Dosage & Administration
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Aristada & Aristada Initio Prescribing Information
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.
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. ARISTADA is not approved for the treatment of patients with dementia-related psychosis
ARISTADA is indicated for the treatment of schizophrenia in adults
The efficacy of ARISTADA in the treatment of patients with schizophrenia was established, in part, on the basis of efficacy data from trials with the oral formulation of aripiprazole. In addition, the efficacy of ARISTADA was established in a 12-week, randomized, double-blind, placebo-controlled, fixed-dose study in adult patients with schizophrenia meeting DSM-IV TR criteria [Study 1, n = 622; 207 (ARISTADA 441 mg monthly), 208 (ARISTADA 882 mg monthly), and 207 (placebo)]. After establishing tolerability to oral aripiprazole, patients received oral aripiprazole or placebo daily for the first 3 weeks. The intramuscular (IM) injections were administered on Days 1, 29 and 57.
Efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Improvement Scale (CGI-I):
- 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 CGI-I rates improvement in mental illness on a scale of 1 (very much improved) to 7 (very much worse) based on the change from baseline in clinical condition.
Eligible patients were 18 to 70 years of age with PANSS total score of 70 to 120 and a score of ≥4 for at least 2 of the selected Positive Scale items. Patients were also required to have a CGI-S score of ≥4.
The primary efficacy variable was the change from baseline to endpoint (Day 85) in PANSS total score. Statistically significant separation from placebo on PANSS total score change was observed in each ARISTADA dose group .
Study Number | Treatment Group | Primary Efficacy Measure: PANSS Total Score | ||
|---|---|---|---|---|
Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference a (95% CI) | ||
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiple comparisons. | ||||
aDifference (drug minus placebo) in least-squares mean change from baseline. | ||||
bDoses that are demonstrated to be effective. | ||||
| Study 1 | ARISTADA 441 mg monthlyb | 92.6 (10.2) | -20.9 (1.4) | -10.9 (-14.5, -7.3) |
| ARISTADA 882 mg monthlyb | 92.0 (10.8) | -21.8 (1.4) | -11.9 (-15.4, -8.3) | |
| Placebo | 93.9 (11.3) | -9.8 (1.4) | -- | |
The visit-wise mean change from baseline on PANSS total score change for each treatment group is shown in Figure 6.
Abbreviations: AL= ARISTADA; PBO=placebo; PANSS=Positive and Negative Syndrome Scale.
Vertical dotted line indicates end of oral supplementation.
Subgroup analyses did not suggest any clear evidence of differential responsiveness in treatment outcome as a function of age, gender, race, or weight.
The secondary efficacy endpoint was defined as the CGI-I score at Day 85. Both ARISTADA treatment groups demonstrated statistically significantly better CGI-I scores versus placebo.
The efficacy of ARISTADA 662 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months in the treatment of adults with schizophrenia was established by pharmacokinetic bridging which demonstrated that these dosing regimens resulted in plasma aripiprazole concentrations that are within the range provided by doses of 441 mg monthly and 882 mg monthly. As depicted in Figure 6, the doses of 441 mg monthly and 882 mg monthly showed clinical responses similar to each other in the ARISTADA placebo-controlled trial.
- Administer ARISTADA by intramuscular injection in the deltoid (441 mg dose only) or gluteal (441 mg, 662 mg, 882 mg or 1064 mg) muscle by a healthcare professional ().
2.1 Recommended DosageARISTADA is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
There are two ways to initiate treatment with ARISTADA:
- Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)andone dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.
- The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.
- Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.
Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively
[see Clinical Pharmacology ].Table 1: ARISTADA Dosing Frequency and Site of Injection DoseDosing FrequencySite of Intramuscular Injection441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.
Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day 441 mg every month 15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg,
orcontinue treatment with oral aripiprazole for 21 consecutive days[see Recommended Dosage(2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA
[see Clinical Pharmacology(12.3)]. - Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)
- For patients naïve to aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA ().
2.1 Recommended DosageARISTADA is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
There are two ways to initiate treatment with ARISTADA:
- Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)andone dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.
- The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.
- Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.
Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively
[see Clinical Pharmacology ].Table 1: ARISTADA Dosing Frequency and Site of Injection DoseDosing FrequencySite of Intramuscular Injection441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.
Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day 441 mg every month 15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg,
orcontinue treatment with oral aripiprazole for 21 consecutive days[see Recommended Dosage(2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA
[see Clinical Pharmacology(12.3)]. - Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)
- There are two options for initiating treatment with ARISTADA:
- Option #1: Administer one injection of 675 mg of ARISTADA INITIO® and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.
().2.1 Recommended DosageARISTADA is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
There are two ways to initiate treatment with ARISTADA:
- Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)andone dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.
