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warnings and cautions
5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased incidence of cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack) ( 5.3 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.4 ) Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.5 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain ( 5.6 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing REXULTI if a clinically significant decline in WBC occurs in absence of other causative factors ( 5.7 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.8 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.10 ) 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. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3) ] . 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3. No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. Table 3: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing REXULTI, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.3 Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.1) ]. 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue REXULTI and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly, especially elderly women, but it is not possible to predict which patients are likely to develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown. The risk of tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, REXULTI should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and (2) for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment needed to produce a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on REXULTI, drug discontinuation should be considered. However, some patients may require treatment with REXULTI despite the presence of the syndrome. 5.6 Metabolic Changes Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile. 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. There have been reports of hyperglycemia in patients treated with REXULTI [see Adverse Reactions (6.1 )] . Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. Major Depressive Disorder In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In the long-term, open-label depression studies, 5% of patients with normal baseline fasting glucose experienced a shift to high while taking REXULTI+Antidepressant (ADT); 25% of subjects with borderline fasting glucose experienced shifts to high. Combined, 9% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies. Schizophrenia In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo. In the long-term, open-label schizophrenia studies, 8% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI, 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies. Dyslipidemia Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Major Depressive Disorder In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 4 shows the proportions of patients with changes in fasting triglycerides. Table 4: Change in Fasting Triglycerides in the 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials Proportion of Patients with Shifts Baseline to Post-Baseline Placebo 1 mg/day 2 mg/day 3 mg/day Triglycerides Normal to High (<150 mg/dL to ≥200 and <500 mg/dL) 6% (15/257) * 5% (7/145) * 13% (15/115) * 9% (13/150) * Normal/Borderline to Very High (<200 mg/dL to ≥500 mg/dL) 0% (0/309) * 0% (0/177) * 0.7% (1/143) * 0% (0/179) * * denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result. n=the number of subjects with shift. In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies. Schizophrenia In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients. Table 5 shows the proportions of patients with changes in fasting triglycerides. Table 5: Change in Fasting Triglycerides in the 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials Proportion of Patients with Shifts Baseline to Post-Baseline Placebo 1 mg/day 2 mg/day 4 mg/day Triglycerides Normal to High (<150 mg/dL to ≥200 and <500 mg/dL) 6% (15/253) * 10% (7/72) * 8% (19/232) * 10% (22/226) * Normal/Borderline to Very High (<200 mg/dL to ≥500mg/dL) 0% (0/303) * 0% (0/94) * 0% (0/283) * 0.4% (1/283) * * denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result. n=the number of subjects with shift. In the long-term, open-label schizophrenia studies, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies. Weight Gain Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter. Major Depressive Disorder Table 6 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with MDD. Table 6: Increases in Body Weight in the 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials Placebo 1 mg/day 2 mg/day 3 mg/day n=407 n=225 n=187 n=228 Mean Change from Baseline (kg ) at Last Visit All Patients +0.3 +1.3 +1.6 +1.6 Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (*n/N) 2% 5% 5% 2% (8/407) * (11/225) * (9/187) * (5/228) * * N=the total number of subjects who had a measurement at baseline and at least one post-baseline result. n=the number of subjects with a shift ≥7%. In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 2.9 kg at week 26 and 3.1 kg at week 52. In the long-term, open label depression studies, 30% of patients demonstrated a ≥7% increase in body weight and 4% demonstrated a ≥7% decrease in body weight. Schizophrenia Table 7 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with schizophrenia. Table 7: Increases in Body Weight in the 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials Placebo 1 mg/day 2 mg/day 4 mg/day n=362 n=120 n=362 n=362 Mean Change from Baseline (kg ) at Last Visit All Patients +0.2 +1.0 +1.2 +1.2 Proportion of Patients with a ≥7% Increase in Body Weight (kg) at Any Visit (*n/N) 4% 10% 11% 10% (15/362) * (12/120) * (38/362) * (37/362) * * denotes n/N where N=the total number of subjects who had a measurement at baseline and at least one post-baseline result. n=the number of subjects with a shift ≥7%. In the long-term, open-label schizophrenia studies, 0.6% of patients discontinued due to weight increase. REXULTI was associated with mean change from baseline in weight of 1.3 kg at week 26 and 2.0 kg at week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight and 10% demonstrated a ≥7% decrease in body weight. 5.7 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of REXULTI at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue REXULTI in patients with absolute neutrophil count <1000/mm 3 and follow their WBC until recovery. 5.8 Orthostatic Hypotension and Syncope Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of REXULTI+ADT in patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in REXULTI+ADT-treated patients compared to placebo+ADT patients included: dizziness (2% vs. 2%) and orthostatic hypotension (0.1% vs. 0%). In the short-term, placebo-controlled clinical studies of REXULTI in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in REXULTI-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. REXULTI has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical trials. 5.9 Falls . Antipsychotics, including REXULTI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.10 Seizures Like other antipsychotic drugs, REXULTI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients. 5.11 Body Temperature Dysregulation Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use REXULTI with caution in patients who may experience these conditions. 5.12 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including REXULTI, should be used cautiously in patients at risk for aspiration. 5.13 Potential for Cognitive and Motor Impairment REXULTI, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week, placebo-controlled clinical trials in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for REXULTI+ADT-treated patients compared to 1% of placebo+ADT patients. In 6-week, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.