Aripiprazole - Aripiprazole tablet, Orally Disintegrating

Aripiprazole orally disintegrating tablets are indicated for the treatment of:

• Schizophrenia
  14.1 Schizophrenia

  Adults

  The efficacy of aripiprazole in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish aripiprazole from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of aripiprazole and the active comparators.

  In the four positive trials for aripiprazole, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient.

  In a 4-week trial (n=414) comparing two fixed doses of aripiprazole (15 mg/day or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale.

  In a 4-week trial (n=404) comparing two fixed doses of aripiprazole (20 mg/day or 30 mg/day) to placebo, both doses of aripiprazole were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score.

  In a 6-week trial (n=420) comparing three fixed doses of aripiprazole (10 mg/day, 15 mg/day, or 20 mg/day) to placebo, all three doses of aripiprazole were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale.

  In a 6-week trial (n=367) comparing three fixed doses of aripiprazole (2 mg/day, 5 mg/day, or 10 mg/day) to placebo, the 10 mg dose of aripiprazole was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. The 2 mg and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure.

  Thus, the efficacy of 10 mg, 15 mg, 20 mg, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies.

  An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race.

  A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from their antipsychotic medications and randomized to aripiprazole 15 mg/day or placebo for up to 26-weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of ≥5 (minimally worse), scores ≥5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or ≥20% increase in the PANSS total score. Patients receiving aripiprazole 15 mg/day experienced a significantly longer time to relapse over the subsequent 26-weeks compared to those receiving placebo (Study 5 in Figure 6).

  Pediatric Patients

  The efficacy of aripiprazole in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of aripiprazole (10 mg/day or 30 mg/day) to placebo, aripiprazole was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of aripiprazole were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

  Table 26: Schizophrenia Studies

  Study Number	Treatment Group	Primary Efficacy Measure: PANSS
  		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference * (95% CI)
  Study 1	Aripiprazole (15 mg/day)†	98.5 (17.2)	-15.5 (2.40)	-12.6 (-18.9, -6.2)
  	Aripiprazole (30 mg/day)†	99.0 (19.2)	-11.4 (2.39)	-8.5 (-14.8, -2.1)
  	Placebo	100.2 (16.5)	-2.9 (2.36)	--
  Study 2	Aripiprazole (20 mg/day)†	92.6 (19.5)	-14.5 (2.23)	-9.6 (-15.4, -3.8)
  	Aripiprazole (30 mg/day)†	94.2 (18.5)	-13.9 (2.24)	-9.0 (-14.8, -3.1)
  	Placebo	94.3 (18.5)	-5.0 (2.17)	--
  Study 3	Aripiprazole (10 mg/day)†	92.7 (19.5)	-15.0 (2.38)	-12.7 (-19, -6.41)
  	Aripiprazole (15 mg/day)†	93.2 (21.6)	-11.7 (2.38)	-9.4 (-15.71, -3.08)
  	Aripiprazole (20 mg/day)†	92.5 (20.9)	-14.4 (2.45)	-12.1 (-18.53, -5.68)
  	Placebo	92.3 (21.8)	-2.3 (2.35)	--
  Study 4	Aripiprazole (2 mg/day)	90.7 (14.5)	-8.2 (1.90)	-2.9 (-8.29, 2.47)
  	Aripiprazole (5 mg/day)	92.0 (12.6)	-10.6 (1.93)	-5.2 (-10.7, 0.19)
  	Aripiprazole (10 mg/day)†	90.0 (11.9)	-11.3 (1.88)	-5.9 (-11.3, -0.58)
  	Placebo	90.8 (13.3)	-5.3 (1.97)	--
  Study 6 (Pediatric, 13 to 17 Years)	Aripiprazole (10 mg/day)†	93.6 (15.7)	-26.7 (1.91)	-5.5 (-10.7, -0.21)
  	Aripiprazole (30 mg/day)†	94.0 (16.1)	-28.6 (1.92)	-7.4 (-12.7, -2.13)
  	Placebo	94.6 (15.6)	-21.2 (1.93)	--
  SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
  *Difference (drug minus placebo) in least-squares mean change from baseline.
  †Doses statistically significantly superior to placebo.

  Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

  
• Irritability Associated with Autistic Disorder
  [

  14.4 Irritability Associated with Autistic Disorder

  Pediatric Patients

  The efficacy of aripiprazole in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age.

  Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder.

  The results of these trials are as follows:

  In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or aripiprazole 2 to 15 mg/day. aripiprazole, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of aripiprazole at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 29).

  In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. aripiprazole dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 29). All three doses of aripiprazole significantly improved scores on the ABC-I subscale compared with placebo.

  Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric)

  SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
  *Difference (drug minus placebo) in least-squares mean change from baseline.
  †Doses statistically significantly superior to placebo.
  Study Number	Treatment Group	Primary Efficacy Measure: ABC-I
  		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference* (95% CI)
  Study 1	Aripiprazole (2-15 mg/day)†	29.6 (6.37)	-12.9 (1.44)	-7.9 (-11.7, -4.1)
  	Placebo	30.2 (6.52)	-5.0 (1.43)	--
  Study 2	Aripiprazole (5 mg/day)†	28.6 (7.56)	-12.4 (1.36)	-4.0 (-7.7, -0.4)
  	Aripiprazole (10 mg/day)†	28.2 (7.36)	-13.2 (1.25)	-4.8 (-8.4, -1.3)
  	Aripiprazole (15 mg/day)†	28.9 (6.41)	-14.4 (1.31)	-6.0 (-9.6, -2.3)
  	Placebo	28.0 (6.89)	-8.4 (1.39)	--

  ]
• Treatment of Tourette's Disorder
  14.5 Tourette's Disorder

  Pediatric Patients

  The efficacy of aripiprazole in the treatment of Tourette's disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette's disorder and had a Total Tic score (TTS) ≥ 20 -22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age.

  The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0-50).

  The results of these trials are as follows:

  In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette's disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose aripiprazole, high dose aripiprazole, or placebo. The target doses for the low and high dose aripiprazole groups were based on weight. Patients < 50 kg in the low dose aripiprazole group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients ≥ 50 kg in the low dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients <50 kg in the high dose aripiprazole group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients ≥ 50 kg in the high dose aripiprazole group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. Aripiprazole (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.

  Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette's Disorder Study 1)

  

  In the 10-week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette's disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or aripiprazole, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. Aripiprazole demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of aripiprazole at the end of 10-week treatment was 6.54 mg/day.

  Table 30: Tourette's Disorder Studies (Pediatric)

  Study	Treatment Group	Primary Efficacy Measure: YGTSS TTS
  Number		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference*(95% CI)
  Study 1	Aripiprazole (low dose)†	29.2 (5.63)	-13.4 (1.59)	-6.3 (-10.2, -2.3)
  	Aripiprazole (high dose)†	31.2 (6.40)	-16.9 (1.61)	-9.9 (-13.8, -5.9)
  	Placebo	30.7 (5.95)	-7.1 (1.55)	--
  Study 2	Aripiprazole (2-20 mg/day)†	28.3 (5.51)	-15.0 (1.51)	-5.3 (-9.8, -0.9)
  	Placebo	29.5 (5.60)	-9.6 (1.64)	--
  SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
  *Difference (drug minus placebo) in least-squares mean change from baseline
  †Doses statistically significantly superior to placebo

• Orally Disintegrating Tablets: Administer once daily without regard to meals
  2 DOSAGE AND ADMINISTRATION

  		Initial Dose	Recommended Dose	Maximum Dose
  Schizophrenia – adults (2.1)		10 to 15 mg/day	10 to 15 mg/day	30 mg/day
  Schizophrenia – adolescents (2.1)		2 mg/day	10 mg/day	30 mg/day
  Irritability associated with autistic disorder – pediatric patients (2.4)		2 mg/day	5 to 10 mg/day	15 mg/day
  Tourette's Disorder –	Patients < 50 kg	2 mg/day	5 mg/day	10 mg/day
  	Patients ≥ 50 kg	2 mg/day	10 mg/day	20 mg/day

  • Orally Disintegrating Tablets: Administer once daily without regard to meals (2)
  • Known CYP2D6 poor metabolizers: Half of the usual dose (2.7)

  2.1 Schizophrenia

  Adults

  The recommended starting and target dose for aripiprazole is 10 mg/day or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 mg/day to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 mg/day or 15 mg/day were not more effective than 10 mg/day or 15 mg/day. Dosage increases should generally not be made before 2-weeks, the time needed to achieve steady-state

  [see Clinical Studies (14.1)]

  .

  Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either aripiprazole 15 mg/day or placebo, and observed for relapse

  [see Clinical Studies (14.1)]

  . Patients should be periodically reassessed to determine the continued need for maintenance treatment.

  Adolescents

  The recommended target dose of aripiprazole is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Aripiprazole can be administered without regard to meals

  [see Clinical Studies (14.1)]

  . Patients should be periodically reassessed to determine the need for maintenance treatment.

  Switching from Other Antipsychotics

  There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

  2.4 Irritability Associated with Autistic Disorder

  Pediatric Patients (6 to 17 years)

  The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day.

  Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week

  [see Clinical Studies (14.4)].

  Patients should be periodically reassessed to determine the continued need for maintenance treatment.

  2.5 Tourette’s Disorder

  Pediatric Patients (6 to 18 years)

  The recommended dosage range for Tourette's Disorder is 5 to 20 mg/day.

  For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than 1 week.

  For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than 1 week.

  [See Clinical Studies (14.5)]

  .

  Patients should be periodically reassessed to determine the continued need for maintenance treatment.

  2.7 Dosage Adjustments for Cytochrome P450 Considerations

  Dosage 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 2). When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole 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 to achieve a favorable clinical response.

