Abilify Maintena

ABILIFY MAINTENA (aripiprazole) is indicated:

• for the treatment of schizophrenia in adults
• for maintenance monotherapy treatment of bipolar I disorder in adults

• Only to be administered by intramuscular injection in the deltoid or gluteal muscle by a healthcare professional (
  2.1 Important Administration Information

  For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability.

  ABILIFY MAINTENA must be administered by intramuscular injection by a healthcare professional. Do not administer by any other route.

  For detailed preparation and administration instructions,

  [see Dosage and Administration (2.6, 2.7)]

  .
  )
• For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating ABILIFY MAINTENA (
  2.1 Important Administration Information

  For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ABILIFY MAINTENA. Due to the half-life of oral aripiprazole (i.e., 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively), it may take up to 2 weeks to fully assess tolerability.

  ABILIFY MAINTENA must be administered by intramuscular injection by a healthcare professional. Do not administer by any other route.

  For detailed preparation and administration instructions,

  [see Dosage and Administration (2.6, 2.7)]

  .
  )
• Recommended dosage is 400 mg administered monthly as a single injection. Dose can be reduced to 300 mg in patients with adverse reactions (
  2.2 Recommended Dosage for ABILIFY MAINTENA

  The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection).

  There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics:

  1-day initiation:

  • Administer two intramuscular injections of ABILIFY MAINTENA 400 mg in two different injection sites (in either the deltoid or gluteal muscle), and one dose of oral aripiprazole 20 mg on the first day of treatment with ABILIFY MAINTENA.
  • Do not administer both injections into the same muscle.

  14-day initiation:

  • When ABILIFY MAINTENA injection is initiated in patients receiving oral aripiprazole administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy.
  • For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy.

  If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly.
  )
• There are two ways to initiate treatment with ABILIFY MAINTENA
  • 1-day initiation: Administer two separate intramuscular injections of ABILIFY MAINTENA 400 mg and a single oral dose of aripiprazole 20 mg (
    2.2 Recommended Dosage for ABILIFY MAINTENA

    The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection).

    There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics:

    1-day initiation:

    • Administer two intramuscular injections of ABILIFY MAINTENA 400 mg in two different injection sites (in either the deltoid or gluteal muscle), and one dose of oral aripiprazole 20 mg on the first day of treatment with ABILIFY MAINTENA.
    • Do not administer both injections into the same muscle.

    14-day initiation:

    • When ABILIFY MAINTENA injection is initiated in patients receiving oral aripiprazole administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy.
    • For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy.

    If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly.
    )
  • 14-day initiation: In conjunction with first ABILIFY MAINTENA 400 mg dose, take 14 consecutive days of concurrent oral aripiprazole (10 mg to 20 mg) or current oral antipsychotic (
    2.2 Recommended Dosage for ABILIFY MAINTENA

    The recommended dose of ABILIFY MAINTENA is 400 mg monthly (no sooner than 26 days after the previous injection).

    There are two ways to initiate treatment with ABILIFY MAINTENA in patients receiving oral antipsychotics:

    1-day initiation:

    • Administer two intramuscular injections of ABILIFY MAINTENA 400 mg in two different injection sites (in either the deltoid or gluteal muscle), and one dose of oral aripiprazole 20 mg on the first day of treatment with ABILIFY MAINTENA.
    • Do not administer both injections into the same muscle.

    14-day initiation:

    • When ABILIFY MAINTENA injection is initiated in patients receiving oral aripiprazole administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with oral aripiprazole (10 mg to 20 mg) for 14 consecutive days to achieve therapeutic aripiprazole concentrations during initiation of therapy.
    • For patients already stable on another oral antipsychotic (and known to tolerate aripiprazole), administer one intramuscular injection of ABILIFY MAINTENA 400 mg in either the deltoid or gluteal muscle and continue treatment with the oral antipsychotic for 14 consecutive days to maintain therapeutic antipsychotic concentrations during initiation of therapy.

    If there are adverse reactions with the 400 mg dosage, the dosage may be reduced to 300 mg once monthly.
    )
• Dosage adjustments are required for missed doses (
  2.3 Missed Doses

  If the second or third doses are missed:

  • If more than 4 weeks and less than 5 weeks have elapsed since the last injection,
    administer the injection as soon as possible
    .
  • If more than 5 weeks have elapsed since the last injection,

    restart treatment with either 1-day initiation or 14-day initiation with ABILIFY MAINTENA

    [see Dosage and Administration (2.2)]

    .

