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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, including fatalities) ( 5.2 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring ( 5.3 ) Tardive Dyskinesia: Discontinue if clinically appropriate ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain ( 5.5 ) Pathological Gambling and Other Compulsive Behaviors: Consider dose reduction or discontinuation ( 5.6 ) Orthostatic Hypotension: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood cell counts in patients with a history of a clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC). Consider discontinuing MEZOFY if clinically significant decline in WBC/ANC in the absence of other causative factors ( 5.9 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold ( 5.10 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery ( 5.11 ) 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. MEZOFY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning , Warnings and Precautions (5.2) ] . 5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. MEZOFY is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning ] . 5.3 Neuroleptic Malignant Syndrome (NMS) Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including aripiprazole. Rare cases of NMS have been reported during aripiprazole treatment in the global clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue MEZOFY and provide intensive symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia A syndrome 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 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 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. Tardive dyskinesia 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, MEZOFY 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: 1) who suffer from a chronic illness that 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient on MEZOFY, drug discontinuation should be considered. However, some patients may require treatment with MEZOFY despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Although all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/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 aripiprazole [see Adverse Reactions (6.1 , 6.2) ] . Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment. Adults In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 2 shows the proportion of aripiprazole -treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). Table 2 Changes in Fasting Glucose from Placebo-Controlled Monotherapy Trials in Adult Patients Fasting Glucose Category Change (at least once) from Baseline Treatment Arm n/N % Normal to High (<100 mg/dL to ≥126 mg/dL) Aripiprazole 31/822 3.8 Placebo 22/605 3.6 Borderline to High (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) Aripiprazole 31/176 17.6 Placebo 13/142 9.2 At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively]. Pediatric Patients In an analysis of two placebo-controlled trials of 4- to 6-weeks duration in pediatric patients with schizophrenia (13 to 17 years) and another indication, the mean change in fasting glucose in aripiprazole-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123). At 12 weeks in pooled trials in pediatric schizophrenia and another indication, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively]. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients. Adults Table 3 shows the proportion of adult patients, primarily from pooled schizophrenia and another indication monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). Table 3 Changes in Blood Lipid Parameters from Placebo-Controlled Monotherapy Trials in Adults Treatment Arm n/N % Total Cholesterol Aripiprazole 34/1357 2.5 Normal to High (<200 mg/dL to ≥240 mg/dL) Placebo 27/973 2.8 Fasting Triglycerides Aripiprazole 40/539 7.4 Normal to High (<150 mg/dL to ≥200 mg/dL) Placebo 30/431 7.0 Fasting LDL Cholesterol Aripiprazole 2/332 0.6 Normal to High (<100 mg/dL to ≥160 mg/dL) Placebo 2/268 0.7 HDL Cholesterol Aripiprazole 121/1066 11.4 Normal to Low (≥40 mg/dL to <40 mg/dL) Placebo 99/794 12.5 In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. Pediatric Patients In monotherapy trials of pediatric patients with schizophrenia and another indication, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Adults In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and another indication with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients. In trials of adjunctive aripiprazole for another indication, patients first received 8 weeks of treatment with another medication followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing treatment. The mean change in body weight in patients receiving adjunctive aripiprazole was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo. Table 4 shows the percentage of adult patients with weight gain ≥7% of body weight by indication. Table 4 Percentage of Patients from Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight Weight gain ≥7% of body weight Indication Treatment Arm n/N Patients n (%) Schizophrenia (4- to 6-week duration) Aripiprazole 852 69 (8.1) Placebo 379 12 (3.2) Other Indication (3-week duration) Aripiprazole 719 16 (2.2) Placebo 598 16 (2.7) Other Indication (6-week duration) Aripiprazole 347 18 (5.2) Placebo 330 2 (0.6) Pediatric Patients In an analysis of two placebo-controlled trials in pediatric patients with schizophrenia (13 to 17 years) and another indication (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in aripiprazole -treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients. In two short-term, placebo-controlled trials in patients (6 to 17 years) in another indication with median exposure of 56 days, the mean change in body weight in aripiprazole-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients. Table 5shows the percentage of pediatric patients with weight gain ≥7% of body weight by indication. Table 5 Percentage of Patients from Placebo-Controlled Monotherapy Trials in Pediatric Patients with Weight Gain ≥7% of Body Weight Weight gain ≥7% of body weight Indication Treatment Arm n/N Patients n (%) Pooled Schizophrenia and Another Indication (4- to 6-week duration) Aripiprazole 381 20 (5.2) Placebo 187 3 (1.6) Another Indication (8-week duration) Aripiprazole 209 55 (26.3) Placebo 98 7 (7.1) In an open-label trial that enrolled patients from the two placebo-controlled trials of pediatric patients with schizophrenia (13 to 17 years) and another indication (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with aripiprazole. After 26 weeks, 32.8% of patients gained ≥7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients by comparisons to age- and gender-matched population standards. A z-score change <0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD. When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth. MEZOFY is not approved for use in pediatric patients less than 13 years of age [Use in Specific Populations (8.4)]. 5.6 Pathological Gambling and Other Compulsive Behaviors Postmarketing reports with aripiprazole suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with MEZOFY. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges. 5.7 Orthostatic Hypotension and Syncope MEZOFY may cause orthostatic hypotension and syncope, perhaps due to its α 1- -adrenergic receptor antagonism. Generally, the risk is greatest during initial dose titration and when increasing the dose. The incidence of orthostatic hypotension-associated reactions from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 17 years of age (n=611) on oral aripiprazole included orthostatic hypotension (0.5%, 0%), postural dizziness (0.3%, 0%), and syncope (0.2%, 0%) [see Adverse Reactions (6.1) ] . The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence): in adult oral aripiprazole-treated patients (4%, 2%), in pediatric oral aripiprazole-treated patients aged 6 to 17 years (0.2%, 1%). MEZOFY is not approved for use in pediatric patients less than 13 years of age [Use in Specific Populations (8.4)]. Use MEZOFY with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see Drug Interactions (7.1) ]. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension. 5.8 Falls Antipsychotics, including MEZOFY, 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 periodically during long-term therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia have been reported during treatment with antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported. 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/neutropenia. In patients with a pre-existing WBC or ANC or 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 MEZOFY 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 MEZOFY in patients with absolute neutrophil count <1000/mm 3 and follow their WBC until recovery. 5.10 Seizures Like other antipsychotics, MEZOFY may cause seizures. The 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. In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral aripiprazole, and in 0.2% (1/611) of pediatric patients (6 to 17 years). MEZOFY is not approved for use in pediatric patients less than 13 years of age [Use in Specific Populations (8.4)]. 5.11 Potential for Cognitive and Motor Impairment MEZOFY, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking, or motor skills. In short-term, placebo-controlled clinical trials, somnolence (including sedation) was reported as follows (aripiprazole incidence, placebo incidence): in adult patients (n=2467) treated with oral aripiprazole (11%, 6%), and in pediatric patients ages 6 to 17 (n=611) (24%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (15/611) of pediatric patients (6 to 17 years) on oral aripiprazole in short-term, placebo-controlled trials. MEZOFY is not approved for use in pediatric patients less than 13 years of age [Use in Specific Populations (8.4)]. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with MEZOFY does not affect them adversely. 5.12 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 MEZOFY with caution in patients who may experience these conditions . 5.13 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Antipsychotic drugs, including MEZOFY, should be used cautiously in patients at risk for aspiration.