Aripiprazole

Warnings and Precautions ( 5.5 ) 08/2019

1 INDICATIONS AND USAGE Aripiprazole Oral Solution is indicated for the treatment of: Schizophrenia [see Clinical Studies (14.1) ] Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder [see Clinical Studies (14.2) ] Adjunctive Treatment of Major Depressive Disorder [see Clinical Studies (14.3) ] Irritability Associated with Autistic Disorder [see Clinical Studies (14.4) ] Treatment of Tourette’s Disorder [see Clinical Studies (14.5) ] Aripiprazole oral solution is an atypical antipsychotic. The oral formulations are indicated for: Schizophrenia ( 14.1 ) Acute Treatment of Manic and Mixed Episodes associated with Bipolar I ( 14.2 ) Adjunctive Treatment of Major Depressive Disorder ( 14.3 ) Irritability Associated with Autistic Disorder ( 14.4 ) Treatment of Tourette’s disorder ( 14.5 )

2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia – adults (2.1) 10 to 15 mg/day 10 to 15 mg/day 30 mg/day Schizophrenia – adolescents (2.1) 2 mg/day 10 mg/day 30 mg/day Bipolar mania – adults: monotherapy (2.2) 15 mg/day 15 mg/day 30 mg/day Bipolar mania – adults: adjunct to lithium or valproate (2.2) 10 to 15 mg/day 15 mg/day 30 mg/day Bipolar mania – pediatric patients: monotherapy or as an adjunct to lithium or valproate (2.2) 2 mg/day 10 mg/day 30 mg/day Major Depressive Disorder - Adults adjunct to antidepressants (2.3) 2 to 5 mg/day 5 to 10 mg/day 15 mg/day Irritability associated with autistic disorder – pediatric patients (2.4) 2 mg/day 5 to 10 mg/day 15 mg/day Tourette's disorder – (2.5) Patients < 50 kg 2 mg/day 5 mg/day 10 mg/day Patients ≥ 50 kg 2 mg/day 10 mg/day 20 mg/day Oral formulations: Administer once daily without regard to meals (2) Known CYP2D6 poor metabolizers: Half of the usual dose (2.7) 2.1 Schizophrenia Adults The recommended starting and target dose for aripiprazole oral solution is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. Aripiprazole has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies (14.1)] . Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either aripiprazole 15 mg/day or placebo, and observed for relapse [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the continued need for maintenance treatment. Adolescents The recommended target dose of aripiprazole oral solution is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. Aripiprazole oral solution can be administered without regard to meals [see Clinical Studies (14.1)] . Patients should be periodically reassessed to determine the need for maintenance treatment. Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to aripiprazole or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. 2.2 Bipolar I Disorder Acute Treatment of Manic and Mixed Episodes Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. Aripiprazole oral solution can be given without regard to meals. The recommended target dose of aripiprazole oral solution is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials. Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with tit …

3 DOSAGE FORMS AND STRENGTHS Aripiprazole Oral Solution (1 mg/mL) is a clear, colorless to light yellow solution with distinctive orange aroma, supplied in child-resistant bottles along with a calibrated oral dosing cup. Oral Solution: 1 mg/mL (3)

4 CONTRAINDICATIONS Aripiprazole oral solution is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see Adverse Reactions (6.2) ]. • Known hypersensitivity to aripiprazole oral solution (4)

6 ADVERSE REACTIONS 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 following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ] Cerebrovascular Adverse Events, Including Stroke [see WARNINGS AND PRECAUTIONS (5.2) ] Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.3) ] Neuroleptic Malignant Syndrome (NMS) [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/Convulsions [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) ] Suicide [see WARNINGS AND PRECAUTIONS (5.14) ] Dysphagia [see WARNINGS AND PRECAUTIONS (5.15) ] The most common adverse reactions in adult patients in clinical trials (≥10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. The most common adverse reactions in the pediatric clinical trials (≥10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased. Aripiprazole has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimer’s type, Parkinson’s disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral aripiprazole. A total of 3390 patients were treated with oral aripiprazole for at least 180 days and 1933 patients treated with oral aripiprazole had at least 1 year of exposure. Aripiprazole has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette’s disorder and who had approximately 1,342 patient-years of exposure to oral aripiprazole. A total of 959 pediatric patients were treated with oral aripiprazole for at least 180 days and 556 pediatric patients treated with oral aripiprazole had at least 1 year of exposure. The conditions and duration of treatment with aripiprazole (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open- label studies, inpatient and outpatient studies, fixed- and flexible-dose studies, and short- and longer-term exposure. Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were (6.1) : Adult patients with schizophrenia: akathisia Pediatric patients (13 to 17 years) with schizophrenia: extrapyramidal disorder, somnolence, and tremor Adult patients (monotherapy) with bipolar mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder Adult patients (adjunctive therapy with lithium or valproate) with bipolar mania: akathisia, insomnia, and extrapyramidal disorder Pediatric patients (10 to 17 years) with bipolar mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness Adult patients with major depressive disorder (adjunctive treatment to antidepressant therapy): akathisia …

