IMPORTANT SAFETY INFORMATION FOR INVEGA^® (paliperidone)

• 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.
• 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.
• 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.
• 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^®.

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