FDA Issues Complete Response Letter for Digital Medicine New Drug Application

TOKYO & REDWOOD CITY, Calif.

Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Proteus Digital Health (Proteus) today announced that the United States Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for their Digital Medicine, a drug/device combination product, which combines Otsuka’s ABILIFY® (aripiprazole), an atypical antipsychotic, with the FDA-cleared Proteus ingestible sensor embedded in a single tablet at point of manufacture. The NDA was submitted as a system that measures medication adherence to aripiprazole to be indicated for the treatment of schizophrenia, as an acute treatment of manic and mixed episodes associated with Bipolar I Disorder (BP1) and as an adjunctive treatment for Major Depressive Disorder (MDD).

This Smart News Release features multimedia. View the full release here: http://www.businesswire.com/news/home/20160426006993/en/

FDA has completed its review and has requested additional information, including data regarding the performance of the product under the conditions in which it is likely to be used, and further human factors investigations. The goal of human factors testing is to evaluate use-related risks and confirm that users can use the device safely and effectively.

“While we are disappointed in the FDA’s decision not to approve this Digital Medicine at this time, both Otsuka and Proteus are committed to working with the FDA to address its questions and provide the additional data that has been requested,” said Robert McQuade, executive vice president and chief strategy officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We believe in the potential of this product to help people with serious mental illness manage their daily medication, which remains a serious unmet need.”¹

About ABILIFY^® (aripiprazole)

Discovered by Otsuka Pharmaceutical Co., Ltd., ABILIFY was the first available dopamine partial agonist and is indicated as a treatment of schizophrenia, as an acute treatment of manic or mixed episodes associated with BP1 and as an adjunctive treatment in MDD. ABILIFY tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths. Otsuka welcomes you to visit its U.S. website at www.otsuka-us.com for more information about the company.

About the Proteus^® Ingestible Sensor and Wearable Patch

The Proteus ingestible sensor and wearable patch have been cleared by the Food and Drug Administration (FDA) for use in the United States, and CE marked per the Medical Device Directive for use in the European Union. More information is available at www.proteus.com.

INDICATIONS and IMPORTANT SAFETY INFORMATION for ABILIFY^® (aripiprazole)

INDICATIONS

ABILIFY is an atypical antipsychotic. The oral formulations are indicated for:

• Schizophrenia

• Acute Treatment of Manic and Mixed Episodes associated with Bipolar I

• Adjunctive Treatment of Major Depressive Disorder

IMPORTANT SAFETY INFORMATION

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs 2.6%, respectively). Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.

Suicidal Thoughts and Behaviors

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of adjunctive ABILIFY or another antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increased risk of suicidality in adults beyond age 24. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. ABILIFY is not approved for use in pediatric patients with depression.

See Full Prescribing Information for complete BOXED WARNING

Contraindication – Known hypersensitivity reaction to ABILIFY. Reactions have ranged from pruritus/urticaria to anaphylaxis.

• Cerebrovascular Adverse Events, Including Stroke – Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY
• Neuroleptic Malignant Syndrome (NMS) – As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with ABILIFY. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. 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) – The risk of developing TD and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn
• Metabolic Changes – Atypical antipsychotic drugs have been associated with metabolic changes that include:
  • Hyperglycemia/Diabetes Mellitus– Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including ABILIFY (aripiprazole). Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required 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. There were no significant differences between Abilify- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs
  • Weight Gain- Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. When treating pediatric patients, weight gain should be monitored and assessed against that expected for normal growth

Orthostatic Hypotension – ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

Leukopenia, Neutropenia, and Agranulocytosis – Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics, including ABILIFY. Patients with history of a clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of ABILIFY should be considered at the first sign of a clinically significant decline in WBC count in the absence of other causative factors.

Seizures/Convulsions – As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold (e.g., Alzheimer’s dementia).

Potential for Cognitive and Motor Impairment – Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.

Body Temperature Regulation – Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.

Suicide – The possibility of a suicide attempt is inherent in psychotic illnesses, Bipolar Disorder, and Major Depressive Disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

Dysphagia – Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY (aripiprazole); use caution in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer’s dementia.

Physicians should advise patients to avoid alcohol while taking ABILIFY.

Strong CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine) inhibitors will increase ABILIFY drug concentrations; reduce ABILIFY dose by one-half when used concomitantly, except when used as adjunctive treatment with antidepressants in adults with Major Depressive Disorder. If a strong CYP3A4 inhibitor and strong CYP2D6 inhibitor are co-administered or a known CYP2D6 poor metabolizer is receiving a concomitant strong CYP3A4 inhibitor, the ABILIFY dose should be reduced to one-quarter (25%) of the usual dose.

CYP3A4 inducers (e.g., carbamazepine) will decrease ABILIFY drug concentrations; double ABILIFY dose when used concomitantly.

Commonly observed adverse reactions: (≥5% incidence and at least twice the rate of placebo for ABILIFY vs placebo, respectively):

• Adult patients with Major Depressive Disorder (adjunctive treatment to antidepressant therapy): akathisia (25% vs 4%), restlessness (12% vs 2%), insomnia (8% vs 2%), constipation (5% vs 2%), fatigue (8% vs 4%), and blurred vision (6% vs 1%)
• Adult patients (monotherapy) with Bipolar Mania: akathisia (13% vs 4%), sedation (8% vs 3%), tremor (6% vs 3%), restlessness (6% vs 3%), and extrapyramidal disorder (5% vs 2%)
• Adult patients with Schizophrenia: akathisia (8% vs 4%)

Dystonia is a class effect of antipsychotic drugs. Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Non-Teratogenic Effects – Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. These complications have varied in severity; from being self-limited to requiring intensive care and prolonged hospitalization. ABILIFY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers - ABILIFY is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Please see accompanying U.S. FULL PRESCRIBING INFORMATION, including BOXED WARNING, and Medication Guide for ABILIFY.

¹ Kane JM, Kishimoto T, Correll CU. Nonadherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry. 2013;12:216-226

View source version on businesswire.com: http://www.businesswire.com/news/home/20160426006993/en/