Otsuka and Proteus Digital Health® Resubmit Application to FDA for First Digital Medicine
- Potential new Digital Medicine consists of Otsuka’s ABILIFY® (aripiprazole) embedded with the Proteus ingestible sensor, for serious mental illness
- Drug/ice product digitally records medication ingestion and, with patient consent, shares information with patient’s healthcare providers and selected family and friends
- If approved by the FDA, Digital Medicine would provide patients and physicians with an objective, personalized measure of medication adherence and activity level, as well as self-reported rest and mood 
Tokyo, Japan and Redwood City, Calif. – May 23, 2017 – Otsuka Pharmaceutical Co., Ltd. (Otsuka) and Proteus Digital Health® (Proteus) today announce that the United States Food and Drug Administration (FDA) has acknowledged receipt of the New Drug Application (NDA) resubmission for the drug-device combination product of ABILIFY® (aripiprazole) embedded with a Proteus ingestible sensor in a single tablet. The NDA resubmission will now be reviewed by the FDA, with an anticipated action date by the agency in the fourth quarter of 2017.
The FDA requested additional information, including further human factors investigations. The goal of human factors testing is to evaluate use-related risks and confirm that individuals can use the system safely and effectively. 
If approved, this Digital Medicine would securely measure patient medication-taking patterns, as well as select physiological data and self-reported behavioral information. This information would help enable individuals along with their healthcare professional team to better manage their serious mental illness. With the patient’s consent, this information could be shared with their healthcare professional team and selected family and friends, with the goal of allowing physicians to be more informed in making treatment decisions that are specific to the patient’s needs. This Digital Medicine would be used in the treatment of adults with schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, and as adjunctive therapy for the treatment of major depressive disorder.
This Digital Medicine is comprised of FDA-approved ABILIFY with the only FDA-cleared ingestible sensor, the size of a grain of sand, embedded inside a single tablet at the point of manufacture.  The Proteus ingestible sensor activates when it reaches stomach fluids and communicates with the patch, which is a wearable sensor that detects and records the ingestion of the ABILIFY tablet, and select physiological data, such as activity level. A mobile patient application, or medical app, displays the data collected by the patch to allow individuals to review their objective medication intake and activity level, as well as enter self-reported measures of rest and mood. A web-based portal for healthcare professionals and selected family and friends displays this information for the duration of treatment.
About ABILIFY® (aripiprazole)
Discovered by Otsuka Pharmaceutical Co., Ltd., ABILIFY was the first available dopamine partial agonist and is indicated for the treatment of schizophrenia in adults, for the acute treatment of manic or mixed episodes associated with Bipolar I Disorder as monotherapy and as an adjunct to lithium or valproate in adults, and for use as an adjunctive therapy to antidepressants in adults with Major Depressive Disorder who have had an inadequate response to antidepressant therapy. ABILIFY tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg and 30 mg strengths.
About the Proteus Digital Health® Ingestible Sensor and Wearable Sensor Patch
The Proteus ingestible sensor and wearable sensor patch have been cleared by the Food and Drug Administration (FDA) for use in the United States, CE marked per the Medical Device Directive for use in the European Union and approved by the CFDA for use in China. More information is available at www.proteus.com.
INDICATIONS and IMPORTANT SAFETY INFORMATION for ABILIFY® (aripiprazole)
ABILIFY is indicated for:
- Treatment of Schizophrenia in adults
- Acute treatment of manic or mixed episodes associated with Bipolar I Disorder as monotherapy and as an adjunct to lithium or valproate in adults
- Use as an adjunctive therapy to antidepressants in adults with Major Depressive Disorder who have had an inadequate response to antidepressant therapy
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 (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 is not approved for the treatment of patients with dementia-related psychosis.
WARNING: 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.
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) – A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.
Tardive Dyskinesia (TD) – The risk of developing TD (a syndrome of abnormal, involuntary movements) 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. There is no known treatment for established TD, although 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. 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.
