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ARIPiprazole Tablets with Sensor

Class: Atypical Antipsychotics
Chemical Name: 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one
Molecular Formula: C23H27Cl2N3O2
CAS Number: 1089115-04-7
Brands: Abilify MyCite

Medically reviewed on Feb 12, 2018

Warning

Warning: Increased Mortality in Elderly Patients with Dementia-related Psychosis and Suicidal Thoughts and Behaviors1

See full prescribing information for complete boxed warning.1

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole tablet with sensor is not approved for the treatment of patients with dementia-related psychosis.1

  • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor for worsening and emergence of suicidal thoughts and behaviors. 1

  • The safety and effectiveness of aripiprazole tablets with sensor have not been established in pediatric patients.1

Introduction

See also: Ingrezza

Aripiprazole tablet with sensor is a drug-device combination product comprised of an aripiprazole tablet embedded with an Ingestible Event Marker (IEM) sensor intended to track drug ingestion; aripiprazole is an atypical antipsychotic agent.1

Uses for ARIPiprazole Tablets with Sensor

Aripiprazole tablet with sensor has the following uses:

Aripiprazole tablet with sensor is indicated for the treatment of adults with schizophrenia. 1

Aripiprazole tablet with sensor is indicated for the acute treatment of adults with manic and mixed episodes associated with bipolar I disorder and for the maintenance treatment of adults with bipolar I disorder; the drug-device combination may be used as monotherapy or as an adjunct to lithium or valproate. 1

Aripiprazole tablet with sensor is indicated for the adjunctive treatment of adults with major depressive disorder (MDD).1

Aripiprazole tablet with sensor has the following limitations of use:

The ability of aripiprazole tablets with sensor to improve patient compliance or modify aripiprazole dosage has not been established.1

The use of aripiprazole tablets with sensor to track drug ingestion in "real-time" or during an emergency is not recommended because detection may be delayed or not occur.1

ARIPiprazole Tablets with Sensor Dosage and Administration

General

Aripiprazole tablets with sensor are available in the following dosage form(s) and strength(s):

Tablets with sensor: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg. 1

The tablet with sensor is used in conjunction with a patch (wearable sensor), a compatible mobile device, and smartphone application.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage of Aripiprazole Tablets with Sensor

Initial Dose

Recommended Dose

Maximum Dose

Schizophrenia

10-15 mg/day

10-15 mg/day

30 mg/day

Bipolar mania (monotherapy)

15 mg/day

15 mg/day

30 mg/day

Bipolar mania (adjunct to lithium or valproate)

10-15 mg/day

15 mg/day

30 mg/day

Major Depressive Disorder (adjunct to antidepressants)

2-5 mg/day

5-10 mg/day

15 mg/day

  • Administer once daily without regard to meals. 1

  • Swallow whole; do not divide, crush, or chew. 1

  • Known CYP2D6 poor metabolizers: Administer half of the usual dose. 1

Cautions for ARIPiprazole Tablets with Sensor

Contraindications

Known hypersensitivity to aripiprazole. 1

Warnings/Precautions

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.1

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Aripiprazole tablet with sensor is not approved for the treatment of patients with dementia-related psychosis.1

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients,the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The safety and efficacy of aripiprazole tablets with sensor have not been established in pediatric patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3.1

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.1

Table 3: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range (years)

Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated

Increases Compared to Placebo

<18

14 additional patients

18-24

5 additional patients

Decreases Compared to Placebo

25-64

1 fewer patient

≥65

6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.1

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing aripiprazole tablets with sensor, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.1

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis

In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in aripiprazole-treated patients (mean age: 84 years; range: 78-88 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with aripiprazole. Aripiprazole tablet with sensor is not approved for the treatment of patients with dementia-related psychosis.1

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including aripiprazole tablets with sensor. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.1

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. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.1

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.1

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including aripiprazole tablets with sensor. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.1

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.1

The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.1

Given these considerations, aripiprazole tablets with sensor should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.1

If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole tablets with sensor, drug discontinuation should be considered. However, some patients may require treatment with aripiprazole tablets with sensor despite the presence of the syndrome.1