  If the fourth or subsequent doses are missed:

  • If more than 4 weeks and less than 6 weeks have elapsed since the last injection,
    administer the injection as soon as possible.
  • If more than 6 weeks have elapsed since the last injection,

    restart treatment with either 1-day initiation or 14-day initiation with ABILIFY MAINTENA

    [see Dosage and Administration (2.2)]

    .
  )
• Known CYP2D6 poor metabolizers: Recommended starting and maintenance dose is 300 mg administered monthly as a single injection (
  2.4 Dosage Modifications for Cytochrome P450 Considerations

  Refer to Table 1 and Table 2 for dosage modifications for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days.

  If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased to the previous dose

  [see Dosage and Administration (2.2)]

  .

  Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

  Dosage modifications are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

  Table 1: Dosage Modifications for ABILIFY MAINTENA (1-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days

  Factors	Adjusted DoseNo change for oral dosage required during initiation.
  CYP2D6 Poor Metabolizers
  Known CYP2D6 Poor Metabolizers	300 mg
  Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors	Avoid use
  Concomitant use with CYP Inhibitors and/or Inducers
  Strong CYP2D6 or CYP3A4 inhibitors	300 mg
  CYP2D6 and CYP3A4 inhibitors	Avoid use
  CYP3A4 inducers	Avoid use

  Table 2: Dosage Modifications for ABILIFY MAINTENA (14-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days

  Factors	Adjusted DoseNo change for oral dosage required during initiation.
  CYP2D6 Poor Metabolizers
  Known CYP2D6 Poor Metabolizers	300 mg
  Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors	200 mg200 mg and 160 mg dosage adjustment is obtained only by using the 300 mg or 400 mg strength vials.
  Patients Taking 400 mg of ABILIFY MAINTENA
  Strong CYP2D6 or CYP3A4 inhibitors	300 mg
  CYP2D6 and CYP3A4 inhibitors	200 mg
  CYP3A4 inducers	Avoid use
  Patients Taking 300 mg of ABILIFY MAINTENA
  Strong CYP2D6 or CYP3A4 inhibitors	200 mg
  CYP2D6 and CYP3A4 inhibitors	160 mg
  CYP3A4 inducers	Avoid use

  ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe

  [see Dosage and Administration (2.6)]

  , and 2) Vials

  [see Dosage and Administration (2.7)]

  .
  )
• See full prescribing information for ABILIFY MAINTENA dosage modifications due to drug interactions (
  2.4 Dosage Modifications for Cytochrome P450 Considerations

  Refer to Table 1 and Table 2 for dosage modifications for patients who are CYP2D6 poor metabolizers and/or in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days.

  If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased to the previous dose

  [see Dosage and Administration (2.2)]

  .

  Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.

  Dosage modifications are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

  Table 1: Dosage Modifications for ABILIFY MAINTENA (1-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days

  Factors	Adjusted DoseNo change for oral dosage required during initiation.
  CYP2D6 Poor Metabolizers
  Known CYP2D6 Poor Metabolizers	300 mg
  Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors	Avoid use
  Concomitant use with CYP Inhibitors and/or Inducers
  Strong CYP2D6 or CYP3A4 inhibitors	300 mg
  CYP2D6 and CYP3A4 inhibitors	Avoid use
  CYP3A4 inducers	Avoid use

  Table 2: Dosage Modifications for ABILIFY MAINTENA (14-Day Initiation) in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers for Greater than 14 days

  Factors	Adjusted DoseNo change for oral dosage required during initiation.
  CYP2D6 Poor Metabolizers
  Known CYP2D6 Poor Metabolizers	300 mg
  Known CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors	200 mg200 mg and 160 mg dosage adjustment is obtained only by using the 300 mg or 400 mg strength vials.
  Patients Taking 400 mg of ABILIFY MAINTENA
  Strong CYP2D6 or CYP3A4 inhibitors	300 mg
  CYP2D6 and CYP3A4 inhibitors	200 mg
  CYP3A4 inducers	Avoid use
  Patients Taking 300 mg of ABILIFY MAINTENA
  Strong CYP2D6 or CYP3A4 inhibitors	200 mg
  CYP2D6 and CYP3A4 inhibitors	160 mg
  CYP3A4 inducers	Avoid use

  ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe

  [see Dosage and Administration (2.6)]

  , and 2) Vials

  [see Dosage and Administration (2.7)]

  .
  ).
• ABILIFY MAINTENA comes in two types of kits. See instructions for reconstitution/injection/disposal procedures for 1) Pre-filled Dual Chamber Syringe (
  2.6 Pre-filled Dual Chamber Syringe: Preparation and Administration Instructions

  Preparation Prior to Reconstitution

  For deep intramuscular deltoid or gluteal injection by healthcare professionals only. Do not administer by any other route. Inject full syringe contents immediately following reconstitution. Administer once monthly.

  Lay out and confirm that components listed below are provided in the kit:

  • One ABILIFY MAINTENA (aripiprazole) pre-filled dual chamber syringe (400 mg or 300 mg as appropriate) for extended-release injectable suspension containing lyophilized powder and Sterile Water for Injection
  • One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients
  • One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients
  • One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients

  Reconstitution of Lyophilized Powder in Pre-filled Dual Chamber Syringe

  Reconstitute at room temperature.

  • a)Push plunger rod slightly to engage threads. And then, rotate plunger rod until the rod stops rotating to release diluent. After plunger rod is at complete stop, middle stopper will be at the indicator line (see Figure 1).
    
    Figure 1
  • b)Vertically shake the syringe vigorously for 20 seconds until drug is uniformly milky-white (see Figure 2).
    
    Figure 2
  • c)Visually inspect the syringe for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA suspension should appear to be a uniform, homogeneous suspension that is opaque and milky-white in color.

  Figure 1

  Figure 2

  Injection Procedure

  Use appropriate aseptic techniques throughout injection procedure. For deep intramuscular injection only.

  • a)Twist and pull off Over-cap and Tip-cap (see Figure 3).
    
    Figure 3
  • b)Select appropriate needle (see Figure 4).
    
    Figure 4

    For deltoid administration:

    • 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for non-obese patients
    • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for obese patients

    For gluteal administration:

    • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
    • 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for obese patients

  • c)While holding the needle cap, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until SNUGLY fitted (see Figure 5).
    
    Figure 5
  • d)Then
    PULL
    needle-cap straight up (see Figure 6).
    
    Figure 6
  • e)Hold syringe UPRIGHT and
    ADVANCE PLUNGER ROD SLOWLY TO EXPEL THE AIR
    . Expel air until suspension fills needle base. If it's not possible to advance plunger rod to expel the air, check that plunger rod is rotated to a complete stop (see Figure 7).
    
    Figure 7
  • f)
    Inject slowly into the deltoid or gluteal muscle.
    Do
    not
    massage the injection site.

  Figure 3

  Figure 4

  Figure 5

  Figure 6

  Figure 7

  Disposal Procedure

  • a)Engage the needle safety device and safely discard all kit components (see Figure 8).
    ABILIFY MAINTENA pre-filled dual chamber syringe is for single-use only.
    
    
    Figure 8
  • b)Rotate sites of injections between the two deltoid or gluteal muscles.

  Figure 8

  ), and 2) Vials (
  2.7 Vial: Preparation and Administration Instructions

  Preparation Prior to Reconstitution

  For deep intramuscular injection by healthcare professionals only. Do not administer by any other route. Inject immediately after reconstitution. Administer once monthly.

  • a)Lay out and confirm that components listed below are provided in the kit:
    • Vial of ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension lyophilized powder
    • 2.5 mL or 5 mL single-dose vial of Sterile Water for Injection, USP. For drug diluent use only. Not for intravenous use.
    • One 3 mL, luer lock syringe with pre-attached 21-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device
    • One 3 mL, luer lock disposable syringe with luer lock tip
    • One vial adapter
    • One 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for deltoid administration in non-obese patients
    • One 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for gluteal administration in non-obese patients or deltoid administration in obese patients
    • One 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for gluteal administration in obese patients
  • b)ABILIFY MAINTENA should be suspended using the Sterile Water for Injection as supplied in the kit.
  • c)The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-dose only.
  • d)Use appropriate aseptic techniques throughout reconstitution and reconstitute at room temperature.
  • e)Select the amount of Sterile Water for Injection needed for reconstitution (see Table 3).

