FDA Issues Complete Response Letter for Digital Medicine New Drug Application

TOKYO & REDWOOD CITY, Calif.–(BUSINESS WIRE)–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).
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