Abilify Asimtufii Drug Information

is indicated: for the treatment of schizophrenia in adults for maintenance monotherapy treatment of bipolar I disorder in adults ABILIFY ASIMTUFII is an atypical antipsychotic indicated: for the treatment of schizophrenia in adults as maintenance monotherapy treatment of bipolar I disorder in adults

Clinical Trials Experience

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. The safety of ABILIFY ASIMTUFII for the treatment of schizophrenia in adults and maintenance monotherapy treatment of bipolar I disorder in adults is based on adequate and well-controlled studies of Abilify Maintena. The safety data from those studies is presented below.

Safety Database of Abilify Maintena (once monthly dosing) and Oral Aripiprazole. Oral aripiprazole has been evaluated for safety in 16,114 adult patients who participated in multiple-dose, clinical trials in schizophrenia and other indications, and who had approximately 8,578 patient-years of exposure to oral aripiprazole. A total of 3,901 patients were treated with oral aripiprazole for at least 180 days, 2,259 patients were treated with oral aripiprazole for at least 360 days, and 933 patients continuing aripiprazole treatment for at least 720 days.

Abilify Maintena (once monthly dosing) has been evaluated for safety in 2,128 adult patients in clinical trials in schizophrenia, with approximately 2,633 patient-years of exposure to Abilify Maintena. A total of 1,229 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 935 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections). Abilify Maintena has been evaluated for safety in 804 adult patients in clinical trials in bipolar I disorder, with approximately 530 patient-years of exposure to Abilify Maintena. A total of 419 patients were treated with Abilify Maintena for at least 180 days (at least 7 consecutive injections) and 287 patients treated with Abilify Maintena had at least 1 year of exposure (at least 13 consecutive injections). Safety Database of ABILIFY ASIMTUFII (once every 2 month dosing) In a 32 week open-label study of ABILIFY ASIMTUFII in adult patients with schizophrenia or bipolar I disorder, 266 patients were randomized to receive either ABILIFY ASIMTUFII 960 mg (132 patients) or Abilify Maintena 400 mg (134 patients). A total of the 132 patients received at least one injection of ABILIFY ASIMTUFII, a total of 114 patients received at least two consecutive injections (4 months treatment) of ABILIFY ASIMTUFII, and a total of 104 patients received at least four consecutive injections (8 months treatment) of ABILIFY ASIMTUFII. Of the total 266 patients receiving ABILIFY ASIMTUFII 960 mg or Abilify Maintena 400 mg, 185 had schizophrenia and 81 had bipolar I disorder.

Injection site reactions for ABILIFY ASIMTUFII (once every 2 month dosing) presented in this section is based on this open-label study (see section titled " Injection Site Reactions with Abilify ASIMTUFII "). Adverse Reactions in Studies with Abilify Maintena (once monthly dosing) The conditions and duration of treatment with Abilify Maintena included double-blind and open-label studies. The safety data presented below are derived from the 12-week double-blind placebo-controlled study of Abilify Maintena in adult patients with schizophrenia. Most Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena Based on the placebo-controlled trial of Abilify Maintena in schizophrenia, the most commonly observed adverse reactions associated with the use of Abilify Maintena in patients (incidence of 5% or greater and aripiprazole incidence at least twice that for placebo) were increased weight (16.8% vs. 7.0%), akathisia (11.4% vs. 3.5%), injection site pain (5.4% vs. 0.6%) and sedation (5.4% vs. 1.2%). Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials in Schizophrenia with Abilify Maintena The following findings are based on the double-blind, placebo-controlled trial that compared Abilify Maintena 400 mg or 300 mg to placebo in patients with schizophrenia.

Table 6 lists the adverse reactions reported in 2% or more of Abilify Maintena-treated patients and at a greater proportion than in the placebo group. Table 6: Adverse Reactions in ≥2% of Adult Patients with Schizophrenia Treated with Abilify Maintena in a 12-Week Double-Blind, Placebo-Controlled Study This table does not include adverse reactions which had an incidence equal to or less than placebo. Preferred Term Abilify Maintena (n=167) Placebo (n=172) Gastrointestinal Disorders Constipation 10 7 Dry Mouth 4 2 Diarrhea 3 2 Vomiting 3 1 Abdominal Discomfort 2 1 General Disorders and Administration Site Conditions Injection Site Pain 5 1 Infections and Infestations Upper Respiratory Tract Infection 4 2 Investigations Increased Weight 17 7 Decreased Weight 4 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 1 Back Pain 4 2 Myalgia 4 2 Musculoskeletal pain 3 1 Nervous System Disorders Akathisia 11 4 Sedation 5 1 Dizziness 4 2 Tremor 3 1 Respiratory, Thoracic and Mediastinal Nasal Congestion 2 1 Demographic Differences An examination of population subgroups was performed across demographic subgroup categories for adverse reactions experienced by at least 5% of Abilify Maintena patients at least twice the rate of placebo (i.e., increased weight, akathisia, injection site pain, and sedation) in the double-blind placebo-controlled trial.