- Weight Gain – Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Pathological Gambling and Other Compulsive Behaviors – Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking ABILIFY. Other compulsive urges (e.g., eating, sexual, or shopping) have been reported less frequently. Prescribers should ask patients or their caregivers specifically about, and closely monitor for, the development of new or intense compulsive urges. Consider dose reduction or stopping ABILIFY, if such urges develop.
Orthostatic Hypotension – ABILIFY may cause orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.
Falls – Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.
Leukopenia, Neutropenia, and Agranulocytosis – Leukopenia, neutropenia, and agranulocytosis have been reported. In patients with a history of clinically significant low white blood cell count (WBC)/absolute neutrophil count (ANC) or history of drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. Consider discontinuing ABILIFY 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 ABILIFY in patients with severe neutropenia (ANC <1000/mm3) and follow their WBC counts until recovery.
Seizures/Convulsions – ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.
Potential for Cognitive and Motor Impairment – ABILIFY may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery, including automobiles, 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 antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration.
Suicide – The possibility of a suicide attempt is inherent in psychotic illnesses, Bipolar Disorder, and Major Depressive Disorder. 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; 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.
Alcohol – Advise patients to avoid alcohol while taking ABILIFY.
Concomitant Medication – Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers. When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. For patients who are known CYP2D6 poor metabolizers, administer half of usual dose. For patients who are known CYP2D6 poor metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer a quarter of usual dose. For patients taking strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), administer half of usual dose. For patients taking strong CYP2D6 and CYP3A4 inhibitors, administer a quarter of usual dose. For patients taking strong CYP3A4 inducers (e.g., carbamazepine, rifampin), double usual dose over 1 to 2 weeks.
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 (adjunctive therapy with lithium or valproate) with Bipolar Mania: akathisia (19% vs 5%), insomnia (8% vs 4%), and extrapyramidal disorder (5% vs 1%)
- Adult patients with Schizophrenia: akathisia (8% vs 4%)
Dystonia – Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.
Pregnancy – Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. 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 present 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 and any potential risks to the infant.
To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).
Please see accompanying FULL PRESCRIBING INFORMATION, including BOXED WARNING.
About Otsuka Pharmaceutical Co., Ltd.
Otsuka Pharmaceutical is a global healthcare company with the corporate philosophy: “Otsuka-people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.
Otsuka Pharmaceutical is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 45,000 people worldwide and had consolidated sales of approximately USD 11 billion (€ 9.9 billion) in 2016.
All Otsuka stories start by taking the road less travelled. Learn more about Otsuka Pharmaceutical Company on its global website at https://www.otsuka.co.jp/en. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on Twitter at @OtsukaUS.
About Proteus Digital Health®
Headquartered in Redwood City, Calif., Proteus is privately held and funded by leading institutional and corporate investors, including: Novartis, Otsuka, Medtronic and Kaiser Permanente. For more information, visit www.proteus.com. Connect with us on Twitter @ProteusDH.
Otsuka Media Contacts
In U.S. Outside U.S.
Kimberly Whitefield Jeffrey Gilbert
Corporate Communications Leader, Pharmaceutical PR
Otsuka America Pharmaceutical, Inc. Otsuka Pharmaceutical, Co., Ltd.
+1 609 535 9259 +81 3 6361 7379, +81 80 8728 6039
Proteus Digital Health Media Contact
Proteus Digital Health
+1 408 425 7097
 Rohatagi S et al. Optimization of a Digital Medicine System in Psychiatry. J Clin Psychiatry 2016;77(9):e1101-1107.
 U.S. Food & Drug Administration. Premarket Information – Device Design and Documentation Processes. https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HumanFactors/ucm119190.htm. Updated 9/15/2016. Accessed April 11, 2017.
 U.S. Food & Drug Administration. 510(k) Premarket Notification. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K133263. Accessed April 21, 2017.