Abilify Mycite Prescribing Information
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY MYCITE is not approved for the treatment of patients with dementia-related psychosis. ()
5.1 Increased Mortality in Elderly Patients with Dementia-Related PsychosisElderly 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.
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. ABILIFY MYCITE is not approved for the treatment of patients with dementia-related psychosis
[see Boxed Warning, and Warnings and Precautions (5.3)]. - 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. ()
5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult PatientsIn 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 ABILIFY MYCITE have not been established in pediatric patients[see Use in Specific Populations (8.4)].The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 3.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.
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 to 24 5 additional patients Decreases Compared to Placebo25 to 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.
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 ABILIFY MYCITE, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
- The safety and effectiveness of ABILIFY MYCITE have not been established in pediatric patients. ()
8.4 Pediatric UseSafety and effectiveness of ABILIFY MYCITE in pediatric patients have not been established.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients
[see Boxed Warning,and Warnings and Precautions (5.2)].
ABILIFY MYCITE, a drug-device combination product comprised of aripiprazole tablets embedded with an Ingestible Event Marker (IEM) sensor intended to track drug ingestion, is indicated for the:
- Treatment of adults with schizophrenia.
- Treatment of bipolar I disorder
- Acute treatment of adults with manic and mixed episodes as monotherapy and as adjunct to lithium or valproate.
- Maintenance treatment of adults as monotherapy and as adjunct to lithium or valproate.
- Adjunctive treatment of adults with Major Depressive Disorder.
| Initial Dose | Recommended Dose | Maximum Dose | |
|---|---|---|---|
Schizophrenia – adults (The recommended starting and target dosage for ABILIFY MYCITE in adults with schizophrenia is 10 or 15 mg daily. Dosage increases should generally not be made before 2 weeks [see Clinical Pharmacology (12.3)] . The maximum recommended dosage is 30 mg daily; however, doses above 15 mg daily have shown no additional clinically meaningful benefit. | 10 to 15 mg/day | 10 to 15 mg/day | 30 mg/day |
Bipolar mania – adults: monotherapy (The recommended starting dosage in adults with acute and mixed episodes associated with bipolar I disorder is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive treatment with lithium or valproate. The recommended target dose of ABILIFY MYCITE is 15 mg daily, as monotherapy or as adjunctive treatment with lithium or valproate. The dosage may be increased to 30 mg daily based on clinical response. The maximum recommended daily dosage is 30 mg. | 15 mg/day | 15 mg/day | 30 mg/day |
Bipolar mania – adults: adjunct to lithium or valproate (The recommended starting dosage in adults with acute and mixed episodes associated with bipolar I disorder is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive treatment with lithium or valproate. The recommended target dose of ABILIFY MYCITE is 15 mg daily, as monotherapy or as adjunctive treatment with lithium or valproate. The dosage may be increased to 30 mg daily based on clinical response. The maximum recommended daily dosage is 30 mg. | 10 to 15 mg/day | 15 mg/day | 30 mg/day |
Major Depressive Disorder – adults: adjunct to antidepressants (The recommended starting dose for ABILIFY MYCITE as adjunctive treatment of adults with MDD taking an antidepressant is 2 to 5 mg daily. The recommended dosage range is 2 to 15 mg daily. Dosage adjustments of up to 5 mg daily should occur gradually, at intervals of no less than one week. The maximum recommended daily dosage is 15 mg. Periodically reassess to determine the continued need for maintenance treatment. | 2 to 5 mg/day | 5 to 10 mg/day | 15 mg/day |
- Administer once daily without regard to meals ()
2.2 Administration InstructionsABILIFY MYCITEAdminister ABILIFY MYCITE orally with or without food
[see Clinical Pharmacology (12.3)]. Swallow tablets with sensor whole; do not divide, crush, or chew.MYCITE PatchRefer to the Instructions for Use (IFU) within the
app [see How Supplied/Storage and Handling (16.1)]:- Apply only when instructed by the app to theright or left sideof the body just above the lower edge of the rib cage.
