Actavis Announces FDA Acceptance of sNDA for SAPHRIS® (asenapine) for the Treatment of Bipolar I Disorder in Pediatric Patients

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Nov 13, 2014, 08:00 ET

DUBLIN, Nov. 13, 2014 /PRNewswire/ -- Actavis plc (NYSE: ACT) today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing Actavis' Supplemental New Drug Application (sNDA) for SAPHRIS^® (asenapine) for the acute treatment of manic or mixed episodes associated with bipolar I disorder in pediatric patients 10 to 17 years of age. Actavis' sNDA for SAPHRIS has been granted priority review status by the FDA.

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"The sNDA filing of SAPHRIS speaks to our commitment to ongoing research and development of our mental health portfolio," said C. David Nicholson, PhD, Senior Vice President, Actavis Global Brands R&D. "We are pleased that the FDA has accepted this sNDA, marking the first step towards our goal of bringing this important antipsychotic treatment option to pediatric patients."

Actavis expects the Prescription Drug User Fee Act (PDUFA) date to be in Q1 2015. The sNDA submission for asenapine is based on the results of a 3-week monotherapy trial in 403 pediatric patients (10 to 17 years of age), of whom 302 received asenapine. In the trial, asenapine was shown to be statistically superior to placebo in the reductions of both the Young Mania Rating Scale (YMRS) total score and Clinical Global Impression-Bipolar (CGI-BP) score at fixed doses of 2.5 mg, 5 mg and 10 mg twice daily. The most commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were somnolence, dizziness, dysgeusia, oral hypoesthesia, oral paresthesia, nausea, increased appetite, fatigue and increased weight.

About SAPHRIS^®
SAPHRIS^® (asenapine) is an atypical antipsychotic that has been prescribed over one million times since it was first approved by the FDA in 2009. It is indicated for the treatment of schizophrenia in adults, and for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, as monotherapy or as adjunctive therapy with either lithium or valproate.

About Bipolar I Disorder
Bipolar disorder, which encompasses bipolar I and bipolar II disorders, affects approximately 5.7 million people in the U.S. Bipolar I disorder, also known as manic-depressive illness, is characterized by unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks. Patients experience "mood episodes" that manifest as either a manic episode (overexcited, extreme irritability, racing thoughts, and difficulties with sleep) or a depressive episode (extreme sadness, fatigue, or hopelessness), or a combination of both.

IMPORTANT SAFETY INFORMATION

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

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS® (asenapine) is not approved for the treatment of patients with dementia-related psychosis.

Hypersensitivity Reactions: SAPHRIS is contraindicated in patients with known hypersensitivity to SAPHRIS or to its formulation components. Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed.

Cerebrovascular Adverse Events: In clinical trials with risperidone, aripiprazole, or olanzapine, elderly subjects with dementia had a higher incidence of cerebrovascular adverse reactions, including fatalities vs placebo. SAPHRIS 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 antipsychotic drugs, including SAPHRIS. Signs and symptoms of NMS may include hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia. Management should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems.

Tardive Dyskinesia (TD): There is a risk of TD associated with atypical antipsychotics, including SAPHRIS. Prescribing should be consistent with the need to minimize TD.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These changes include hyperglycemia, dyslipidemia, and weight gain. While all 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, in some cases associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. It is not known if SAPHRIS is associated with this increased risk. Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with, and at risk for, diabetes.
Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Weight Gain: Increases in weight have been observed with SAPHRIS. Patients should receive regular monitoring of weight.

Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects: SAPHRIS may induce orthostatic hypotension and syncope. SAPHRIS should be used with caution in patients with cardiovascular disease, cerebrovascular disease, or conditions which predispose to hypotension, and in the elderly. SAPHRIS should be used cautiously with other drugs that can induce hypotension, bradycardia, or respiratory or central nervous system depression. Monitoring of orthostatic vital signs, and a dose reduction if hypotension occurs, should be considered.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. Agranulocytosis (including fatal cases) has been reported with other antipsychotics. At-risk patients, including those with a pre-existing low white blood cell count (WBC) or history of drug-induced leukopenia/neutropenia, should have their complete blood count (CBC) monitored, and SAPHRIS should be discontinued at the first sign of a declining WBC and in severely neutropenic patients.

