INVEGA TRINZA® (paliperidone palmitate)

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IMPORTANT SAFETY INFORMATION and INDICATION for INVEGA TRINZA^® (paliperidone palmitate)

INVEGA TRINZA^® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA^® (1-month paliperidone palmitate) for at least four months.

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IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

See full Prescribing Information for complete Boxed Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death
INVEGA TRINZA^® is not approved for the treatment of patients with dementia-related psychosis

Contraindications: Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the formulation.

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone, aripiprazole, and olanzapine. The incidence of cerebrovascular adverse reactions was significantly higher than with placebo. INVEGA TRINZA^® is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly female patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

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, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension and Syncope: INVEGA TRINZA^® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. INVEGA TRINZA^® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including paliperidone. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of INVEGA TRINZA^® should be considered. 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 INVEGA TRINZA^® and have their WBC followed until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ receptors, INVEGA TRINZA^® elevates prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA TRINZA^®. INVEGA TRINZA^® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA TRINZA^® does not adversely affect them.

Seizures: INVEGA TRINZA^® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Administration: For intramuscular injection only by a healthcare professional. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA TRINZA^® when a strong inducer of both CYP3A4 and P-gp (e.g. carbamazepine, rifampin, St. John's wort) is co-administered. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets.

Pregnancy/Nursing: Patients should be advised to notify their physician if they become pregnant/intend to become pregnant or intend to nurse during treatment with INVEGA TRINZA^®.

Commonly Observed Adverse Reactions for INVEGA TRINZA^®: The most common adverse reactions (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reaction, weight increased, headache, upper respiratory tract infection, akathisia and parkinsonism.

Please see full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA^®.

045408-160107

Reference: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016.

References: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 2. Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015;72(8):830-839. Supplemental data available at: http://archpsyc.jamanetwork.com/article.aspx?articleid=2211343#tab12. Accessed March 28, 2016.

References: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 2. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ.

References: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 2. INVEGA SUSTENNA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 3. INVEGA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016.

References: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 2. INVEGA SUSTENNA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016.

Reference: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016.

References: 1. INVEGA TRINZA^® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; March 2016. 2. Berwaerts J, Liu Y, Gopal S, et al. Efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo for relapse prevention of schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2015;72(8):830-839. Supplemental data available at: http://archpsyc.jamanetwork.com/article.aspx?articleid=2211343#tab12. Accessed March 28, 2016.

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IMPORTANT SAFETY INFORMATION and INDICATION for INVEGA SUSTENNA^® (paliperidone palmitate)

INVEGA SUSTENNA^® (paliperidone palmitate) is indicated for the treatment of:

Schizophrenia.
Schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers or antidepressants.

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

See full Prescribing Information for complete Boxed Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
INVEGA SUSTENNA^® is not approved for the treatment of patients with dementia-related psychosis.

Contraindications: Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of the formulation.

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone, aripiprazole, and olanzapine. The incidence of cerebrovascular adverse reactions was significantly higher than with placebo. INVEGA SUSTENNA^® is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QTc interval and in patients with risk factors for prolonged QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly female patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

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, hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics (APS). Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia during treatment should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Orthostatic Hypotension and Syncope: INVEGA SUSTENNA^® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. INVEGA SUSTENNA^® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive medications). Monitoring should be considered in patients for whom this may be of concern.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including paliperidone. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of INVEGA SUSTENNA^® should be considered. 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 INVEGA SUSTENNA^® and have their WBC followed until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ receptors, INVEGA SUSTENNA^® elevates prolactin levels, and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA SUSTENNA^®. INVEGA SUSTENNA^® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA SUSTENNA^® does not adversely affect them.

Seizures: INVEGA SUSTENNA^® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Administration: For intramuscular injection only by a healthcare professional. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA SUSTENNA^® when a strong inducer of both CYP3A4 and P-gp (e.g. carbamazepine, rifampin, St. John's wort) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA SUSTENNA^®.

Pregnancy/Nursing: Patients should be advised to notify their physician if they become pregnant/intend to become pregnant or intend to nurse during treatment with INVEGA SUSTENNA^®.