This analysis did not reveal evidence of differences in safety differential adverse reaction incidence on the basis of age, gender, or race alone; however, there were few patients ≥65 years of age. Injection Site Reactions with ABILIFY ASIMTUFII ABILIFY ASIMTUFII was evaluated in 266 patients with schizophrenia or bipolar I disorder in an open-label, multiple-dose, randomized, parallel-arm multi-center study. The percentage of patients in the open-label study reporting any injection site-related adverse reactions (all reported as injection site pain) was 19% for patients treated with ABILIFY ASIMTUFII 960 mg and 9% for patients treated with Abilify Maintena 400 mg.

In both treatment groups, the majority of the injection site pain events coincided with the first injection of ABILIFY ASIMTUFII 960 mg (21/24 patients) or Abilify Maintena 400 mg (7/12 patients), was reported with decreasing frequency upon subsequent injections. The overall mean visual analog scale scores (0=no pain to 100=unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the ABILIFY ASIMTUFII 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group. Extrapyramidal Symptoms (EPS) In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of reported EPS-related events, excluding events related to akathisia, for Abilify Maintena-treated patients was 9.6% vs. 5.2% for placebo.

The incidence of akathisia-related events for Abilify Maintena-treated patients was 11.5% vs. 3.5% for placebo. Dystonia 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. In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of dystonia was 1.8% for Abilify Maintena vs. 0.6% for placebo.

Neutropenia In the short-term, placebo-controlled trial of Abilify Maintena in adults with schizophrenia, the incidence of neutropenia (absolute neutrophil count ≤1.5 thous/mcL) for Abilify Maintena-treated patients was 5.7% vs. 2.1% for placebo. An absolute neutrophil count of <1 thous/mcL (i.e., 0.95 thous/mcL) was observed in only one patient on Abilify Maintena and resolved spontaneously without any associated adverse reactions. Other Adverse Reactions During the Clinical Trial Evaluation of Abilify Maintena 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.

Blood and Lymphatic System Disorders: thrombocytopenia Cardiac Disorders: bradycardia, sinus tachycardia, tachycardia Endocrine Disorders: hypoprolactinemia Eye Disorders: vision blurred, oculogyric crisis Gastrointestinal Disorders: abdominal pain upper, dyspepsia, nausea, swollen tongue General Disorders and Administration Site Conditions: chest discomfort, fatigue, gait disturbance, injection site reaction (erythema, induration, pruritus, swelling, rash, inflammation, hemorrhage), irritability, pyrexia Hepatobiliary Disorders: drug-induced liver injury Immune System Disorders: drug hypersensitivity Infections and Infestations: nasopharyngitis Investigations: blood creatine phosphokinase increased, blood cholesterol decreased, blood pressure decreased, blood triglycerides decreased, electrocardiogram T wave abnormal, electrocardiogram QT-prolonged, hepatic enzyme increased, liver function test abnormal Metabolism and Nutrition Disorders: decreased appetite, hyperinsulinemia, obesity Musculoskeletal and Connective Tissue Disorders: joint stiffness, muscle twitching, rhabdomyolysis, trismus Nervous System Disorders: bradykinesia, convulsion, dysgeusia, extrapyramidal disorder, hypersomnia, lethargy, memory impairment, oromandibular dystonia, Psychiatric Disorders: anxiety, insomnia, restlessness, agitation, bruxism, psychotic disorder, suicidal ideation, aggression, hypersexuality, panic attack Renal and Urinary Disorders : glycosuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders: ejaculation delayed Vascular Disorders: hypertension Adverse Reactions Reported in Clinical Trials with Oral Aripiprazole The following is a list of additional adverse reactions that have been reported in clinical trials with oral aripiprazole and not reported above for Abilify Maintena: Cardiac Disorders: angina pectoris, atrial flutter, atrioventricular block, cardiopulmonary failure, cardio-respiratory arrest, extrasystoles, myocardial infarction, myocardial ischemia, palpitations, supraventricular tachycardia, ventricular tachycardia Eye Disorders: diplopia, photophobia, eyelid edema, photopsia Gastrointestinal Disorders: gastroesophageal reflux disease, swollen tongue, esophagitis, pancreatitis, stomach discomfort, toothache General Disorders and Administration Site Conditions: asthenia, chest pain, face edema, hypothermia, peripheral edema, pain Hepatobiliary Disorders: hepatitis, jaundice Immune System Disorders: hypersensitivity Injury, Poisoning, and Procedural Complications: heat stroke Investigations: blood prolactin decreased, blood bilirubin increased, blood creatinine increased, blood glucose increased, blood lactate dehydrogenase increased, blood prolactin increased, blood urea increased, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: anorexia, diabetic ketoacidosis, hyponatremia, hypoglycemia, polydipsia Musculoskeletal and Connective Tissue Disorders: mobility decreased, muscle rigidity, muscle tightness, muscular weakness, musculoskeletal stiffness, pain in extremity, muscle spasms Nervous System Disorders: akinesia, choreoathetosis, coordination abnormal, hypokinesia, hypotonia, myoclonus, speech disorder Psychiatric Disorders: anger, anorgasmia, catatonia, completed suicide, delirium, loss of libido, homicidal ideation, intentional self-injury, hostility, libido increased, sleepwalking, suicide attempt, tic Renal and Urinary Disorders: nocturia, polyuria, urinary retention Reproductive System and Breast Disorders: amenorrhea, breast pain, erectile dysfunction, gynecomastia, menstruation irregular, priapism Respiratory, Thoracic, and Mediastinal Disorders: dyspnea, nasal congestion, pharyngolaryngeal pain, cough Skin and Subcutaneous Tissue Disorders: alopecia, hyperhidrosis, photosensitivity reaction, pruritus, rash (including erythematous, exfoliative, generalized, macular, maculopapular, papular rash; acneiform, allergic, contact, exfoliative, seborrheic dermatitis, neurodermatitis, and drug eruption), urticaria

