Important Safety Information For

• INVEGA HAFYERA™

  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.

  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™ is not approved for use in patients with dementia-related psychosis.

  Contraindications: INVEGA HAFYERA™ is 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 or INVEGA HAFYERA™ 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™ 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 HAFYERA™, drug discontinuation should be considered. However, some patients may require treatment with INVEGA HAFYERA™ 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 HAFYERA™ may induce orthostatic hypotension in some patients due to its alpha-adrenergic blocking activity. INVEGA HAFYERA™ 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™, 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™. 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™ 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™ 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™ 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 HAFYERA™ 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 HAFYERA™ does not adversely affect them.

  Seizures: INVEGA HAFYERA™ 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 gluteal intramuscular injection only by a healthcare professional using only the needles provided in the INVEGA HAFYERA™ 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™. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets.

  Pregnancy/Nursing: INVEGA HAFYERA™ 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™. Patients should be advised that there is a pregnancy registry that monitors outcomes in women exposed to INVEGA HAFYERA™ during pregnancy. INVEGA HAFYERA™ can pass into human breast milk. The benefits of breastfeeding should be considered along with the mother’s clinical need for INVEGA HAFYERA™ and any potential adverse effect on the breastfed infant from INVEGA HAFYERA™ 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™.

  cp-256050v1

  INDICATION