Additional
patchinstructions:- Do not place thepatchin areas where the skin is scraped, cracked, inflamed, or irritated, or in a location that overlaps the area of the most recently removedpatch(if there is skin irritation, instruct patients to remove thepatch).
- Theappwill prompt the patient to change thepatch(at least weekly or sooner), and to apply and remove thepatchcorrectly.
- Keep thepatchon when showering, swimming, or exercising.
- For those undergoing an MRI, remove thepatchand replace with a newpatchas soon as possible.
- Apply only when instructed by the app to the
- Swallow whole; do not divide, crush, or chew ()
2.2 Administration InstructionsABILIFY MYCITEAdminister ABILIFY MYCITE orally with or without food
[see Clinical Pharmacology (12.3)]. Swallow tablets with sensor whole; do not divide, crush, or chew.MYCITE PatchRefer to the Instructions for Use (IFU) within the
app [see How Supplied/Storage and Handling (16.1)]:- Apply only when instructed by the app to theright or left sideof the body just above the lower edge of the rib cage.
Additional
patchinstructions:- Do not place thepatchin areas where the skin is scraped, cracked, inflamed, or irritated, or in a location that overlaps the area of the most recently removedpatch(if there is skin irritation, instruct patients to remove thepatch).
- Theappwill prompt the patient to change thepatch(at least weekly or sooner), and to apply and remove thepatchcorrectly.
- Keep thepatchon when showering, swimming, or exercising.
- For those undergoing an MRI, remove thepatchand replace with a newpatchas soon as possible.
- Apply only when instructed by the app to the
- Known CYP2D6 poor metabolizers: Administer half of the usual dose ()
2.6 Dosage Adjustments for Cytochrome P450 ConsiderationsDosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 1). When the coadministered drug is withdrawn from the combination therapy, ABILIFY MYCITE dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY MYCITE dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted based on clinical response.
Table 1: Dose Adjustments for ABILIFY MYCITE in Patients Who Are Known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for ABILIFY MYCITE Known CYP2D6 Poor Metabolizers Administer half of recommended dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of recommended dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) orCYP3A4 inhibitors (e.g., itraconazole, clarithromycin)Administer half of recommended dose Strong CYP2D6 andCYP3A4 inhibitorsAdminister a quarter of recommended dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double recommended dose over 1 to 2 weeks When adjunctive ABILIFY MYCITE is administered to patients with major depressive disorder, ABILIFY MYCITE should be administered without dosage adjustment as specified in
[Dosage and Administration (2.5)].
ABILIFY MYCITE (aripiprazole tablets with sensor) is available as described in Table 2.
| Strength | Color/Shape | Markings |
|---|---|---|
2 mg | pale green modified rectangle | "DA-029" and "2" |
5 mg | pale blue modified rectangle | "DA-030" and "5" |
10 mg | off-white to pale pink modified rectangle | "DA-031" and "10" |
15 mg | pale yellow round | "DA-032" and "15" |
20 mg | white to pale yellowish white round | "DA-033" and "20" |
30 mg | off-white to pale pink round | "DA-034" and "30" |
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY MYCITE 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/.
Neonates exposed to antipsychotic drugs, including ABILIFY MYCITE, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms
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 MRHD produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival.
The background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants.
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
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.
In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits.
Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on mg/m2basis) 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.
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.
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).
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.
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 mg/m2basis) 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.
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.
The effect of ABILIFY MYCITE on labor and delivery in humans is unknown.
Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period may lead to clinically relevant decreases in milk supply which may be reversible with discontinuation of the drug. There are also reports of aripiprazole exposure during pregnancy and no maternal milk supply in the post-partum period. Effects on milk supply may be mediated through decreases in prolactin levels, which have been observed
ABILIFY MYCITE is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis
The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), hiccups, oculogyric crisis, pathological gambling, and fecal incontinence.