Commonly Observed Adverse Reactions for INVEGA SUSTENNA^®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5% and twice placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder. No adverse events occurred at a rate of ≥5% and twice placebo during the long-term double-blind, placebo-controlled study in patients with schizoaffective disorder. The following adverse reactions occurred more frequently (a ≥2% difference vs. placebo) in the long-term study in patients with schizoaffective disorder: weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.

Please see full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA^®.

037717-150728

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IMPORTANT SAFETY INFORMATION and INDICATION for RISPERDAL CONSTA^® (risperidone)

RISPERDAL CONSTA^® (risperidone) long-acting injection is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder and for the treatment of schizophrenia.

WARNING: 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 the 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. RISPERDAL CONSTA^® is not approved for the treatment of patients with dementia-related psychosis.

Contraindications: RISPERDAL CONSTA^® is contraindicated in patients with a known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL CONSTA^®.

Cerebrovascular Adverse Events (CAEs): CAEs (e.g., stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone. The incidence of CAEs was significantly higher than with placebo. RISPERDAL CONSTA^® is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

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, some cases extreme and associated with ketoacidosis, hyperosmolar coma or death have been reported in patients treated with atypical antipsychotics (APS), including RISPERDAL CONSTA^®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Monitor glucose regularly in patients with diabetes or at risk for diabetes. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

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.

Orthostatic Hypotension and Syncope: RISPERDAL CONSTA^® may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period. RISPERDAL CONSTA^® should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia) and additionally elderly patients with renal or hepatic impairment. Monitoring should be considered in patients for whom this may be of concern.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including RISPERDAL CONSTA^®. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of RISPERDAL CONSTA^® should be considered. 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 RISPERDAL CONSTA^® and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment: Somnolence was reported in multiple trials in subjects treated with RISPERDAL CONSTA^®. Since RISPERDAL CONSTA^® has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that RISPERDAL CONSTA^® does not adversely affect them.

Seizures: RISPERDAL CONSTA^® should be used cautiously in patients with a history of seizures.

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. Use cautiously in patients at risk for aspiration pneumonia.

Priapism has been reported. Severe priapism may require surgical intervention.

Thrombotic Thrombocytopenic Purpura (TTP) has been reported.

Administration: For intramuscular injection only. Care should be taken to avoid inadvertent injection into a blood vessel.

Suicide: The possibility of suicide attempt is inherent in schizophrenia or bipolar disorder. Close supervision of high-risk patients should accompany drug therapy.

Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies has been reported. Manifestations and features are consistent with NMS.

Use RISPERDAL CONSTA^® with caution in patients with conditions and medical conditions that could affect metabolism or hemodynamic responses (e.g., recent myocardial infarction or unstable cardiac disease).

Commonly Observed Adverse Reactions for RISPERDAL CONSTA^®: The most common adverse reactions in clinical trials in patients with schizophrenia (≥5%) were headache, Parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremities, and dry mouth. The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and Parkinsonism (≥10% in adjunctive therapy trial).

Please see full Prescribing Information, including Boxed WARNING, for RISPERDAL CONSTA^®.

039937-160310

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IMPORTANT SAFETY INFORMATION and INDICATION for INVEGA^® (paliperidone)

INVEGA^® (paliperidone) extended-release tablets are indicated for the treatment of schizophrenia in adults and adolescents (12-17 years of age). The efficacy of INVEGA^® in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents (12-17 years of age), as well as one maintenance trial in adults.

INVEGA^® (paliperidone) extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy in adults. The efficacy of INVEGA^® in schizoaffective disorder was established in two 6-week trials in adults.

WARNING: 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 the 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 (eg, heart failure, sudden death) or infectious (eg, 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. INVEGA^® is not approved for the treatment of patients with dementia-related psychosis.

Contraindications: Paliperidone is contraindicated in patients with a known hypersensitivity to paliperidone, risperidone, or to any excipients in INVEGA^®.