Metabolic Changes

Atypical antipsychotic drugs have caused metabolic changes that include hyperglycemia, diabetes mellitus, 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.1

Hyperglycemia/Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with aripiprazole. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. 1

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. 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 during treatment with atypical antipsychotics should 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 atypical antipsychotic drug.1

In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in aripiprazole -treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 4 shows the proportion of aripiprazole-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days).1

Table 4: Changes in Fasting Glucose in Placebo-Controlled Monotherapy Trials in Adult Patients (Primarily Schizophrenia and Bipolar Disorder)

Category Change (at least once) from Baseline

Treatment Arm

n/N

%

Fasting Glucose

Normal to High

(<100 mg/dL to ≥126 mg/dL)

Aripiprazole

31/822

3.8

Placebo

22/605

3.6

Borderline to High

(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)

Aripiprazole

31/176

17.6

Placebo

13/142

9.2

At 24 weeks, the mean change in fasting glucose in aripiprazole-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively].1

The mean change in fasting glucose in adjunctive aripiprazole-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 5 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder.1

Table 5: Changes in Fasting Glucose From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder

Category Change (at least once) from Baseline

Treatment Arm

n/N

%

Fasting Glucose

Normal to High

(<100 mg/dL to ≥126 mg/dL)

Aripiprazole

2/201

1.0

Placebo

2/204

1.0

Borderline to High

(≥100 mg/dL and <126 mg/dL to ≥126 mg/dL)

Aripiprazole

4/34

11.8

Placebo

3/37

8.1

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.1

Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients. Table 6 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days).1

Table 6: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Adults (Primarily Schizophrenia and Bipolar Disorder)

Treatment Arm

n/N

%

Total Cholesterol

Normal to High

(<200 mg/dL to ≥240 mg/dL)

Aripiprazole

34/1357

2.5

Placebo

27/973

2.8

Fasting Triglycerides

Normal to High

(<150 mg/dL to ≥200 mg/dL)

Aripiprazole

40/539

7.4

Placebo

30/431

7.0

Fasting LDL Cholesterol

Normal to High

(<100 mg/dL to ≥160 mg/dL)

Aripiprazole

2/332

0.6

Placebo

2/268

0.7

HDL Cholesterol

Normal to Low

(≥40 mg/dL to <40 mg/dL)

Aripiprazole

121/1066

11.4

Placebo

99/794

12.5

In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between aripiprazole- and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively.1

Table 7 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days).1

Table 7: Changes in Blood Lipid Parameters From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder

Treatment Arm

n/N

%

Total Cholesterol

Normal to High

(<200 mg/dL to ≥240 mg/dL)

Aripiprazole

3/139

2.2

Placebo

7/135

5.2

Fasting Triglycerides

Normal to High

(<150 mg/dL to ≥200 mg/dL)

Aripiprazole

14/145

9.7

Placebo

6/147

4.1

Fasting LDL Cholesterol

Normal to High

(<100 mg/dL to ≥160 mg/dL)

Aripiprazole

0/54

0

Placebo

0/73

0

HDL Cholesterol

Normal to Low

(≥40 mg/dL to <40 mg/dL)

Aripiprazole

17/318

5.3

Placebo

10/286

3.5

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.1

In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in aripiprazole-treated patients was +0.3 kg (N=1673) compared to –0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in aripiprazole-treated patients was –1.5 kg (n=73) compared to –0.2 kg (n=46) in placebo-treated patients.1

In the trials adding aripiprazole to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive aripiprazole or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive aripiprazole was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo.1

Table 8 shows the percentage of adult patients with weight gain ≥7% of body weight by indication.1

4-6 weeks duration.

3 weeks duration.

6 weeks duration.

