INVEGA TRINZA® Extrapyramidal Symptoms 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^® 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.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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 INVEGA SUSTENNA^® or INVEGA TRINZA^® and provide symptomatic treatment and monitoring.

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, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing TD and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA^® or INVEGA TRINZA^®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA^® or INVEGA TRINZA^® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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

cp-64206v3

INDICATION

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

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

IMPORTANT SAFETY INFORMATION

IMPORTANT SAFETY INFORMATION FOR INVEGA SUSTENNA^® (paliperidone palmitate)

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 in association with antipsychotic drugs, including paliperidone.

If NMS is suspected, immediately discontinue INVEGA SUSTENNA^® and provide symptomatic treatment and monitoring.

If signs and symptoms of TD appear in a patient on INVEGA SUSTENNA^®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA SUSTENNA^® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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-64202v3

INDICATION

INVEGA HAFYERA™, an every-six-month injection, is an atypical antipsychotic indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

A once-a-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA SUSTENNA^®) for at least four months or
An every-three-month paliperidone palmitate extended release injectable suspension (e.g., INVEGA TRINZA^®) for at least one three-month cycle.

INVEGA TRINZA^® is an atypical antipsychotic indicated for the treatment of schizophrenia in patients after they have been adequately treated with INVEGA SUSTENNA^® for at least four months.

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

Contraindications: INVEGA HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^®, or INVEGA SUSTENNA^® in elderly patients with dementia. These medications 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 in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse of 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 INVEGA HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^® and provide symptomatic treatment and monitoring.

If signs and symptoms of TD appear in a patient on INVEGA HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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 HAFYERA™, INVEGA TRINZA^® and INVEGA SUSTENNA^® may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^® and INVEGA SUSTENNA^®. INVEGA HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^® and INVEGA SUSTENNA^® do not adversely affect them.

Seizures: INVEGA HAFYERA™, 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 HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^®. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

Pregnancy/Nursing: INVEGA HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^®. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^® during pregnancy. INVEGA HAFYERA™, 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 HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^® and any potential adverse effect on the breastfed infant from INVEGA HAFYERA™, INVEGA TRINZA^® or INVEGA SUSTENNA^® or the mother’s underlying condition.

Commonly Observed Adverse Reactions for INVEGA HAFYERA™: The most common adverse reactions (incidence at least 5% in the double-blind phase) in the INVEGA HAFYERA™ clinical trial were upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.

Please click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA HAFYERA™, click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA TRINZA^® and click here to read the full Prescribing Information, including Boxed WARNING, for INVEGA SUSTENNA^®.

cp-256260v1

INDICATION

RISPERDAL CONSTA^® (risperidone) long-acting injection is indicated for the treatment of schizophrenia.

IMPORTANT SAFETY INFORMATION FOR RISPERDAL CONSTA^® (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 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 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 in association with antipsychotic drugs.

If NMS is suspected, immediately discontinue RISPERDAL CONSTA^® and provide symptomatic treatment and monitoring.

If signs and symptoms of TD appear in a patient on RISPERDAL CONSTA^®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL CONSTA^® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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 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.

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

cp-64212v3

INDICATION

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

IMPORTANT SAFETY INFORMATION FOR INVEGA^® (paliperidone)

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 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 in association with antipsychotic drugs, including paliperidone.

If NMS is suspected, immediately discontinue INVEGA^® and provide symptomatic treatment and monitoring.

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.

If signs and symptoms of TD appear in a patient on INVEGA^®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA^® despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

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 temporally related to antipsychotic agents, including INVEGA^®. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) or drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. Discontinuation should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly. Patients with severe neutropenia should discontinue INVEGA^® and follow their WBC until recovery.

Potential for Cognitive and Motor Impairment: Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA^®. Antipsychotics including INVEGA^® 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^® 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-64196v3

INVEGA TRINZA^® Extrapyramidal Symptoms Data Observed¹

Extrapyramidal Symptoms (EPS) Data: Long-term Maintenance Trial¹

INVEGA TRINZA® Extrapyramidal Symptoms Data Observed1

Extrapyramidal Symptoms (EPS) Data: Long-term Maintenance Trial1

INVEGA TRINZA^® Extrapyramidal Symptoms Data Observed¹

Extrapyramidal Symptoms (EPS) Data: Long-term Maintenance Trial¹