- The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.
- Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.
Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively
[see Clinical Pharmacology ].Table 1: ARISTADA Dosing Frequency and Site of Injection DoseDosing FrequencySite of Intramuscular Injection441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.
Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day 441 mg every month 15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg,
orcontinue treatment with oral aripiprazole for 21 consecutive days[see Recommended Dosage(2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA
[see Clinical Pharmacology(12.3)]. - Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection
().2.1 Recommended DosageARISTADA is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
There are two ways to initiate treatment with ARISTADA:
- Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)andone dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.
- The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.
- Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.
Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively
[see Clinical Pharmacology ].Table 1: ARISTADA Dosing Frequency and Site of Injection DoseDosing FrequencySite of Intramuscular Injection441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.
Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day 441 mg every month 15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg,
orcontinue treatment with oral aripiprazole for 21 consecutive days[see Recommended Dosage(2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA
[see Clinical Pharmacology(12.3)]. - Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)
- Option #1: Administer one injection of 675 mg of ARISTADA INITIO® and one 30 mg dose of oral aripiprazole in conjunction with the first ARISTADA injection.
- ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg dose every 6 weeks, or 1064 mg dose every 2 months ().
2.1 Recommended DosageARISTADA is only to be administered as an intramuscular injection by a healthcare professional. For patients who have never taken aripiprazole, establish tolerability with oral aripiprazole prior to initiating treatment with ARISTADA. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability. Refer to the prescribing information of oral aripiprazole for the recommended dosage and administration of the oral formulation.
There are two ways to initiate treatment with ARISTADA:
- Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)andone dose of oral aripiprazole 30 mg in conjunction with the first ARISTADA injection.
- The first ARISTADA injection may be administered on the same day as ARISTADA INITIO or up to 10 days thereafter. See the ARISTADA INITIO prescribing information for additional information regarding administration of ARISTADA INITIO.
- Avoid injecting both ARISTADA INITIO and ARISTADA concomitantly into the same deltoid or gluteal muscle.
- Option #2: Administer 21 consecutive days of oral aripiprazole in conjunction with the first ARISTADA injection.
Depending on individual patient's needs, treatment with ARISTADA can be initiated at a dose of 441 mg, 662 mg or 882 mg administered monthly, 882 mg administered every 6 weeks or 1064 mg administered every 2 months. The 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of aripiprazole, respectively
[see Clinical Pharmacology ].Table 1: ARISTADA Dosing Frequency and Site of Injection DoseDosing FrequencySite of Intramuscular Injection441 mg Monthly Deltoid or Gluteal 662 mg Monthly Gluteal 882 mg Monthly or every 6 weeks Gluteal 1064 mg Every 2 months Gluteal Use the following ARISTADA doses for patients who are stabilized on oral aripiprazole, as shown in Table 2.
Table 2: ARISTADA Doses Based on Oral Aripiprazole Total Daily Dose Oral Aripiprazole DoseIntramuscular ARISTADA Dose10 mg per day 441 mg every month 15 mg per day 662 mg every month
882 mg every 6 weeks
1064 mg every 2 months20 mg or higher per day 882 mg every month In conjunction with the first ARISTADA injection, administer a single injection of ARISTADA INITIO and one dose of oral aripiprazole 30 mg,
orcontinue treatment with oral aripiprazole for 21 consecutive days[see Recommended Dosage(2.1)].Adjust the ARISTADA dose as needed. When making dose and dosing interval adjustments, consider the pharmacokinetics and prolonged-release characteristics of ARISTADA
[see Clinical Pharmacology(12.3)]. - Option #1: Administer one intramuscular injection of ARISTADA INITIO 675 mg (in either the deltoid or gluteal muscle)
- Dosing regimen adjustments may be required for missed doses ().
2.2 Missed DosesWhen a dose of ARISTADA is missed, administer the next injection of ARISTADA as soon as possible. Depending on the time elapsed since the last ARISTADA injection, supplement the next ARISTADA injection as recommended in Table 3below.
Table 3: Recommendation for Concomitant Supplementation Following Missed Doses of ARISTADA Dose of Patient's Last ARISTADA InjectionLength of Time Since Last InjectionaThe patient should supplement with the same dose of oral aripiprazole as when the patient began ARISTADA (see Table 2).
441 mg ≤ 6 weeks > 6 and ≤ 7 weeks > 7 weeks 662 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 882 mg ≤ 8 weeks > 8 and ≤ 12 weeks > 12 weeks 1064 mg ≤ 10 weeks > 10 and ≤ 12 weeks > 12 weeks Dosage and Administration for Re-initiation of ARISTADANo Supplementation Required Supplement with a Single Dose of ARISTADA INITIO OR7 Days of Oral AripiprazoleaRe-initiate with a Single Dose of ARISTADA INITIO anda Single Dose of Oral Aripiprazole 30 mgORsupplement with 21 Days of Oral Aripiprazolea - Dose adjustments are required for 1) known CYP2D6 poor metabolizers and 2) for patients taking CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks ().
