INVEGA SUSTENNA® Prolactin Data

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 SUSTENNA^® is not approved for use in patients with dementia-related psychosis.

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

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA^®, or the 3-month paliperidone palmitate extended-release injectable suspension in elderly patients with dementia. These medicines are 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-adrenergic 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.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA SUSTENNA^®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA SUSTENNA^®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA SUSTENNA^® 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 INVEGA SUSTENNA^® in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC 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 using only the needles provided in the INVEGA SUSTENNA^® kit. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g. carbamazepine, rifampin, St. John’s Wort) during a dosing interval for INVEGA SUSTENNA^®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

Pregnancy/Nursing: INVEGA SUSTENNA^® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA SUSTENNA^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA SUSTENNA^® during pregnancy. INVEGA SUSTENNA^® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA SUSTENNA^® and any potential adverse effects on the breastfed infant from INVEGA SUSTENNA^® or the mother’s underlying condition.

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 15-month 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 click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA^®.

cp-64202v1

INDICATION

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.

INVEGA SUSTENNA^® (paliperidone palmitate) is an atypical antipsychotic indicated for the treatment of schizophrenia in adults.

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 SUSTENNA^® and INVEGA TRINZA^® are not approved for use in patients with dementia-related psychosis.

Contraindications: INVEGA TRINZA^® and INVEGA SUSTENNA^® are contraindicated in patients with a known hypersensitivity to either paliperidone, risperidone, or to any excipients of their formulation.

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attacks), including fatalities, were reported at a higher incidence in elderly patients with dementia-related psychosis taking risperidone, aripiprazole, and olanzapine compared to placebo. No studies have been conducted with oral paliperidone, INVEGA SUSTENNA^®, or INVEGA TRINZA^® in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis.

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^® and INVEGA SUSTENNA^® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA TRINZA^® and 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.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA TRINZA^® and INVEGA SUSTENNA^®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including INVEGA TRINZA^® and INVEGA SUSTENNA^®. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or drug-induced leukopenia/neutropenia, perform a complete blood count frequently during the first few months of therapy. Consider discontinuing INVEGA TRINZA^® and INVEGA SUSTENNA^® 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 INVEGA TRINZA^® and INVEGA SUSTENNA^® in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery.

Hyperprolactinemia: As with other drugs that antagonize dopamine D₂ receptors, INVEGA TRINZA^® and INVEGA SUSTENNA^® elevate 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^® and INVEGA SUSTENNA^®. INVEGA TRINZA^® and INVEGA SUSTENNA^® have 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^® and INVEGA SUSTENNA^® do not adversely affect them.

Seizures: INVEGA TRINZA^® and 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 using only the needles provided in the INVEGA TRINZA^® or INVEGA SUSTENNA^® kits. Care should be taken to avoid inadvertent injection into a blood vessel.

Drug Interactions: Strong CYP3A4/P-glycoprotein (P-gp) inducers: Avoid using a strong inducer of CYP3A4 and/or P-gp (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA TRINZA^® or INVEGA SUSTENNA^®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

Pregnancy/Nursing: INVEGA TRINZA^® and INVEGA SUSTENNA^® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA TRINZA^® or INVEGA SUSTENNA^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA TRINZA^® or INVEGA SUSTENNA^® during pregnancy. INVEGA TRINZA^® and INVEGA SUSTENNA^® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA TRINZA^® or INVEGA SUSTENNA^® and any potential adverse effect on the breastfed infant from INVEGA TRINZA^® or INVEGA SUSTENNA^® or the mother’s underlying condition.

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.
Commonly Observed Adverse Reactions for INVEGA SUSTENNA^®: The most common adverse reactions in clinical trials in patients with schizophrenia (incidence ≥ 5% and occurring at least twice as often as placebo) were injection site reactions, somnolence/sedation, dizziness, akathisia and extrapyramidal disorder.

Please read the full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA^® and INVEGA SUSTENNA^®.

cp-64206v1

INDICATION

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.

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. RISPERDAL CONSTA^® is not approved for use in 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 dementiarelated 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 appear 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.

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 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.

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 in some patients due to its alpha-adrenergic blocking activity. RISPERDAL CONSTA^® 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.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL CONSTA^®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

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.

Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with RISPERDAL CONSTA^® use.

Thrombotic Thrombocytopenic Purpura (TTP) has been reported.

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

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).

