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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). ( 5.2 ) QTc Interval Prolongation: may be associated with torsade de pointes and sudden death. Avoid concomitant use of BYSANTI with other drugs that prolong the QTc interval, and in patients with a significant risk of developing torsade de pointes; consider decreasing the BYSANTI dosage when prescribing BYSANTI with other drugs that inhibit milsaperidone metabolism or in CYP2D6 poor metabolizers. Monitor serum potassium and magnesium at baseline and during treatment in patients at risk for significant electrolyte disturbances ( 5.3 , 7.1 , 7.2 ) Neuroleptic Malignant Syndrome (NMS): If NMS is suspected, immediately discontinue BYSANTI and provide intensive symptomatic treatment 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 ) Orthostatic hypotension and Syncope: Monitor heart rate and blood pressure in patients who are vulnerable to hypotension, and in those with known cardiovascular or cerebrovascular disease. ( 5.7 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower seizure threshold. ( 5.9 ) Leukopenia, Neutropenia, and Agranulocytosis: Patients with a pre-existing low white blood cell count (WBC) or absolute neutrophil count or a history of drug induced leukopenia or neutropenia should have frequent monitoring of their complete blood count during the first few months of BYSANTI therapy and should discontinue BYSANTI at the first sign of a decline in WBC in the absence of other causative factors. Discontinue BYSANTI in patients with absolute ANC <1000/mm3 and follow their WBC until recovery. ( 5.10 ) Priapism: Severe priapism may require surgical intervention. ( 5.14 ) Potential for Cognitive and Motor Impairment: Use caution about driving a motor vehicle or operating hazardous machinery until patients are reasonably certain that therapy with BYSANTI does not adversely affect them. ( 5.15 ) Intraoperative Floppy Iris Syndrome (IFIS): IFIS during cataract surgery may require modifications to the surgical cataract technique. ( 5.16 ) 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 for dementia-related psychosis, revealed a risk of death in antipsychotic drug-treated patients was 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 incidence of death in antipsychotic drug-treated patients was about 4.5%, compared to an incidence of about 2.6% in placebo-treated patients. 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. BYSANTI is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis In placebo-controlled trials in elderly patients with dementia-related psychosis treated with risperidone, aripiprazole, or olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke compared to those treated with placebo. BYSANTI is not approved for the treatment of patients with dementia-related psychosis [see Indications and Usage (1) ] . 5.3 QTc Interval Prolongation In a QTc study, the use of iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) was associated with QTc interval prolongation, especially with concomitant use of a CYP2D6 inhibitor or a CYP3A4 inhibitor. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the iloperidone studies. Risk Factors for Clinically Significant Risks of QTc Interval Prolongation Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including ischemic cardiomyopathy; hypokalemia; genetic predisposition, concomitant use of other drugs that prolong the QTc interval or increases the exposure of the drug; and elevated baseline QTc interval. Steps to Prevent or Mitigate Clinically Significant Adverse Reactions or Risks Associated with QTc Interval Prolongation The concomitant use of BYSANTI should be avoided with other drugs that prolong the QTc interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic drugs that prolong the QTc interval (e.g., chlorpromazine, thioridazine), antibiotics that prolong the QTc interval (e.g., gatifloxacin, moxifloxacin), or any other class of drugs known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). BYSANTI should also be avoided in other patients with significant risk of developing torsades de pointes including those with congenital long QT syndrome, recent myocardial infarction, ischemic cardiomyopathy, unstable angina, bradyarrhythmias, uncontrolled hypertension, high degree atrioventricular block, severe aortic stenosis, or uncontrolled hypothyroidism. When BYSANTI is used concomitantly with other drugs (e.g., strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and taking both a CYP2D6 inhibitor and a CYP3A4 inhibitor) [see Drug