2.4 Dose Adjustments for CYP450 ConsiderationsRefer to the prescribing information for oral aripiprazole for recommendations regarding dosage adjustments due to drug interactions, for the first 21 days when the patient is taking 21 days of oral aripiprazole concomitantly with the first dose of ARISTADA. Avoid initiating ARISTADA treatment with ARISTADA INITIO in patients requiring dose adjustments.
Once stabilized on ARISTADA, refer to the dosing recommendations below for patients taking strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, or strong CYP3A4 inducers:
- No dosage changes recommended for ARISTADA, if CYP450 modulators are added for less than 2 weeks.
- Make dose changes to ARISTADA if CYP450 modulators are added for greater than 2 weeks (see Table 4).
Table 4: ARISTADA Dose Adjustments with Concomitant CYP450 Modulator Use Concomitant MedicineDose Change for ARISTADAaaFor the 882 mg dose administered every 6 weeks and the 1064 mg administered every 2 months, the next lower strength should be 441 mg administered monthly.
Strong CYP3A4 Inhibitor Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: Reduce dose to 441 mg from 662 mg, 882 mg, or 1064 mg. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated.Strong CYP2D6 Inhibitor Reduce the dose of ARISTADA to the next lower strength. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. For patients known to be poor metabolizers of CYP2D6: No dose adjustment required.Both Strong CYP3A4 Inhibitor and Strong CYP2D6 Inhibitor Avoid use for patients at 662 mg, 882 mg, or 1064 mg dose. No dosage adjustment is necessary in patients taking 441 mg ARISTADA, if tolerated. CYP3A4 Inducers No dose adjustment for 662 mg, 882 mg, or 1064 mg dose; increase the 441 mg dose to 662 mg.
ARISTADA is a white to off-white aqueous extended-release injectable suspension provided in a single-dose pre-filled syringe.
ARISTADA is available as described in
Dose Strength | Volume | Inject Intramuscularly | Color Label |
|---|---|---|---|
| 441 mg | 1.6 mL | Deltoid or Gluteal Muscle | Light Blue |
| 662 mg | 2.4 mL | Gluteal Muscle Only | Green |
| 882 mg | 3.2 mL | Gluteal Muscle Only | Burgundy |
| 1064 mg | 3.9 mL | Gluteal Muscle Only | Dark Blue |
Dose Strength | Volume | Inject Intramuscularly | Color Label |
|---|---|---|---|
| 441 mg | 1.6 mL | Deltoid or Gluteal Muscle | Light Blue |
| 662 mg | 2.4 mL | Gluteal Muscle Only | Green |
| 882 mg | 3.2 mL | Gluteal Muscle Only | Burgundy |
| 1064 mg | 3.9 mL | Gluteal Muscle Only | Dark Blue |
- Pregnancy:May cause extrapyramidal and/or withdrawal symptoms in neonates in women exposed during the third trimester of pregnancy ().
8.1 PregnancyPregnancy Exposure RegistryThere is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ARISTADA 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 SummaryNeonates exposed to antipsychotic drugs, including ARISTADA, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Limited published data on aripiprazole use in pregnant women are not sufficient to inform any drug-associated risks for birth defects or miscarriage
(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 and with exposure to antipsychotics, including ARISTADA, during pregnancy(see Clinical Considerations). Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period[see Use in Specific Populations ].No teratogenicity was observed in animal reproductive studies with intramuscular administration of aripiprazole lauroxil to rats and rabbits during organogenesis at doses up to 5 and 15 times, respectively, the maximum recommended human dose (MRHD) of 1,064 mg based on body surface area (mg/m2). However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits
(see Data).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 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskThere is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is 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 ReactionsExtrapyramidal 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 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 recover within hours or days without specific treatment; others required prolonged hospitalization.
DataAnimal Data for Aripiprazole LauroxilAripiprazole lauroxil did not cause adverse developmental or maternal effects in rats or rabbits when administered intramuscularly during the period of organogenesis at doses of 18, 49, or 144 mg/animal in pregnant rats which are approximately 0.6 to 5 times the MRHD of 1064 mg on mg/m2basis, and at doses of 241, 723, and 2893 mg/animal in pregnant rabbits which are approximately 1 to 15 times the MRHD on mg/m2basis. However, aripiprazole caused developmental toxicity and possible teratogenic effects in rats and rabbits
[see Data below].Animal Data for AripiprazolePregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day which are approximately 1 to 10 times the oral MRHD of 30 mg/day on 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 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). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to the highest dose. Postnatally, delayed vaginal opening was seen at 3 and 10 times the oral MRHD on 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 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 on mg/m2basis of aripiprazole 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 oral MRHD based on AUC.
