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warnings and cautions
WARNINGS AND PRECAUTIONS SECTION 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. 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. RISPERIDONE (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning ]. 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (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. RISPERIDONE is not approved for the treatment of patients with dementia-related psychosis [see also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]. 5.3 Neuroleptic Malignant Syndrome Antipsychotic drugs including RISPERIDONE can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase (CPK), 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. 5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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, prescribe RISPERIDONE 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 RISPERIDONE, consider drug discontinuation. However, some patients may require treatment with RISPERIDONE despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERIDONE. 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, including RISPERIDONE, 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, including RISPERIDONE, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERIDONE, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including RISPERIDONE, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERIDONE, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERIDONE. Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2. Table 2Change in Random Glucose from Seven Placebo-Controlled, 3 to 8 Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania RISPERIDONE Placebo 1 to 8 mg/day > 8 to 16 mg/day Mean change from baseline (mg/dL) n=555 n=748 n=164 Serum Glucose -1.4 0.8 0.6 Proportion of patients with shifts Serum Glucose (< 140 mg/dL to ≥ 200 mg/dL) 0.6% (3/525) 0.4% (3/702) 0% (0/158) In longer-term, controlled and uncontrolled studies, RISPERIDONE was associated with a mean change in glucose of + 2.8 mg/dL at Week 24 (n=151) and + 4.1 mg/dL at Week 48 (n = 50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3. Table 3Change in Fasting Glucose from Three Placebo-Controlled, 3 to 6 Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13 to 17 years of age), Bipolar Mania (10 to 17 years of age), or Autistic Disorder (5 to 17 years of age) Placebo RISPERIDONE 0.5-6 mg/day Mean change from baseline (mg/dL) n=76 n=135 Serum Glucose -1.3 2.6 Proportion of patients with shifts Serum Glucose (<100 mg/dL to ≥126 mg/dL) 0% (0/64) 0.8% (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, RISPERIDONE was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n = 119). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4. Table 4Change in Random Lipids From Seven Placebo-Controlled, 3 to 8 Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERIDONE Placebo 1 to 8 mg/day >8 to 16 mg/day Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9 1.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4 -4.9 -8.3 RISPERIDONE Placebo 1 to 8 mg/day >8 to 16 mg/day Proportion of patients With Shifts Cholesterol (<200 mg/dL to ≥240 mg/dL) 2.7% (10/368) 4.3% (22/516) 6.3% (6/96) Triglycerides (<500 mg/dL to ≥500 mg/dL) 1.1% (2/180) 2.7% (8/301) 2.5% (3/121) In longer-term, controlled and uncontrolled studies, RISPERIDONE was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n = 231) and +5.5 mg/dL at Week 48 (n = 86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n = 52). Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 5. Table 5Change in Fasting Lipids From Three Placebo-Controlled, 3 to 6 Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) Placebo RISPERIDONE 0.5 to 6 mg/day Mean change from baseline (mg/dL) Cholesterol n=74 n=133 Change from baseline 0.3 -0.3 LDL n=22 n=22 Change from baseline 3.7 0.5 HDL n=22 n=22 Change from baseline 1.6 -1.9 Triglycerides n=77 n=138 Change from baseline -9 -2.6 Placebo RISPERIDONE 0.5 to 6 mg/day Proportion of patients with shifts Cholesterol (<170 mg/dL to ≥200 mg/dL) 2.4% (1/42) 3.8% (3/80) LDL (<110 mg/dL to ≥130 mg/dL) 0% (0/16) 0% (0/16) HDL (≥40 mg/dL to <40 mg/dL) 0% (0/19) 10% (2/20) Triglycerides (<150 mg/dL to ≥200 mg/dL) 1.5% (1/65) 7.1% (8/113) In longer-term, uncontrolled, open-label extension pediatric studies, RISPERIDONE was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n = 114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n = 103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n = 120). Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6. Table 6Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3 to 8 Week, Fixed-or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERIDONE Placebo 1 to 8 mg/day >8 to 16 mg/day (n = 597) (n = 769) (n = 158) Weight (kg) Change from baseline -0.3 0.7 2.2 Weight Gain ≥7% increase from baseline 2.9% 8.7% 20.9% In longer-term, controlled and uncontrolled studies, RISPERIDONE was associated with a mean change in weight of +4.3 kg at Week 24 (n = 395) and +5.3 kg at Week 48 (n = 203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 7. Table 7Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥ 7% Gain in Body Weight From Nine Placebo-Controlled, 3 to 8 Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13 to 17 Years of Age), Bipolar Mania (10 to 17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5 to 17 Years of Age) Placebo RISPERIDONE 0.5 to 6 mg/day (n=375) (n=448) Weight (kg) Change from baseline 0.6 2 Weight Gain ≥7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, RISPERIDONE was associated with a mean change in weight of +5.5 kg at Week 24 (n = 748) and +8 kg at Week 48 (n = 242). In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9 kg was observed after 8 months of RISPERIDONE treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index. 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 RISPERIDONE 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 RISPERIDONE. 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. In one 3 week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERIDONE groups than the placebo group, but not dose related (1.90 kg in the RISPERIDONE 0.5 to 2.5 mg group, 1.44 kg in the RISPERIDONE 3 to 6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with RISPERIDONE for any indication, weight gain should be assessed against that expected with normal growth. 5.6 Hyperprolactinemia 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. Long standing 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 Non-Clinical Toxicology ( 13.1 )]. 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. 5.7 Orthostatic Hypotension 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 RISPERIDONE-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see DOSAGE AND ADMINISTRATION ( 2.1 , 2.4 )]. 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. RISPERIDONE 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 RISPERIDONE and antihypertensive medication. 5.8 Leukopenia, Neutropenia, and Agranulocytosis Class Effect In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERIDONE. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of RISPERIDONE should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue RISPERIDONE and have their WBC followed until recovery. 5.9 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reaction associated with RISPERIDONE treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERIDONE 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 RISPERIDONE 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since RISPERIDONE 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 RISPERIDONE therapy does not affect them adversely. 5.10 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERIDONE-treated patients, two in association with hyponatremia. RISPERIDONE should be used cautiously in patients with a history of seizures. 5.11 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. RISPERIDONE and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see also BOXED WARNING and WARNINGS AND PRECAUTIONS ( 5.1 )]. 5.12 Priapism Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention. 5.13 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 RISPERIDONE use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.