Interactions (7.1) ] or in patients with decreased activity of CYP2D6 [see Clinical Pharmacology (12.5) ] decrease the BYSANTI dosage [see Dosage and Administration (2.x) ] . Patients being considered for BYSANTI treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring because hypokalemia (and/or hypomagnesemia) may increase the risk of QTc interval prolongation and arrhythmia. BYSANTI should be discontinued in patients who are found to have persistent QTc measurements >500 msec. If patients taking BYSANTI experience symptoms that could indicate the occurrence of arrhythmias, e.g., dizziness, palpitations, or syncope, the health care provider should initiate further evaluation, including cardiac monitoring. 5.4 Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue BYSANTI and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia Tardive dyskinesia (TD), may develop in patients treated with antipsychotic drugs, including BYSANTI. TD can develop after relatively brief treatment period at low dosages and may also occur after discontinuation of treatment. If antipsychotic drug treatment is discontinued, TD may partially or completely remission. Antipsychotic treatment, however, may suppress or partially suppress the signs and symptoms of TD, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of TD is unknown. The TD risk in patients treated with antipsychotic drugs appears to be highest among the elderly, especially elderly women, but it is impossible to predict, which patients will develop TD. The risk of developing TD and the likelihood that TD will become irreversible increase with the duration of antipsychotic drug treatment and the cumulative dosage. In patients who require chronic antipsychotic drug treatment, use the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. If signs and symptoms of TD appear in a BYSANTI-treated patient, consider drug discontinuation. However, some patients may require BYSANTI treatment despite the presence of TD. 5.6 Metabolic Changes Atypical antipsychotic drugs have caused metabolic changes (e.g., hyperglycemia, dyslipidemia, and body weight gain) that may increase cardiovascular/cerebrovascular risk. 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 iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo). Assess fasting plasma glucose before or soon after initiation BYSANTI and monitor periodically during long-term treatment. Schizophrenia: In a 4-week fixed-dose placebo-controlled study of adults with schizophrenia (Study 2) [see Clinical Studies (14.1) ] , the mean change from baseline in serum glucose was 6.6 mg/dL and -0.5 mg/dL for iloperidone- and placebo-treated patients, respectively. The proportion of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) were 10.7% and 2.5% for the iloperidone- and placebo-treated patients, respectively. In pooled analyses from clinical studies, for adults with schizophrenia who remained on treatment with iloperidone 10-16 mg/day glucose increased, on average, from baseline by 1.8 mg/dL at 3-6 months (N=773), by 5.4 mg/dL at 6-12 months (N=723), and by 5.4 mg/dL at >12 months (N=425) of treatment. In a smaller subpopulation of patients who remained on treatment with iloperidone 20-24 mg/day, glucose decreased by 3.6 mg/dL at 3-6 months (N=34); by 9 mg/dL at 6-12 months (N=31), and by 18 mg/dL at >12 months (N=20) of treatment. Bipolar Mania: In a 4-week fixed dose study of adults with bipolar mania (Study 4) [see Clinical Studies (14.2) ] , mean changes from baseline in serum glucose and the proportion of patients with shifts in fasting glucose from Normal (<100 mg/dL) to High (≥126 mg/dL) for iloperidone-treated patients placebo-treated patients were similar. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or soon after initiation of antipsychotic drugs, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Schizophrenia: In a 4-week fixed dose study of adults with schizophrenia (Study 2), the mean change from baseline in fasted total cholesterol was 8.2 mg/dL and -2.2 mg/dL for iloperidone- and placebo-treated patients, respectively. The effects on LDL were similar to those on total cholesterol (changes of 9 mg/dL and -1.4 mg/dL for iloperidone- and placebo-treated patients, respectively). Mean changes from baseline in fasted triglycerides were -0.8 mg/dL and 16.5 mg/dL for iloperidone-and placebo-treated patients, respectively. The proportion of patients with shifts from normal to high fasted total cholesterol, LDL, and triglycerides were similar for iloperidone- and placebo-treated patients. The proportion of patients with shifts in fasted