Table 8: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain ≥7% of Body Weight

Indication

Treatment Arm

N

Patients n (%)

Schizophrenia

Aripiprazole

852

69 (8.1)

Placebo

379

12 (3.2)

Bipolar Mania

Aripiprazole

719

16 (2.2)

Placebo

598

16 (2.7)

Major Depressive Disorder (Adjunctive Therapy)

Aripiprazole

347

18 (5.2)

Placebo

330

2 (0.6)

Pathological Gambling and Other Compulsive Behaviors

Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole tablets with sensor. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.1

Orthostatic Hypotension

Aripiprazole tablets with sensor may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral aripiprazole (n=2467) included (aripiprazole incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%). 1

The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure ≥20 mmHg accompanied by an increase in heart rate ≥25 bpm when comparing standing to supine values) for aripiprazole was not meaningfully different from placebo (aripiprazole incidence, placebo incidence) in adult oral aripiprazole-treated patients (4%, 2%).1

Aripiprazole tablets with sensor should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).1

Falls

Antipsychotics, including aripiprazole tablets with sensor, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.1

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including aripiprazole. Agranulocytosis has also been reported.1

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of aripiprazole tablets with sensor at the first sign of a clinically significant decline in WBC in the absence of other causative factors. 1

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 aripiprazole tablets with sensor in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC counts until recovery.1

Seizures

In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral aripiprazole.1

As with other antipsychotic drugs, aripiprazole tablets with sensor should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.1

Potential for Cognitive and Motor Impairment

Aripiprazole, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11% of aripiprazole-treated patients compared with 6% of placebo-treated patients. Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients on oral aripiprazole in short-term, placebo-controlled trials.1

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with aripiprazole tablets with sensor does not affect them adversely.1

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing aripiprazole tablets with sensor for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).1

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including aripiprazole. Aripiprazole tablets with sensor and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aripiprazole tablets with sensor during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. 1

Risk Summary: Neonates exposed to antipsychotic drugs, including aripiprazole tablets with sensor, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. There are no available data on aripiprazole use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Consider the benefits and risks of aripiprazole tablets with sensor and possible risks to the fetus when prescribing the drug to a pregnant woman. Advise pregnant women of potential fetal risk. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms.1

Animal Data1

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.1

Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m2 basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg/day. Treatment at the high dose of 30 mg/kg/day caused a slight delay in fetal development (decreased fetal weight), undescended testes, and delayed skeletal ossification (also seen at 10 mg/kg/day). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg/day), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg/day and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg/day. Some maternal toxicity was seen at 30 mg/kg/day however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.1

In pregnant rats receiving aripiprazole injection intravenously (3, 9, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose where it also caused maternal toxicity.1

Pregnant rabbits were treated with oral doses of 10, 30, and 100 mg/kg/day (2 , 3, and 11 times human exposure at MRHD based on AUC and 6, 19, and 65 times the MRHD based on mg/m2) of aripiprazole during the period of organogenesis. At the high dose of 100 mg/kg/day decreased maternal food consumption, and increased abortions were seen as well as increased fetal mortality, decreased fetal weight (also seen at 30 mg/kg/day), increased incidence of a skeletal abnormality (fused sternebrae) (also seen at 30 mg/kg/day).1

In pregnant rabbits receiving aripiprazole injection intravenously (3, 10, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg/day, which is 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m2.1

In a study in which rats were treated peri- and post-natally with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m2 basis) of aripiprazole from gestation day 17 through day 21 postpartum, slight maternal toxicity, slightly prolonged gestation, an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were seen at 30 mg/kg/day.1

In rats receiving aripiprazole injection intravenously (3, 8, and 20 mg/kg/day) from gestation day 6 through day 20 postpartum, an increase in stillbirths was seen at 8 and 20 mg/kg/day, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg/day; these effects were seen in presence of maternal toxicity. There were no effects on postnatal behavioral and reproductive development.1

The effect of aripiprazole tablets with sensor on labor and delivery in humans is unknown.1

Lactation

Aripiprazole is present in human breast milk; however, there are insufficient data to assess the amount in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for aripiprazole tablets with sensor and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness of aripiprazole tablets with sensor in pediatric patients have not been established. 1

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients. 1

Geriatric Use

No dosage adjustment of aripiprazole tablets with sensor is recommended for elderly patients for the approved indications.1

Of the 13,543 patients treated with oral aripiprazole in clinical trials, 1073 (8%) were ≥65 years old and 799 (6%) were ≥75 years old. Placebo-controlled studies of oral aripiprazole in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 1

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Elderly patients treated with antipsychotic drugs with dementia-related psychosis had a greater incidence of stroke and transient ischemic attack. Aripiprazole tablet with sensor is not approved for the treatment of elderly patients with dementia-related psychosis.1