  Table 3: Amount of Sterile Water for Injection Needed for Reconstitution

  400 mg Vial		300 mg Vial
  Dose	Sterile Water for Injection	Dose	Sterile Water for Injection
  400 mg	1.9 mL	300 mg	1.5 mL

  Important: There is more Sterile Water for Injection in the vial than is needed to reconstitute ABILIFY MAINTENA (aripiprazole) for extended-release injectable suspension. The vial will have excess Sterile Water for Injection; discard any unused portion.

  Reconstitution of Lyophilized Powder in Vial

  • a)Remove the cap of the vial of Sterile Water for Injection and remove the cap of the vial containing ABILIFY MAINTENA lyophilized powder and wipe the tops with a sterile alcohol swab.
  • b)Using the syringe with pre-attached hypodermic safety needle, withdraw the pre-determined Sterile Water for Injection volume from the vial of Sterile Water for Injection into the syringe (see Figure 9). Residual Sterile Water for Injection will remain in the vial following withdrawal; discard any unused portion.
    
    Figure 9
  • c)Slowly inject the Sterile Water for Injection into the vial containing the ABILIFY MAINTENA lyophilized powder (see Figure 10).
    
    Figure 10
  • d)Withdraw air to equalize the pressure in the vial by pulling back slightly on the plunger. Subsequently, remove the needle from the vial. Engage the needle safety device by using the one-handed technique (see Figure 11). Gently press the sheath against a flat surface until the needle is firmly engaged in the needle protection sheath. Visually confirm that the needle is fully engaged into the needle protection sheath, and discard.
    
    Figure 11
  • e)Shake the vial vigorously for 30 seconds until the reconstituted suspension appears uniform (see Figure 12).
    
    Figure 12
  • f)Visually inspect the reconstituted suspension for particulate matter and discoloration prior to administration. The reconstituted ABILIFY MAINTENA is a uniform, homogeneous suspension that is opaque and milky-white in color.
  • g)If the injection is not performed immediately after reconstitution keep the vial at room temperature and shake the vial vigorously for at least 60 seconds to re-suspend prior to injection.
  • h)Do not store the reconstituted suspension in a syringe.

  Figure 9

  Figure 10

  Figure 11

  Figure 12

  Preparation Prior to Injection

  • a)Use appropriate aseptic techniques throughout injection of the reconstituted ABILIFY MAINTENA suspension.
  • b)Remove the cover from the vial adapter package (see Figure 13). Do not remove the vial adapter from the package.
    
    Figure 13
  • c)Using the vial adapter package to handle the vial adapter, attach the prepackaged luer lock syringe to the vial adapter (see Figure 14).
    
    Figure 14
  • d)Use the luer lock syringe to remove the vial adapter from the package and discard the vial adapter package (see Figure 15).
    Do not touch the spike tip of the adapter at any time
    .
    
    
    Figure 15
  • e)Determine the recommended volume for injection (Table 4).

  Table 4: ABILIFY MAINTENA Reconstituted Suspension Volume to Inject

  400 mg Vial		300 mg Vial
  Dose	Volume to Inject	Dose	Volume to Inject
  400 mg	2 mL	---	---
  300 mg	1.5 mL	300 mg	1.5 mL
  200 mg	1 mL	200 mg	1 mL
  160 mg	0.8 mL	160 mg	0.8 mL

  • f)Wipe the top of the vial of the reconstituted ABILIFY MAINTENA suspension with a sterile alcohol swab.
  • g)Place and hold the vial of the reconstituted ABILIFY MAINTENA suspension on a hard surface. Attach the adapter-syringe assembly to the vial by holding the outside of the adapter and pushing the adapter's spike firmly through the rubber stopper, until the adapter snaps in place (see Figure 16).
    
    Figure 16
  • h)Slowly withdraw the recommended volume from the vial into the luer lock syringe to allow for injection (see Figure 17).
    A small amount of excess product will remain in the vial.
    
    
    Figure 17

  Figure 13

  Figure 14

  Figure 15

  Figure 16

  Figure 17

  Injection Procedure

  • a)Detach the luer lock syringe containing the recommended volume of reconstituted ABILIFY MAINTENA suspension from the vial.
  • b)Select the appropriate hypodermic safety needle and attach the needle to the luer lock syringe containing the suspension for injection. While holding the needle cap, ensure the needle is firmly seated on the safety device with a push. Twist clockwise until snugly fitted and then pull the needle cap straight away from the needle (see Figure 18).