HDL from normal (≥40 mg/dL) to low (<40 mg/dL) was greater for placebo-treated patients (23.8%) compared to iloperidone-treated (12.1%). In pooled analysis from clinical studies, for adults with schizophrenia who remained on treatment with iloperidone, on average, both cholesterol and triglycerides decreased from baseline for those who remained on treatment at 3-6 months, 6-12 months, and >12-month time points in both 10-16 mg/day and 20-24 mg/day dosing groups. Bipolar Mania: In a 4-week fixed dose study of adults with bipolar mania (Study 4), the mean changes from baseline for fasted total cholesterol, LDL, HDL, and triglycerides for iloperidone-treated patients were similar to those for placebo-treated patients. The proportion of patients with shifts in fasted total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL) was greater for iloperidone-treated patients (10.7%) than placebo-treated patients (7.2%). Shifts from normal to high LDL and triglycerides and from normal to low HDL occurred at rates for iloperidone-treated patients similar to those for placebo treated patients. Weight Gain Weight gain has been observed with atypical antipsychotic use. Monitor weight at baseline and frequently thereafter. Schizophrenia: Across all short- and long-term studies of adults with schizophrenia, the overall mean increase in weight in iloperidone-treated patients from baseline at endpoint was 2.1 kg. In 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adults with schizophrenia the mean change in weight was -0.1 kg, 2 kg, and 2.7 kg for the placebo, iloperidone 10-16 mg/day, and iloperidone 20-24 mg/day groups, respectively. The proportion of patients with >7% increase in weight from baseline was 4%, 12%, and 18% for placebo, iloperidone 10-16 mg/day, and iloperidone 20-24 mg/day groups, respectively. Bipolar Mania: In a 4-week fixed dose study of adults with bipolar mania (Study 4), the mean increase in weight was 1.6 kg and 4.6 kg for the placebo and iloperidone 24 mg/day groups, respectively. The proportion of patients with ≥7% increase in weight from baseline was 14% and 35%, in the placebo and iloperidone 24 mg/day groups, respectively. 5.7 Orthostatic Hypotension and Syncope BYSANTI can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies in patients with schizophrenia, where the dosage was increased slowly [see Clinical Studies (14.1) ] , syncope was reported in 0.4% (5/1,344) of iloperidone-treated patients (iloperidone and milsaperidone rapidly interconvert in vivo), compared with 0.2% (1/587) in placebo-treated patients. Orthostatic hypotension was reported in 5% of patients who received 20 mg to 24 mg/day of iloperidone, 3% of patients who received 10 mg to 16 mg/day of iloperidone, and 1% of patients who received placebo. In a double-blind placebo-controlled short-term study in patients with bipolar mania (Study 4), syncope was reported in 0.5% (1/206) of iloperidone-treated patients with, compared with 0% (0/208) in placebo-treated patients. In Study 4, orthostatic hypotension was reported in 4% (9/206) of iloperidone-treated patients and 2% (5/208) of placebo-treated patients. More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive drugs), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. 5.8 Falls Antipsychotics, including BYSANTI, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. If patients have a condition or take concomitant drugs that could exacerbate these effects, complete fall risk assessments when initiating BYSANTI treatment and recurrently for patients on long-term treatment. 5.9 Seizures Like other antipsychotic drugs, BYSANTI may cause seizures. The risk antipsychotic drug-associated 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. Use BYSANTI cautiously in patients with a history of seizures or with other conditions that lower seizure threshold. 5.10 Leukopenia, Neutropenia and Agranulocytosis In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally related to antipsychotic drug treatment. Agranulocytosis (including fatal cases) has also been reported with antipsychotic drug use. Possible risk factors for antipsychotic drug-associated leukopenia or neutropenia include preexisting low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug induced leukopenia or neutropenia. Patients with a pre-existing low WBC or ANC or a history of drug induced leukopenia or neutropenia should have frequently monitoring of their complete blood count (CBC) during the first few months of BYSANTI therapy and should discontinue BYSANTI at the first sign of a 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 BYSANTI in patients with absolute ANC <1000/mm 3 and follow their WBC until recovery. 