A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Risperdal Warnings, Precautions, Pregnancy, Nursing, Abuse - Risperidone
Risperdal Warnings, Precautions, Pregnancy, Nursing, Abuse - Risperidone
WARNINGS
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 ofNMS are hyperpyrexia, muscle rigidity, altered
mental status, and evidence of autonomic instability (irregular pulse or blood
pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs
may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure.
The diagnostic evaluation of patients with this syndrome is
complicated. In arriving at a diagnosis, it is important to identify cases in
which the clinical presentation includes both serious medical illness (e.g.,
pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal
signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever,
and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation
of antipsychotic drugs and other drugs not essential to concurrent therapy;
(2) intensive symptomatic treatment and medical monitoring; and (3) treatment
of any concomitant serious medical problems for which specific treatments are
available. There is no general agreement about specific pharmacological treatment
regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery
from NMS, the potential reintroduction of drug therapy should be carefully considered.
The patient should be carefully monitored, since recurrences of NMS have been
reported.
Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic
movements may develop in patients treated with antipsychotic drugs. Although
the prevalence of the syndrome appears to be highest among the elderly, especially
elderly women, it is impossible to rely upon prevalence estimates to predict,
at the inception of antipsychotic treatment, which patients are likely to develop
the syndrome. Whether antipsychotic drug products differ in their potential
to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood
that it will become irreversible are believed to increase as the duration of
treatment and the total cumulative dose of antipsychotic drugs administered
to the patient increase. However, the syndrome can develop, although much less
commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive
dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic
treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress
(or partially suppress) the signs and symptoms of the syndrome and thereby may
possibly mask the underlying process. The effect that symptomatic suppression
has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® (risperidone)
should be prescribed in a manner that is most likely to minimize the occurrence
of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved
for patients who suffer from a chronic illness that (1) is known to respond
to antipsychotic drugs, and (2) for whom alternative, equally effective, but
potentially less harmful treatments are not available or appropriate. In patients
who do require chronic treatment, the smallest dose and the shortest duration
of treatment producing a satisfactory clinical response should be sought. The
need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient
treated 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 and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis
or hyperosmolar coma or death, has been reported in patients treated with atypical
antipsychotics including RISPERDAL®. Assessment of the relationship
between atypical antipsychotic use and glucose abnormalities is complicated
by the possibility of an increased background risk of diabetes mellitus in patients
with schizophrenia and the increasing incidence of diabetes mellitus in the
general population. Given these confounders, the relationship between atypical
antipsychotic use and hyperglycemia-related adverse events is not completely
understood. However, epidemiological studies suggest an increased risk of treatment-emergent
hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.
Precise risk estimates for hyperglycemia-related adverse events in patients
treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus
who are started on atypical antipsychotics should be monitored regularly for
worsening of glucose control. Patients with risk factors for diabetes mellitus
(e.g., obesity, family history of diabetes) who are starting treatment with
atypical antipsychotics should undergo fasting blood glucose testing at the
beginning of treatment and periodically during treatment. Any patient treated
with atypical antipsychotics should be monitored for symptoms of hyperglycemia
including polydipsia, polyuria, polyphagia, and weakness. Patients who develop
symptoms of hyperglycemia during treatment with atypical antipsychotics should
undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved
when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect
drug.
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.
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 these drugs is contemplated
in a patient with previously detected breast cancer. Although disturbances such
as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported
with prolactin-elevating compounds, the clinical significance of elevated serum
prolactin levels is unknown for most patients. As is common with compounds which
increase prolactin release, an increase in pituitary gland, mammary gland, and
pancreatic islet cell hyperplasia and/or neoplasia was observed in the risperidone
carcinogenicity studies conducted in mice and rats (see PRECAUTIONS
– Carcinogenesis, Mutagenesis, Impairment of Fertility). However, neither clinical
studies nor epidemiologic studies conducted to date have shown an association
between chronic administration of this class of drugs and tumorigenesis in humans;
the available evidence is considered too limited to be conclusive at this time.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated
with RISPERDAL® treatment, especially when ascertained by direct
questioning of patients. This adverse event is dose-related, and in a study
utilizing a checklist to detect adverse events, 41% of the high-dose patients
(RISPERDAL® 16 mg/day) reported somnolence compared to 16% of
placebo patients. Direct questioning is more sensitive for detecting adverse
events than spontaneous reporting, by which 8% of RISPERDAL® 16
mg/day patients and 1% of placebo patients reported somnolence as an adverse
event. Since RISPERDAL® has the potential to impair judgment,
thinking, or motor skills, patients should be cautioned about operating hazardous
machinery, including automobiles, until they are reasonably certain that RISPERDAL®
therapy does not affect them adversely.
Priapism
Rare cases of priapism have been reported. While the relationship
of the events to RISPERDAL® use has not been established, other
drugs with alpha-adrenergic blocking effects have been reported to induce priapism,
and it is possible that RISPERDAL® may share this capacity. Severe
priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient
receiving RISPERDAL® in a large, open premarketing experience
(approximately 1300 patients). She experienced jaundice, fever, and bruising,
but eventually recovered after receiving plasmapheresis. The relationship to
RISPERDAL® therapy is unknown.
Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect
may also occur in humans, and may mask signs and symptoms of overdosage with
certain drugs or of conditions such as intestinal obstruction, Reye's syndrome,
and brain tumor.
Body Temperature Regulation
Disruption of body temperature regulation has been attributed
to antipsychotic agents. Both hyperthermia and hypothermia have been reported
in association with oral RISPERDAL® use. Caution is advised when
prescribing for patients who will be exposed to temperature extremes.
Suicide
The possibility of a suicide attempt is inherent in schizophrenia,
and close supervision of high-risk patients should accompany drug therapy. Prescriptions
for RISPERDAL® should be written for the smallest quantity of
tablets, consistent with good patient management, in order to reduce the risk
of overdose. Use in Patients With Concomitant Illness Clinical experience with
RISPERDAL® in patients with certain concomitant systemic illnesses
is limited. Caution is advisable in using RISPERDAL® in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
RISPERDAL® has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial infarction
or unstable heart disease. Patients with these diagnoses were excluded from
clinical studies during the product's premarket testing. Increased plasma concentrations
of risperidone and 9-hydroxyrisperidone occur in patients with severe renal
impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase
in the free fraction of risperidone is seen in patients with severe hepatic
impairment. A lower starting dose should be used in such patients (see DOSAGE
AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with
patients for whom they prescribe RISPERDAL®:
Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension,
especially during the period of initial dose titration.
Interference With Cognitive and Motor Performance
Since RISPERDAL® has the potential toimpair
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.
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) (16mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice)
or 0.4, 1.5, and 6times 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 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 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.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery
in humans is unknown.
Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are
excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in
human breast milk. Therefore, women receiving risperidone should not breast-feed.
Pediatric Use
Safety and effectiveness in children have not been established.
Geriatric Use
Clinical studies of RISPERDAL® 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).
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