In rats treated with oral doses of 3, 10, and 30 mg/kg/day which are 1 to 10 times the oral MRHD on mg/m2basis of aripiprazole perinatally and postnatally (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.
- Lactation:Monitor the breastfed infant for dehydration and lack of appropriate weight gain ().
8.2 LactationRisk SummaryAripiprazole 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 ]. Monitor the breastfeed infant for dehydration and lack of appropriate weight gain. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for ARISTADA and any potential adverse effects on the breastfed infant from ARISTADA or from the underlying maternal condition.
ARISTADA is contraindicated in patients with a known hypersensitivity reaction to aripiprazole. Hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis
The following are discussed in more details in other sections of the labeling:
- Increased Mortality in Elderly Patients with Dementia-related Psychosis[see Boxed Warning, Warnings and Precautions(5.1)]
- Cerebrovascular Adverse Reactions, Including Stroke[see Boxed Warning, Warnings and Precautions(5.2)]
- Neuroleptic Malignant Syndrome[see Warnings and Precautions(5.4)]
- Tardive Dyskinesia[see Warnings and Precautions(5.5)]
- Metabolic Changes[see Warnings and Precautions(5.6)]
- Pathological Gambling and Other Compulsive Behaviors[see Warnings and Precautions(5.7)]
- Orthostatic Hypotension[see Warnings and Precautions(5.8)]
- Falls[see Warnings and Precautions(5.9)]
- Leukopenia, Neutropenia, and Agranulocytosis[see Warnings and Precautions(5.10)]
- Seizures[see Warnings and Precautions(5.11)]
- Potential for Cognitive and Motor Impairment[see Warnings and Precautions(5.12)]
- Body Temperature Regulation[see Warnings and Precautions(5.13)]
- Dysphagia[see Warnings and Precautions(5.14)]
Most commonly observed adverse reaction with ARISTADA (incidence ≥5% and at least twice that for placebo) was akathisia .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
ARISTADA has been evaluated for safety in 1180 adult patients in clinical trials in schizophrenia.
The most common adverse reaction (incidence ≥5% and at least twice the rate of placebo in patients treated with ARISTADA) was akathisia.
Adverse reactions associated with the use of ARISTADA (incidence of 2% or greater, rounded to the nearest percent and ARISTADA incidence greater than placebo) that occurred are shown in Table 8.
Adverse Reaction System Organ Class Preferred Term | Placebo N=207 (%) | Aripiprazole Lauroxil | |
|---|---|---|---|
441 mg N=207 (%) | 882 mg N=208 (%) | ||
General disorders and administration site conditions | |||
| Injection site pain | 2 | 3 | 4 |
Investigations | |||
| Increased weight | 1 | 2 | 2 |
| Increased blood creatine phosphokinase | 0 | 2 | 1 |
Nervous system disorders | |||
| Akathisia | 4 | 11 | 11 |
| Headache | 3 | 3 | 5 |
Psychiatric disorders | |||
| Insomnia | 2 | 3 | 4 |
| Restlessness | 1 | 3 | 1 |
In an open label pharmacokinetic study, the adverse reactions associated with the use of 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months were similar across the dose groups.
Injection site reactions were reported by 4% of patients treated with 441 mg ARISTADA and 5% of patients treated with 882 mg ARISTADA compared to 2% of patients treated with placebo. Most of these were injection site pain (3%, 4% and 2% in the 441 mg ARISTADA, 882 mg ARISTADA and placebo groups, respectively) and most were associated with the first injection, and decreased with each subsequent injection to less than or equal to 1% for both doses of ARISTADA and placebo. Other injection site reactions (induration, swelling and redness) occurred at less than 1%. In an open label pharmacokinetic study evaluating 441 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months, injection site reactions were similar across the dose groups.
In the 12-week schizophrenia efficacy study
| ARISTADA | |||
|---|---|---|---|
Adverse Reaction Term | Placebo N=207 (%) | 441 mg N=207 (%) | 882 mg N=208 (%) |
Akathisia | 4 | 11 | 11 |
Restlessness | 1 | 3 | 1 |
Other EPS | 4 | 5 | 7 |
| Dystonia | 1 | 2 | 2 |
| Parkinsonism | 3 | 3 | 4 |
Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for ARISTADA.
The following adverse reactions have been identified during post-approval use of oral aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups, blood glucose fluctuation, oculogyric crisis, drug reaction with eosinophilia and systemic symptoms (DRESS), and fecal incontinence.