Cerebrovascular Adverse Events (CAEs): CAEs (eg, stroke, transient ischemia attacks), including fatalities, were reported in placebo-controlled trials in elderly patients with dementia-related psychosis taking oral risperidone, aripiprazole, and olanzapine. The incidence of CAEs was significantly higher than with placebo. INVEGA^® is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported with the use of antipsychotic medications, including paliperidone. Clinical manifestations include muscle rigidity, fever, altered mental status, and evidence of autonomic instability (see full Prescribing Information). Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and close medical monitoring, and treatment of any concomitant serious medical problems.

QT Prolongation: Paliperidone causes a modest increase in the corrected QT (QTc) interval. Avoid the use of drugs that also increase QT interval and in patients with risk factors for prolonged QT interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval.

Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotic medications. The risk of developing TD and the likelihood that dyskinetic movements will become irreversible are believed to increase with duration of treatment and total cumulative dose, but can develop after relatively brief treatment at low doses. Elderly women patients appeared to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. Prescribing should be consistent with the need to minimize the risk of TD (see full Prescribing Information). Discontinue drug if clinically appropriate. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. The 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 – Hyperglycemia, some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death has been reported in patients treated with atypical antipsychotics (APS), including INVEGA^®. Patients starting treatment with APS who have or are at risk for diabetes mellitus should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia. Some patients require continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Dyslipidemia – Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Weight Gain – Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. When treating adolescent patients with INVEGA^®, weight gain should be assessed against that expected with normal growth.

Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ receptors, INVEGA^® elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to risperidone, which is associated with higher levels of prolactin elevation than other antipsychotic agents.

Gastrointestinal: INVEGA^® should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing. Rare instances of obstructive symptoms have been reported in patients with known strictures taking non-deformable formulations. INVEGA^® should only be used in patients who are able to swallow the tablet whole.

Orthostatic Hypotension and Syncope: INVEGA^® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. INVEGA^® should be used with caution in patients with known cardiovascular disease (eg, heart failure, history of MI or ischemia, conduction abnormalities), cerebrovascular disease or conditions that would predispose patients to hypotension (eg, dehydration, hypovolemia, treatment with anti-hypertensive medications). Monitoring should be considered in patients who are vulnerable to hypotension.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including paliperidone. Patients with a history of clinically significant low white blood cell count (WBC) or drug-induced leukopenia/neutropenia should have frequent complete blood cell counts during the first few months of therapy. At the first sign of a clinically significant decline in WBC, and in the absence of other causative factors, discontinuation of INVEGA^® should be considered. 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 INVEGA^® and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment: Somnolence was reported in subjects treated with INVEGA^®. INVEGA^® has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities that require mental alertness such as operating hazardous machinery, including motor vehicles, until they are reasonably certain that INVEGA^® does not adversely affect them.

Seizures: INVEGA^® should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold. Conditions that lower seizure threshold may be more prevalent in patients 65 years or older.

Suicide: The possibility of suicide attempt is inherent in psychotic illnesses. Close supervision of high-risk patients should accompany drug therapy. Prescriptions should be written for the smallest quantity of tablets to reduce the risk of overdose.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA^® when a strong inducer of both CYP3A4 and P-gp (eg, carbamazepine, rifampin, St. John's wort) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA^®.

Commonly Observed Adverse Reactions: The most commonly observed adverse reactions in clinical trials occurring at an incidence of ≥5% and at least 2 times placebo in the treatment of schizophrenia were: Adults – extrapyramidal symptoms, tachycardia, and akathisia; Adolescents (12-17 years of age) were: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increase, and tachycardia. The most commonly observed adverse reactions in clinical trials occurring at an incidence of ≥5% and at least 2 times placebo in the treatment of schizoaffective disorder were: Adults – extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increase, and nasopharyngitis.

Please see full Prescribing Information, including Boxed WARNING, for INVEGA^®.

048983-160310

Expand [+]

IMPORTANT SAFETY INFORMATION and INDICATION for INVEGA TRINZA^® (paliperidone palmitate)

INVEGA TRINZA^® (paliperidone palmitate) a 3-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA^® (1-month paliperidone palmitate) for at least four months.

Expand [+]

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS.

See full Prescribing Information for complete Boxed Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death
INVEGA TRINZA^® is not approved for the treatment of patients with dementia-related psychosis