CYP2D6 Poor Metabolizers

Dosage adjustment of aripiprazole tablets with sensor is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM). 1

Hepatic and Renal Impairment

No dosage adjustment for aripiprazole tablets with sensor is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute).1

Other Specific Populations

No dosage adjustment for aripiprazole tablets with sensor is required on the basis of a patient's sex, race, or smoking status.1

Common Adverse Effects

Commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) in adult patients: 1

  • Schizophrenia: akathisia.1

  • Bipolar mania (monotherapy): akathisia, sedation, restlessness, tremor, and extrapyramidal disorder.1

  • Bipolar mania (adjunctive therapy with lithium or valproate): akathisia, insomnia, and extrapyramidal disorder.1

  • MDD (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Dosage adjustment due to drug interactions and CYP2D6 poor metabolizers: 1

Factors

Dosage Adjustments for Aripiprazole Tablets with Sensor

Known CYP2D6 Poor Metabolizers

Administer half recommended dose

Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors

Administer a quarter of recommended dose

Strong CYP2D6 or CYP3A4 inhibitors

Administer half recommended dose

Strong CYP2D6 and CYP3A4 inhibitors

Administer a quarter of recommended dose

Strong CYP3A4 inducers

Double recommended dose over 1 to 2 weeks

Actions

Mechanism of Action

The mechanism of action of aripiprazole in the treatment of schizophrenia, bipolar 1 disorder, or adjunctive treatment of major depressive disorder is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling.1

General Instructions for Use

Instruct patients to refer to the app store to ensure compatibility with their specific smartphone. 1

Instruct patient to first download the MyCite APP and follow instructions provided by the app.1

Advise patients that the initial use should be facilitated by the healthcare provider. 1

Advise patients that most ingestions will be detected within 30 minutes; however, in some cases it can take over two hours for the smartphone app and web portal to detect the ingestion of aripiprazole tablets with sensor. In some cases, the ingestion of the tablet may not be detected. If the tablet is not detected after ingestion, the dose should not be repeated.1

Managing Lost or Disabled Mobile Device

Advise patients that if their smartphone is lost, impaired or otherwise rendered unusable, some information collected by the system (synced) may be lost. Advise patients to change their MyCite Patch immediately and connect to a new mobile device using their current account information. Information previously synced to the patients account will be available.1

Using the MyCite Patch in Different Environments

The MyCite Patch will communicate with a paired device when it is within 9-foot proximity. The MyCite Patch should remain on an individual whether they are showering, swimming, or exercising as it is intended to tolerate water or perspiration. Patients undergoing an MRI, however, need to remove their patch and replace with a new one as soon as possible. In order for the MyCite Patch to communicate with a smartphone, the device must be powered on and Bluetooth-enabled.1

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider. 1

Neuroleptic Malignant Syndrome

Counsel patients about a potentially fatal adverse reaction referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a health care provider or report to the emergency room if they experience signs or symptoms of NMS. 1

Tardive Dyskinesia

Advise patients that abnormal involuntary movements have been associated with the administration of antipsychotic drugs. Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur. 1

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight. 1

Pathological Gambling and Other Compulsive Behaviors

Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, increased urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped.1

Orthostatic Hypotension and Syncope

Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, when re-initiating treatment, or when increasing the dosage. 1

Leukopenia, Neutropenia, and Agranulocytosis

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking aripiprazole tablets with sensor. 1

Interference with Cognitive and Motor Performance

Because aripiprazole tablets with sensor may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug does not affect them adversely.1

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in avoiding overheating and dehydration.1

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.1

Pregnancy

Advise patients that aripiprazole tablets with sensor may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to aripiprazole tablets with sensor during pregnancy. 1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

ARIPiprazole Tablets with Sensor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

2 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

5 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

10 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

15 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

20 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

30 mg

Abilify MyCite

Otsuka America Pharmaceutical Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions February 12, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Otsuka America Pharmaceutical, Inc. Abilify MyCite (ARIPIPRAZOLE) ORAL prescribing information. 2017 Nov. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e8787c3f-5e41-42d1-8091-44b56346620f

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