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of aripiprazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), blood glucose fluctuation, drug reaction with eosinophilia and systemic symptoms (DRESS), hiccups, pathological gambling, and fecal incontinence.

Drugs Having Clinically Important Interactions with

ABILIFY ASIMTUFII Table 7 presents clinically significant drug interactions with ABILIFY ASIMTUFII. Table 7: Clinically Important Drug Interactions with ABILIFY ASIMTUFII Strong CYP3A4 Inhibitors AND/OR strong CYP2D6 inhibitors Clinical Rationale Concomitant use of oral aripiprazole with strong CYP3A4 AND/OR CYP2D6 inhibitors increased the exposure of aripiprazole. Clinical Recommendation Concomitant use of a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor Reduce the dosage of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor OR a strong CYP2D6 inhibitor for more than 14 days. Concomitant Use of a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor Avoid use of ABILIFY ASIMTUFII when administered concomitantly with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor for more than 14 days.

Strong CYP3A4 Inducers Clinical Rationale Concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole. Clinical Recommendation Avoid use of ABILIFY ASIMTUFII in combination with a strong CYP3A4 inducer (e.g., carbamazepine) for greater than 14 days . Antihypertensive Drugs Clinical Rationale Due to its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Clinical Recommendation Monitor blood pressure and adjust dose accordingly.

Benzodiazepines Clinical Rationale The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone. Clinical Recommendation Monitor sedation and blood pressure.

Adjust dose accordingly.

Drugs Having No Clinically Important Interactions with

ABILIFY ASIMTUFII Based on pharmacokinetic studies with oral aripiprazole, no dosage adjustment of ABILIFY ASIMTUFII is required when administered concomitantly with famotidine, valproate, lithium, lorazepam . In addition, no dosage adjustment is necessary for substrates of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 when coadministered with ABILIFY ASIMTUFII. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when coadministered with ABILIFY ASIMTUFII .

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ABILIFY ASIMTUFII, 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-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including ABILIFY ASIMTUFII, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms (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 ASIMTUFII, during pregnancy (see Clinical Considerations ). Aripiprazole exposure during pregnancy may decrease milk supply in the post-partum period.

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 oral 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 oral 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 No developmental toxicity studies were conducted with intramuscular aripiprazole suspension.

In animal oral or intravenous 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 oral MRHD of 30 mg/day on mg/m 2 basis 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/m 2 basis. At 3 and 10 times the oral MRHD on mg/m 2 basis, 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 mg/m 2 basis 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/m 2 basis, 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/m 2 basis 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 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/m 2 basis 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/m 2 basis. 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/m 2 basis, 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/m 2 basis from Day 6 of gestation through Day 20 postpartum, increased stillbirths were seen at 3 and 6 times the oral MRHD on mg/m 2 basis, 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.

Pediatric Use Safety and effectiveness of ABILIFY ASIMTUFII in pediatric patients have not been established. Juvenile Animal Studies No juvenile animal studies were conducted with intramuscular aripiprazole suspension. A study with oral aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders.

In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels.

A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day.

Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC 0-24 ) for aripiprazole or its major active metabolite in adolescents at the maximum recommended oral pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period.

is contraindicated in patients with a known hypersensitivity to aripiprazole, or any of the excipients. Hypersensitivity reactions ranging from pruritus/urticaria to anaphylaxis have been reported in patients receiving aripiprazole . Known hypersensitivity to aripiprazole, or to any excipients of ABILIFY ASIMTUFII

Human Experience Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral aripiprazole overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Management of Overdosage In case of overdosage, call the Poison Control Center immediately at 1-800-222-1222 or medical toxicologist for additional overdosage management recommendations.