  Table 2: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers

  Factors	Dosage Adjustments for Aripiprazole
  Known CYP2D6 Poor Metabolizers	Administer half of usual dose
  Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)	Administer a quarter of usual dose
  Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)	Administer half of usual dose
  Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
  Strong CYP3A4 inducers (e.g., carbamazepine, rifampin)	Double usual dose over 1 to 2 weeks

  2.8 Dosing of Oral Solution

  The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution

  [see Clinical Pharmacology (12.3)]

  .

  2.9 Dosing of Orally Disintegrating Tablets

  The dosing for aripiprazole orally disintegrating tablets is the same as for the oral tablets

  [see Dosage and Administration (2.1)and (2.4)].
• Known CYP2D6 poor metabolizers: Half of the usual dose
  2.7 Dosage Adjustments for Cytochrome P450 Considerations

  Dosage 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 2). When the coadministered drug is withdrawn from the combination therapy, aripiprazole dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, aripiprazole 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 to achieve a favorable clinical response.

  Table 2: Dose Adjustments for Aripiprazole in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers

  Factors	Dosage Adjustments for Aripiprazole
  Known CYP2D6 Poor Metabolizers	Administer half of usual dose
  Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)	Administer a quarter of usual dose
  Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin)	Administer half of usual dose
  Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
  Strong CYP3A4 inducers (e.g., carbamazepine, rifampin)	Double usual dose over 1 to 2 weeks

Aripiprazole orally disintegrating tablets, USP are available as described in Table 4.

• Pregnancy
  : May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/.

  Risk Summary

  Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (

  see Clinical Considerations

  ). Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or another indication, and with exposure to antipsychotics, including aripiprazole, during pregnancy (

  see Clinical Considerations

  ). Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post-partum period.

  [see Use in Specific Populations (8.2)].

  In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m²body surface area, 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 10 times the MRHD based on mg/m²body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (

  see Data

  ).

  The background risk of major birth defects and miscarriage for the indicated population is 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.

  Clinical Considerations

  Disease-associated maternal and/or embryo/fetal risk

  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.

  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. Monitor neonates for extrapyramidal and/or withdrawal symptoms, and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

  Data

  Human Data

  Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A retrospective study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects.

  Animal Data

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

  In pregnant rats treated orally with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are approximately 1, 3 and 10 times the MRHD of 30 mg/day based on mg/m²body surface area, a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes, were observed at 10 times the MRHD. Delayed skeletal ossification was observed at 3 and 10 times the MRHD. Delivered offspring had increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed at 10 times the MRHD (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the MRHD. Impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) were observed at 10 times the MRHD; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

  In pregnant rats injected intravenously with aripiprazole during organogenesis at doses of 3, 9, and 27 mg/kg/day, which are 1, 3, and 9 times the MRHD of 30 mg/day based on mg/m²body surface area, decreased fetal weight and delayed skeletal ossification were observed at 9 times the MRHD; this dose also caused maternal toxicity.

  In pregnant rabbits treated orally with aripiprazole during organogenesis at doses of 10, 30, and 100 mg/kg/day which are 6, 19, and 65 times the MRHD of 30 mg/day based on mg/m²body surface area, decreased maternal food consumption, and increased abortions as well as increased fetal mortality were observed at 65 times the MRHD. Decreased fetal weight and increased incidence of fused sternebrae were observed at 19 and 65 times the MRHD.

  In pregnant rabbits injected intravenously with aripiprazole during organogenesis at doses of 3, 10, and 30 mg/kg/day, which are 2, 6, and 19 times the MRHD of 30 mg/day based on mg/m²body surface area, decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification were observed at 19 times the MRHD; this dose also caused maternal toxicity. The fetal no-effect dose was 10 mg/kg/day, which is 6 times the MRHD.

  In rats treated orally with aripiprazole peri- and post-natally from gestation day 17 through postpartum day 21 at doses of 3, 10, and 30 mg/kg/day which are 1, 3, and 10 times the MRHD of 30 mg/day based on mg/m²body surface area slight maternal toxicity and slightly prolonged gestation were observed at 10 times the MRHD. An increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

  In rats injected intravenously with aripiprazole from gestation day 6 through lactation day 20 at doses of 3, 8, and 20 mg/kg/day, which are 1, 3, and 6 times the MRHD of 30 mg/day based on mg/m²body surface area, increased stillbirths were observed at 3 and 6 times the MRHD; and decreases in early postnatal pup weight and survival were observed at 6 times the MRHD; these doses also caused some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.
• Lactation:
  Monitor the breastfed infant for dehydration and lack of appropriate weight gain
  8.2 Lactation

  Risk Summary

  Aripiprazole is present in human breast milk. Based on published case reports and pharmacovigilance reports, aripiprazole exposure during pregnancy and/or the postpartum period can lead to variable effects on milk supply in the post-partum period, including 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 are likely mediated through decreases in prolactin levels, which have been observed

  [see Adverse Reactions (6.2)]

  . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for aripiprazole, and any potential adverse effects on the breastfed infant from aripiprazole, or from the underlying maternal condition.

  Clinical Considerations

  Monitor infants exposed to aripiprazole through breastmilk for dehydration and lack of appropriate weight gain.
  .