7 DRUG INTERACTIONS Dosage adjustment due to drug interactions (7.1) : Factors Dosage Adjustments for Aripiprazole Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP2D6 or CYP3A4 inhibitors Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers Double usual dose over 1 to 2 weeks 7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see Dosage and Administration ( 2.7 )]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology ( 12.3 )] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see Dosage and Administration ( 2.7 )]. Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see Warnings and Precautions ( 5.8 )]. Benzodiazepines (e.g., lorazepam) 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 [see Warnings and Precautions ( 5.8 )]. Monitor sedation and blood pressure. Adjust dose accordingly. 7.2 Drugs Having No Clinically Important Interactions with Aripiprazole Based on pharmacokinetic studies, no dosage adjustment of aripiprazole is required when administered concomitantly with famotidine, valproate, lithium, lorazepam. In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when coadministered with aripiprazole. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with aripiprazole [see Clinical Pharmacology ( 12.3 )] .

7.1 Drugs Having Clinically Important Interactions with Aripiprazole Table 25: Clinically Important Drug Interactions with Aripiprazole: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology ( 12.3 )]. With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see Dosage and Administration ( 2.7 )]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see Clinical Pharmacology ( 12.3 )] . With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see Dosage and Administration ( 2.7 )]. Anti …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure ( 8.1 ) Lactation: Monitor the breastfed infant for dehydration and lack of appropriate weight gain ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including aripiprazole, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs, including aripiprazole, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) . Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including aripiprazole, during pregnancy (see Clinical Considerations ) . Aripiprazole exposure during pregnancy can have variable effects on milk supply in the post-partum period [see Use in Specific Populations ( 8.2 )] . In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m 2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m 2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including aripiprazole) during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms, and manage symptoms appropriately. Some neonates recovered within hours or days without specific …

12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear. However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.

11 DESCRIPTION Aripiprazole is an atypical antipsychotic drug that is available as, Aripiprazole Oral Solution. Aripiprazole is 7-[4-[4-(2,3­-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C 23 H 27 Cl 2 N 3 O 2 and its molecular weight is 448.38. The chemical structure is: Aripiprazole Oral Solution is a clear, colorless to yellow solution with orange-vanilla odor available in a concentration of 1 mg/mL. The inactive ingredients for this solution include edetate disodium, fructose (200 mg per mL), glycerin, malic acid, methylparaben, propylene glycol, propylparaben, purified water, sodium hydroxide, sucrose (400 mg per mL). The oral solution is flavored with orange-vanilla flavor (contains propylene glycol, water, artificial flavors). Aripiprazole Molecular Formula

10 OVERDOSAGE MedDRA terminology has been used to classify the adverse reactions. 10.1 Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities. 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. 10.2 Management of Overdosage No specific information is available on the treatment of overdose with aripiprazole. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of aripiprazole, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of aripiprazole, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with aripiprazole, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

10.1 Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral aripiprazole have been reported worldwide. These include overdoses with oral aripiprazole alone and in combination with other substances. No fatality was reported with aripiprazole alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral aripiprazole (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral aripiprazole ingestions up to 195 mg with no fatalities. 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.

10.2 Managemen …

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Aripiprazole Oral Solution (1 mg/mL) is supplied in a 150 mL amber PET metric round bottle with a white polypropylene child-resistant cap with induction seal liner along with a calibrated oral dosing cup. Aripiprazole oral solution is available as follows: 150 mL bottle NDC 60505-0404-5 16.2 Storage Oral Solution Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Opened bottles of aripiprazole oral solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle. The bottle and its contents should be discarded after the expiration date.

16.1 How Supplied Aripiprazole Oral Solution (1 mg/mL) is supplied in a 150 mL amber PET metric round bottle with a white polypropylene child-resistant cap with induction seal liner along with a calibrated oral dosing cup. Aripiprazole oral solution is available as follows: 150 mL bottle NDC 60505-0404-5