Abilify Asimtufii Aripiprazole 960 mg/3.2mL Injection, Suspension, Extended Release, 1 syringe — NDC 59148-114-80 (Billing 59148-0114-80)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown. The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D 2 and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.

12.2Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 (K i s 0.34 and 0.8 nM, respectively), serotonin 5-HT 1A and 5-HT 2A receptors (K i s 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i s of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i= 98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM).

Actions at receptors other than D 2 , 5-HT 1A , and 5-HT 2A could explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha 1 receptors). ABILIFY ASIMTUFII activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D 2 receptors.

12.3Pharmacokinetics ABILIFY ASIMTUFII delivers aripiprazole over a 2-month period. ABILIFY ASIMTUFII has linear pharmacokinetics in the approved dose range. Steady-state aripiprazole exposures were reached by the fourth dose.

Plasma exposures at steady state were compared between ABILIFY ASIMTUFII (960 mg, once every 2 months) and Abilify Maintena (400 mg, once every month). The average plasma concentrations (C avg ) of aripiprazole were 263 ng/mL and 280 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively. The C max of aripiprazole were 342 ng/mL and 344 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively.

Figure 9: Mean Plasma Concentration of Aripiprazole Following the Fourth Administration of ABILIFY ASIMTUFII 960 mg versus the Seventh and Eighth Administration of Abilify Maintena 400 mg Figure 9 Absorption Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.

Distribution Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of

4.9L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin. Elimination Following single dose administration of ABILIFY ASIMTUFII, the mean apparent terminal elimination half-life of aripiprazole was 21 days.

Metabolism Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation.

Following administration of multiple doses of ABILIFY ASIMTUFII, dehydro-aripiprazole, the active metabolite, represents approximately 29% of aripiprazole AUC in plasma. Excretion Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactiv… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of aripiprazole in the treatment of schizophrenia and bipolar I disorder is unknown. The efficacy of aripiprazole could be mediated through a combination of partial agonist activity at dopamine D 2 and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.

12.3Pharmacokinetics ABILIFY ASIMTUFII delivers aripiprazole over a 2-month period. ABILIFY ASIMTUFII has linear pharmacokinetics in the approved dose range. Steady-state aripiprazole exposures were reached by the fourth dose.

Plasma exposures at steady state were compared between ABILIFY ASIMTUFII (960 mg, once every 2 months) and Abilify Maintena (400 mg, once every month). The average plasma concentrations (C avg ) of aripiprazole were 263 ng/mL and 280 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively. The C max of aripiprazole were 342 ng/mL and 344 ng/mL for ABILIFY ASIMTUFII and Abilify Maintena, respectively.

Figure 9: Mean Plasma Concentration of Aripiprazole Following the Fourth Administration of ABILIFY ASIMTUFII 960 mg versus the Seventh and Eighth Administration of Abilify Maintena 400 mg Figure 9 Absorption Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.

Distribution Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributed throughout the body with an apparent volume of distribution of

4.9L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin. Elimination Following single dose administration of ABILIFY ASIMTUFII, the mean apparent terminal elimination half-life of aripiprazole was 21 days.

Metabolism Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation.

Following administration of multiple doses of ABILIFY ASIMTUFII, dehydro-aripiprazole, the active metabolite, represents approximately 29% of aripiprazole AUC in plasma. Excretion Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces.

Studies in Specific Populations No specific pharmacokinetic studies have been performed with ABILIFY ASIMTUFII in specific populations. All the information is obtained from studies with oral aripiprazole or is based on the pharmacokinetic modeling of oral aripiprazole and/or ABILIFY ASIMTUFII. Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 10 and Figure 11, respectively.

In addition, in pediatric patients (10 to 17 years of age) administered with oral aripiprazole (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults. Figure 10: Effect of Intrinsic Factors on Aripiprazole Pharmacokinetics Figure 11: Effects of Intrinsic Factors on Dehydro-aripiprazole Pharmacokinetics Figure 10 Figure 11 Drug Interaction Studies No specific drug interaction studies have been performed with ABILIFY ASIMTUFII. The information below is obtained from studies with oral aripiprazole.

The effect of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 12 and Figure 13, respectively. Based on simulations, a 4.5-fold increase in mean C max and AUC values at… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 (K i s 0.34 and 0.8 nM, respectively), serotonin 5-HT 1A and 5-HT 2A receptors (K i s 1.7 and 3.4 nM, respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i s of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i= 98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM).

