Here's what most people on this drug don't get told...
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. RISPERDAL®(risperidone) is not approved for the treatment of dementia-related psychosis (see BOXED WARNING).
Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® (risperidone) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® despite the presence of the syndrome.
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis (See also BOXED WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including RISPERDAL®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of 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.
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.
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.
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.)
As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Longstanding hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility). 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.
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.
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.
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL® should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.
Use in Patients With Concomitant Illness
Clinical experience with RISPERDAL® in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including RISPERDAL®, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using RISPERDAL® in patients with diseases or conditions that could affect metabolism or hemodynamic responses. RISPERDAL® has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m²), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
No specific laboratory tests are recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m² basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on a mg/m² (mg/kg) basis at which these tumors occurred.
Multiples of Maximum
Human Dose in mg/m²
Tumor Type Species Sex Lowest
Effect Level Highest No-
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).
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 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/m²basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m² basis.
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL® therapy is unknown. Reversible extrapyramidal symptoms in the neonate were observed following postmarketing use of risperidone during the last trimester of pregnancy.
RISPERDAL® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of RISPERDAL® on labor and delivery in humans is unknown.
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.
The safety and effectiveness of RISPERDAL® in pediatric patients with schizophrenia or bipolar mania have not been established.
The efficacy and safety of RISPERDAL® in the treatment of irritability associated with autistic disorder were established in two 8-week, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years (see CLINICAL PHARMACOLOGY - Clinical Trials, INDICATIONS AND USAGE, and ADVERSE REACTIONS). Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with other psychiatric disorders who were of similar age and weight, and who received similar dosages of RISPERDAL® as patients who were treated for irritability associated with autistic disorder.
The safety and effectiveness of RISPERDAL® in pediatric patients with autistic disorder less than 5 years of age have not been established.
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment (see WARNINGS – Tardive Dyskinesia).
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index. When treating patients with RISPERDAL®, weight gain should be assessed against that expected with normal growth. (See also ADVERSE REACTIONS.)
Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. (See also ADVERSE REACTIONS.) Patients experiencing persistent somnolence may benefit from a change in dosing regimen (see DOSAGE AND ADMINISTRATION – Irritability Associated with Autistic Disorder).
Hyperprolactinemia, Growth, and Sexual Maturation
Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults (see PRECAUTIONS - Hyperprolactinemia). In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo.
In clinical trials in 1885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.
The long-term effects of risperidone on growth and sexual maturation have not been fully evaluated.
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 two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of RISPERDAL® regardless of concomitant use with furosemide. RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis. (See BOXED WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)
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FDA Approves Adult Psychiatric Drug for Use on Adolescent Patients
(AP) 02:23:21 PM (ET), Wednesday, August 22, 2007 (WASHINGTON)
The Food and Drug Administration on Wednesday approved a widely used adult psychiatric drug for the treatment of schizophrenia and bipolar disorder in children and adolescents.
The action permits use of Risperdal for schizophrenia in youths aged 13 to 17 and for bipolar disorder in those aged 10 to 17, FDA said.
It was approved last fall for treatment of irritability in autism.
Risperdal, manufactured by Janssen, L.P. of Titusville, N.J., is the No. 3 anti-psychotic drug, with $2.3 billion in sales in 2005, according to the pharmaceutical data company IMS Health. Janssen is a unit of Johnson & Johnson.
Risperdal was approved for use in adults in 1993.
Until now, FDA said, there has been no approved drug for the treatment of schizophrenia in youths and only lithium is approved for the treatment of bipolar disorder in adolescents.
The dose approved for youths is slightly lower than the adult dose, FDA said.
Drowsiness, fatigue, increase in appetite, anxiety, nausea, dizziness, dry mouth, tremor, and rash were among the most common side effects reported, the agency said.