia, stridor. Rare: asthma, increased sputum, aspiration.
Skin
and Appendage Disorders
Frequent: increased pigmentation*,
photosensitivity*,. Infrequent: Increased sweatin, acne, decreased sweating,
alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare: bullous eruption,
skin sulceration, aggravated psoriasis, furunculosis, veruca, dermatitis
lichenoid, hypertrichosis, geital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension,
hypotension, AV block, myocardial infarction. Rare: ventricular tachycardia,
angina pectoris, premature atrial contractions, T wave inversions, bentricular
extasystoles, ST depression, myocarditis.
Vision Disorders
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Infrequent: abnormal accommodation,
xerophthalmia. Rare: diplopia, eye pain, blepharitis, photopsia, photophobia,
abnormal lacrimation.
Metabolic and Nutritional Disorders
Infrequent: hyponatremia, weight increase,
creatinine phosphokinase increse, thirst, weight decrease, diabetes mellitus.
Rare: decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia,
hyperphosphatemia, hypertriglyceridemia, hyperuicemia, hypoglycemia.
Urinary System Disorders
Frequent: polyuria/polydipsia*. Infrequent:
urinary incontinence, hematuria, dysuria. Rare: urinary retention, cystitis,
renal insufficiency.
Musculo-Skeletal System Disorders
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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, hepatocullular damage.
Platelet, Bleeding, and Clotting Disorders
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Infrequent: epistaxis, purpura. Rare:
hemorrhage, superficial phlebitis, thrombophebitis, thrombocytopenia.
Hearing and Vesitbular
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,
antiduretic hormone disorder.
Special Senses
Rare: bitter taste.
*Incidence based on elicited reports.
Postintroduction Reports
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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).
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