Actions at receptors other than D 2 , 5-HT 1A , and 5-HT 2A could explain some of the other adverse reactions of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha 1 receptors). ABILIFY ASIMTUFII activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D 2 receptors.

14 CLINICAL STUDIES

14.1Schizophrenia The efficacy of ABILIFY ASIMTUFII (once every 2 month dosing) for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena (once monthly dosing). The results of these adequate and well-controlled studies are presented below. The efficacy of Abilify Maintena (once monthly dosing) for treatment of schizophrenia was established in: • One short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1) • One longer-term, double-blind, placebo-controlled, randomized-withdrawal (maintenance) trial in adults (Study 2).

Short-Term Efficacy In the short-term (12-week), randomized, double-blind, placebo-controlled trial in acutely relapsed adults (Study 1), the primary measure used for assessing psychiatric signs and symptoms was 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 primary endpoint was the change from baseline in PANSS total score to week 10. The inclusion criteria for this short-term trial included adult inpatients who met DSM-IV-TR criteria for schizophrenia. In addition, all patients entering the trial must have experienced an acute psychotic episode as defined by both PANSS Total Score ≥80 and a PANSS score of >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, unusual thought content) at screening and baseline.

The key secondary endpoint was the change from baseline in Clinical Global Impression-Severity (CGI-S) assessment scale to week 10. The CGI-S rates the severity of mental illness on a scale of 1 (normal) to 7 (among the most extremely ill) based on the total clinical experience of the rater in treating patients with schizophrenia. Patients had a mean PANSS total score of 103 (range 82 to 144) and a CGI-S score of 5.2 (markedly ill) at entry.

In this 12-week study (n=339) comparing Abilify Maintena (n=167) to placebo (n=172), patients were administered 400 mg Abilify Maintena or placebo on days 0, 28, and 56. The dose could be adjusted down and up within the range of 400 to 300 mg on a one-time basis. Abilify Maintena was superior to placebo in improving the PANSS total score at the end of week 10 (see Table 8 ).

Table 8: Efficacy Results of Abilify Maintena in Short-term Schizophrenia Study 1 (Adults) Primary Efficacy Measure: PANSS Total Score Study Number Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study 1 Abilify Maintena (400 to 300 mg) 102.4 (11.4) -26.8 (1.6) -15.1 (-19.4, -10.8) Placebo 103.4 (11.1) -11.7 (1.6) -- The change in PANSS total score by week is shown in Figure 15.

Abilify Maintena also showed improvement in symptoms represented by CGI-S score mean change from baseline to week 10. The results of exploratory subgroup analyses by gender, race, age, ethnicity, and BMI were similar to the results of the overall population. n = the number of patients remaining in the respective study arm at each time point Figure 15: Weekly PANSS Total Score-Change in the 12-Week, Placebo-Controlled Study with Abilify Maintena in Schizophrenia - Study 1 (Adults) Figure 15 Long-Term Efficacy The efficacy of Abilify Maintena in maintaining symptomatic control in schizophrenia was established in a double-blind, placebo-controlled, randomized-withdrawal trial in adult patients (Study 2) who met DSM-IV-TR criteria for schizophrenia and who were being treated with at least one antipsychotic medi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No carcinogenicity studies were conducted with intramuscular aripiprazole suspension. Lifetime carcinogenicity studies were conducted with oral aripiprazole in Swiss albino mice, Sprague-Dawley (SD) rats, and F344 rats. Oral aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 times and 0.3 to 3 times oral MRHD based on mg/m 2 , respectively).

In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the oral MRHD based on mg/m 2 ). Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidence of pituitary gland adenomas, mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the oral MRHD based on mg/m 2 ).

In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the oral MRHD based on mg/m 2 ); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the oral MRHD based on mg/m 2 ). Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated.

Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors.

The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown. Mutagenesis The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation.

The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Impairment of Fertility No mating and fertility studies were conducted with intramuscular aripiprazole suspension.

Female rats were treated with aripiprazole oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the oral MRHD on a mg/m 2 basis) of aripiprazole from 2 weeks prior to mating through Day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg/day and decreased fetal weight was seen at 20 mg/kg/day.

Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the oral MRHD on mg/m 2 basis) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and 60 mg/kg, but no impairment of fertility was seen.

13.2Animal Toxicology and/or Pharmacology The toxicological profile for aripiprazole administered to experimental animals by intramuscular injection is generally similar to that seen following oral administration at comparable plasma levels of the drug. In dogs, repeated intramuscular dosing of the 2-mont… [Excerpted — this section continues on DailyMed.]