  For deltoid administration:

  • 23-gauge, 1-inch (25 mm) hypodermic safety needle with needle protection device for non-obese patients
  • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for obese patients

  For gluteal administration:

  • 22-gauge, 1.5-inch (38 mm) hypodermic safety needle with needle protection device for non-obese patients
  • 21-gauge, 2-inch (51 mm) hypodermic safety needle with needle protection device for obese patients
    
    Figure 18

  • (c)Slowly inject the recommended volume as a single intramuscular injection into the deltoid or gluteal muscle. Do not massage the injection site.

  Figure 18

  Disposal Procedure

  • a)Engage the needle safety device as described in Section 2.6, Step (d) of Reconstitution of Lyophilized Powder in Vial and safely discard all kit components (see Figure 8). Dispose of the vials, adapter, needles, and syringe appropriately after injection.
    The Sterile Water for Injection and ABILIFY MAINTENA vials are for single-dose only.
  • b)Rotate sites of injections between the two deltoid or gluteal muscles.
  ).

• single-dose, pre-filled, dual chamber syringe
• single-dose vial

The reconstituted extended-release injectable suspension is a uniform, homogeneous suspension that is opaque and milky-white in color.

• 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 ABILIFY MAINTENA 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/.

  Risk Summary

  Neonates exposed to antipsychotic drugs, including ABILIFY MAINTENA, 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 outcomes. There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including ABILIFY MAINTENA, during pregnancy

  (see Clinical Considerations)

  . Aripiprazole exposure during pregnancy may decrease 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 11 times, respectively, 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 10 times the MRHD 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 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.

  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 oral 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 exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.

  Data

  Animal Data

  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 which are approximately 1 to 10 times the MRHD of 30 mg/day on a mg/m²basis of aripiprazole during the period of organogenesis. Treatment at the highest dose caused a slight prolongation of gestation and delay in fetal development, as evidenced by decreased fetal weight and undescended testes. Delayed skeletal ossification was observed at 3 and 10 times the oral MRHD on mg/m²basis.

  At 3 and 10 times the oral MRHD on a mg/m²basis, delivered offspring had decreased body weights. Increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia were observed in offspring from the highest dose group (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on a mg/m²basis and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) along with some maternal toxicity were seen at the highest dose; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity.

  In pregnant rats treated with aripiprazole intravenously at doses of 3, 9, and 27 mg/kg/day, which are 1 to 9 times the oral MRHD on mg/m²basis, during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose which also caused maternal toxicity.

  In pregnant rabbits treated with oral doses of 10, 30, and 100 mg/kg/day which are 2 to 11 times human exposure at the oral MRHD based on AUC and 6 to 65 times the oral MRHD of aripiprazole on mg/m²basis during the period of organogenesis, decreased maternal food consumption and increased abortions were seen at the highest dose as well as increased fetal mortality. Decreased fetal weight and increased incidence of fused sternebrae were observed at 3 and 11 times the MRHD based on AUC.

  In pregnant rabbits receiving aripiprazole injection intravenously at doses of 3, 10, and 30 mg/kg/day, which are 2 to 19 times the oral MRHD on mg/m²basis during the period of organogenesis, the highest dose caused pronounced maternal toxicity that resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 5 times the human exposure at the oral MRHD based on AUC and is 6 times the oral MRHD on mg/m²basis.

  In rats treated with oral doses of 3, 10, and 30 mg/kg/day, which are 1 to 10 times the oral MRHD of aripiprazole on a mg/m²basis, peri- and post-natally (from Day 17 of gestation through Day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at the highest dose. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were also seen at this dose.

  In rats treated with aripiprazole intravenously at doses of 3, 8, and 20 mg/kg/day which are 1 to 6 times the oral MRHD on mg/m²basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the MRHD on mg/m²basis, and decreases in early postnatal pup weight and survival were seen at the highest dose; these doses produced 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 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

  [see Adverse Reactions (6.1)]

  . Monitor the breastfed infant for dehydration and lack of appropriate weight gain. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABILIFY MAINTENA and any potential adverse effects on the breastfed infant from ABILIFY MAINTENA or from the underlying maternal condition.
  )