Pregnancy/Nursing: RISPERDAL CONSTA^® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with RISPERDAL CONSTA^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to RISPERDAL CONSTA^® during pregnancy. RISPERDAL CONSTA^® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for RISPERDAL CONSTA^® and any potential adverse effect on the breastfed infant from RISPERDAL CONSTA^® or the mother’s underlying condition.

Fertility: RISPERDAL CONSTA^® may cause a reversible reduction in fertility in females.

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 click here to read the full Prescribing Information, including Boxed WARNING, for RISPERDAL CONSTA^®.

cp-64213v1

INDICATION

INVEGA^® (paliperidone) extended-release tablets are indicated for the treatment of schizophrenia.

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^® is not approved for use in patients with dementiarelated 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 dementiarelated 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.

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 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 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.

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.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA^®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

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.

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.

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

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^®.

Pregnancy/Nursing: INVEGA^® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with INVEGA^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA^® during pregnancy. INVEGA^® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA^® and any potential adverse effects on the breastfed infant from INVEGA^® or the mother’s underlying condition.

Fertility: INVEGA^® may cause a reversible reduction in fertility in females.

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 adults with schizophrenia were extrapyramidal symptoms, tachycardia, and akathisia.

Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA^®.

cp-64196v1

INDICATION

RISPERDAL^® (risperidone) is indicated for the treatment of schizophrenia.

IMPORTANT SAFETY INFORMATION FOR RISPERDAL^® (risperidone)

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. RISPERDAL^® is not approved for use in patients with dementia-related psychosis.

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

Cerebrovascular Adverse Reactions: Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL^® 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 risperidone. Clinical manifestations of NMS include fever, muscle rigidity, altered mental status, and autonomic instability (see full Prescribing Information). The management of NMS 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): A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose increase but can develop after relatively brief treatment periods at low doses. Elderly women appear to be at increased risk for TD, although it is impossible to predict which patients will develop the syndrome. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Prescribing should be consistent with the need to minimize the occurrence of tardive dyskinesia (see full Prescribing Information). The need for continued treatment should be reassessed periodically. Discontinue drug if clinically appropriate.

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 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 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, RISPERDAL^® 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^® may induce orthostatic hypotension in some patients due to its alpha-blocking activity. RISPERDAL^® 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.

Falls: Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL^®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

Leukopenia, Neutropenia and Agranulocytosis have been reported with antipsychotics, including risperidone. Patients with a history of clinically significant low white blood cell count (WBC) or druginduced 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 risperidone 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^® and have their WBC followed until recovery.

Potential for Cognitive and Motor Impairment: Somnolence was a commonly reported adverse reaction associated with RISPERDAL^® treatment. Since RISPERDAL^® has the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that RISPERDAL^® therapy does not affect them adversely.

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

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

Maintenance Treatment: Physicians who elect to use RISPERDAL^® for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Pregnancy/Nursing: RISPERDAL^® may cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. Advise patients to notify their healthcare professional if they become pregnant or intend to become pregnant during treatment with RISPERDAL^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to RISPERDAL^® during pregnancy. RISPERDAL^® can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for RISPERDAL^® and any potential adverse effect on the breastfed infant from RISPERDAL^® or the mother’s underlying condition.

Fertility: RISPERDAL^® may cause a reversible reduction in fertility in females.

Commonly Observed Adverse Reactions for RISPERDAL^®: The most common adverse reactions in all clinical trials (≥5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

Please click here to read the full Prescribing Information, including Boxed WARNING, for RISPERDAL^®.

cp-64210v2

INVEGA SUSTENNA^® Prolactin Data

Prolactin Elevations

Prolactin elevations* in the double-blind phase of the long-term maintenance trial in schizophrenia¹

Percentage of Patients

Percentage of patients with potentially prolactin-related adverse reactions* in the double-blind phase of the long-term maintenance trial in schizophrenia¹

INVEGA SUSTENNA® Prolactin Data

Prolactin Elevations

Prolactin elevations* in the double-blind phase of the long-term maintenance trial in schizophrenia1

Percentage of Patients

Percentage of patients with potentially prolactin-related adverse reactions* in the double-blind phase of the long-term maintenance trial in schizophrenia1

INVEGA SUSTENNA^® Prolactin Data

Prolactin elevations* in the double-blind phase of the long-term maintenance trial in schizophrenia¹

Percentage of patients with potentially prolactin-related adverse reactions* in the double-blind phase of the long-term maintenance trial in schizophrenia¹