QT Prolongation: In a QT study, SAPHRIS was associated with increases in the QTc interval from 2 to 5 msec vs placebo. No SAPHRIS patients had QTc increases of ≥60 msec or a QTc of ≥500 msec. SAPHRIS should be avoided in patients taking drugs that prolong the QTc interval and in patients with other risk factors for prolonged QT interval.

Hyperprolactinemia: Like other drugs that antagonize dopamine D₂ receptors, SAPHRIS can elevate prolactin levels and the elevation can persist during chronic administration.

Seizures: As with other antipsychotic drugs, SAPHRIS should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (eg, Alzheimer's dementia).

Potential for Cognitive and Motor Impairment: Somnolence was reported in patients treated with SAPHRIS. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely.

Body Temperature Regulation: Appropriate care is advised when prescribing SAPHRIS for patients who will experience conditions that increase core body temperature, eg, exercising strenuously, extreme heat, concomitant anticholinergic medication, or dehydration.

Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and bipolar disorder. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets in order to reduce the risk of overdose.

Dysphagia: SAPHRIS should not be used in patients at risk for aspiration pneumonia.

Hepatic Impairment: SAPHRIS is not recommended in patients with severe hepatic impairment.

Drug Interactions: SAPHRIS should be used with caution in combination with centrally-acting drugs or alcohol. SAPHRIS coadministration with strong CYP1A2 inhibitors (fluvoxamine) or drugs that are both CYP2D6 substrates and inhibitors (paroxetine) should be done with caution.

Adverse Reactions: In clinical trials, commonly observed adverse reactions (≥5% and at least twice the rate of placebo) were:

Schizophrenia: akathisia, oral hypoesthesia, and somnolence
Bipolar mania (monotherapy): somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight increased
Bipolar mania (adjunctive): somnolence and oral hypoesthesia

Postmarketing Experience: Application site reactions, primarily sublingual, have been reported. These include oral ulcers, blisters, peeling/sloughing, and inflammation. In many cases, the occurrence of these reactions led to discontinuation of therapy.

Please also see the full Prescribing Information, including Boxed Warning.

About Actavis plc
Actavis plc (NYSE: ACT), headquartered in Dublin, Ireland, is a unique specialty pharmaceutical company focused on developing, manufacturing and commercializing high quality affordable generic and innovative branded pharmaceutical products for patients around the world.

Actavis markets a broad portfolio of branded and generic pharmaceuticals and develops innovative medicines for patients suffering from diseases principally in the central nervous system, gastroenterology, women's health, urology, cardiovascular, respiratory and anti-infective therapeutic categories. The Company is an industry leader in product research and development, with one of the broadest brand development pipelines in the pharmaceutical industry, and a leading position in the submission of generic product applications. Actavis has commercial operations in more than 60 countries and operates more than 30 manufacturing and distribution facilities around the world.

For more information, visit Actavis' website at www.actavis.com.

Actavis Cautionary Statement Regarding Forward-Looking Statements
Statements contained in this communication that refer to Actavis' estimated or anticipated future results, including estimated synergies, or other non-historical facts are forward-looking statements that reflect Actavis' current perspective of existing trends and information as of the date of this communication. Actual results may differ materially from Actavis' current expectations depending upon a number of factors affecting Actavis' business. These factors include, among others, the timing and success of product launches; the difficulty of predicting the timing or outcome of product development efforts and regulatory agency approvals or actions, if any; market acceptance of and continued demand for Actavis' products; difficulties or delays in manufacturing; and such other risks and uncertainties detailed in Actavis' periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis plc's Annual Report on Form 10-K for the year ended December 31, 2013, Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and from time to time in Actavis' other investor communications. Except as expressly required by law, Actavis disclaims any intent or obligation to update or revise these forward-looking statements.