5.11 Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, BYSANTI elevates prolactin levels. 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 with drugs associated with hyperprolactinemia. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male patients. Published epidemiologic studies have shown inconsistent results regarding the potential association between hyperprolactinemia and breast cancer. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro , a factor of potential importance if the use of a dopamine D2 receptor antagonist, including BYSANTI, is contemplated in a patient with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin were seen in mice and rats treated with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) [see Nonclinical Toxicology (13) ] . In a short-term placebo-controlled trial (4-weeks) in patients with schizophrenia (Study 2), the mean change from baseline to endpoint in plasma prolactin levels for the iloperidone 24 mg/day-treated group was an increase of 2.6 ng/mL compared to a decrease of 6.3 ng/mL in the placebo-group. In placebo-controlled trials in adult patients with schizophrenia, elevated plasma prolactin levels (≥1.15xULN) were observed in 26% of iloperidone-treated patients compared to 12% of placebo-treated patients. In the short-term trials, iloperidone was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic drugs. In pooled analysis from clinical studies including longer term trials, in 3,210 adults treated with iloperidone, gynecomastia was reported in 2 iloperidone-treated male patients (0.1%) compared to 0% in placebo-treated patients, and galactorrhea was reported in 8 iloperidone-treated female patients (0.2%) compared to 3 placebo-treated female patients (0.5%). In a 4-week, placebo-controlled trial in patients with bipolar mania (Study 4), the mean change from baseline to endpoint in plasma prolactin levels for the iloperidone group was an increase of 15.7 ng/mL compared to a decrease of 0.6 ng/mL for the placebo group. In this trial, elevated plasma prolactin levels (≥1.15xULN) were observed in 35% of iloperidone-treated patients with compared to 1% of the placebo-treated patients. 5.12 Body Temperature Regulation 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 BYSANTI with caution in patients who may experience these conditions. 5.13 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including BYSANTI, should be used cautiously in patients at risk for aspiration. 5.14 Priapism In the clinical studies [see Clinical Studies (14) ] , three cases of priapism were reported in iloperidone-treated patients (iloperidone and milsaperidone rapidly interconvert in vivo) with schizophrenia and 1 case was reported in an iloperidone-treated patient with manic and mixed episodes associated with bipolar I disorder). Drugs with alpha-adrenergic blocking effects, including BYSANTI, have been reported to induce priapism. Severe priapism may require surgical intervention. 5.15 Potential for Cognitive and Motor Impairment BYSANTI, like other antipsychotics, may cause somnolence and has the potential to impair judgment, thinking or motor skills. In short-term, placebo-controlled trials of schizophrenia in adults, somnolence (including sedation) was reported in 12% (104/874) of patients treated with iloperidone (iloperidone and milsaperidone rapidly interconvert in vivo) at dosage of 10 mg/day or greater versus 5.3% (31/587) of patients treated with placebo. In a short-term, placebo-controlled trial of bipolar mania (Study 4), somnolence (including sedation) was reported in 8% (16/206) of patients treated with iloperidone versus 3% (6/208) of patients treated with placebo. Patients should be cautioned about driving a motor vehicle or operating hazardous machinery, until they are reasonably certain that therapy with BYSANTI does not adversely affect them. 5.16 Intraoperative Floppy Iris Syndrome Intraoperative floppy iris syndrome has been observed during cataract surgery in some patients on or previously treated with alpha-1 adrenergic blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The initiation of therapy with BYSANTI in patients for whom cataract or glaucoma surgery is scheduled is not recommended. In patients taking or previously treated with alpha-1 adrenergic blockers, including BYSANTI, surgeons should be prepared for possible modifications to their surgical cataract technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha1 blocker therapy prior to cataract surgery.