Aripiprazole, ARIPiprazole Lauroxil

General

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 76 77 78 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

• When switching from other antipsychotic agents to aripiprazole, abrupt discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be most appropriate for others.1 In all cases, minimize period of overlapping antipsychotic administration.1

Administration

Administer aripiprazole orally1 or by IM injection.1 118 Administer aripiprazole lauroxil by IM injection.119

Establish tolerability with oral aripiprazole prior to initiating IM therapy with extended-release aripiprazole or aripiprazole lauroxil.118 119

Oral Administration

Administer orally as conventional tablets, orally disintegrating tablets, or oral solution once daily without regard to meals.1 (See Food under Pharmacokinetics.)

Orally Disintegrating Tablets

Just prior to administration, peel open blister package; with dry hands, remove orally disintegrating tablet.1 Do not push tablet through foil.1

Place tablet on tongue to dissolve; manufacturer recommends taking without liquid, but may take with liquid, if necessary.1

Do not divide orally disintegrating tablet.1

IM Administration of Immediate-release Aripiprazole Injection

Immediate-release aripiprazole (9.75 mg per 1.3-mL vial) is used for agitation associated with schizophrenia or bipolar mania; do not confuse with extended-release formulations of aripiprazole (Abilify Maintena; available in 300- and 400-mg vials and prefilled syringes) or aripiprazole lauroxil (Aristada; available in 441-, 662-, and 882-mg prefilled syringes) used for schizophrenia.1 118 119

Administer immediate-release aripiprazole injection only by IM injection slowly and deeply into the muscle mass.1

Do not administer IV or sub-Q.1

IM Administration of Extended-release Aripiprazole (Abilify Maintena)

Extended-release IM aripiprazole is available in 300- and 400-mg vials and prefilled syringes; do not confuse this formulation with extended-release aripiprazole lauroxil (Aristada; available in 441-, 662-, and 882-mg prefilled syringes) or the immediate-release IM aripiprazole formulation (9.75 mg/vial) used for agitation associated with schizophrenia and bipolar mania.1 118

Must be administered by a healthcare professional.118

Administer extended-release aripiprazole injection only by deep IM injection slowly into the deltoid or gluteal muscle.118 Do not massage injection site following IM administration.118 Rotate injection sites.118

Administer monthly; allow at least 26 days to elapse between doses.118

Reconstitution

Abilify Maintena is commercially available in 2 types of kits that contain aripiprazole lyophilized powder in either single-use vials or prefilled dual-chamber syringes with all the components required for reconstitution and administration (e.g., sterile water for injection diluent, needles, syringes); consult manufacturer's instructions for use for specific information on preparation, reconstitution, and administration.118

Because entire contents of prefilled dual-chamber syringes should be administered after reconstitution, use single-use vials for dosages <300 mg.118

Following reconstitution, shake prefilled syringe or vials vigorously for 20 or 30 seconds, respectively, to ensure a uniform and homogeneous suspension, which appears opaque and milky-white.118 If using vials, withdraw the appropriate dose of aripiprazole using the syringe supplied by the manufacturer.118 If a vial of reconstituted suspension is not administered immediately, shake the vial vigorously for at least 60 seconds to resuspend the drug; do not store in syringe after reconstitution.118 If using prefilled syringes, inject entire contents immediately following reconstitution (i.e., within 30 minutes).118

IM Administration of Extended-release Aripiprazole Lauroxil (Aristada)

Extended-release aripiprazole lauroxil is available in 441-, 662-, and 882-mg prefilled syringes; do not confuse this formulation with extended-release aripiprazole (Abilify Maintena; available in 300- and 400-mg vials and prefilled syringes) or the immediate-release aripiprazole formulation (9.75 mg/vial) used for agitation associated with schizophrenia and bipolar mania.1 118 119

Must be administered by a healthcare professional.119

Available as kits containing extended-release aripiprazole lauroxil injectable suspension in prefilled syringes and safety needles for IM injection.119 Prior to use, tap the prefilled syringe ≥10 times to dislodge any material that may have settled, then shake vigorously for ≥30 seconds to ensure a uniform suspension.119 If not administered within 15 minutes, shake the syringe again for 30 seconds.119

Administer only by IM injection rapidly and continuously (i.e., within <10 seconds) into the deltoid (for 441-mg doses only) or gluteal muscle (for 441-, 662-, and 882-mg doses).119 Select needle based on injection site; use longer needles in patients with a larger amount of subcutaneous tissue overlaying the injection site muscle.119

Administer monthly; may administer the 882-mg dose monthly or every 6 weeks.119 Allow at least 14 days to elapse between doses.119

Dosage

Aripiprazole oral solution may be given at same dose on mg-per-mg basis as the tablet strengths of the drug up to a dose of 25 mg.1 However, if oral solution is used in patients receiving 30-mg tablets, use a dose of 25 mg of the oral solution.1

Dosing of aripiprazole orally disintegrating tablets is the same as for conventional tablets of the drug.1

Dosage of aripiprazole lauroxil expressed in terms of aripiprazole lauroxil.119

Extended-release aripiprazole lauroxil (Aristada) dosages of 441, 662, and 882 mg IM once monthly correspond to extended-release aripiprazole (Abilify Maintena) dosages of 300, 450, and 600 mg IM once monthly, respectively.119

If used with CYP3A4 inhibitors, CYP2D6 inhibitors, and/or CYP3A4 inducers, dosage adjustment may be required.1 (See Interactions.)

Pediatric Patients

Schizophrenia Oral

Adolescents ≥13 years of age: Recommended target dosage for acute treatment is 10 mg once daily.1 Therapy has been initiated at 2 mg once daily, with subsequent titration to 5 mg once daily after 2 days and to 10 mg once daily after 2 additional days.1 75 91

Subsequent dosage increases should be made in 5-mg, once-daily increments.1

Dosages of 10 and 30 mg once daily evaluated in clinical trials; the 30-mg daily dosage was not more effective than the 10-mg daily dosage.1 75 91

Although efficacy as maintenance treatment not systematically evaluated in adolescents with schizophrenia, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.1 Periodically reassess need for continued therapy.1 (See Pediatric Use under Cautions.)

Bipolar Disorder Manic or Mixed Episodes: Monotherapy or Combination Therapy Oral

Children and adolescents ≥10 years of age: Target dosage for acute treatment is 10 mg once daily.1 Recommended initial dosage when given as monotherapy is 2 mg once daily, with subsequent titration to 5 mg once daily after 2 days and to the target dosage of 10 mg once daily after 2 additional days.1

Recommended dosage when aripiprazole is given as adjunctive therapy with lithium or valproate is the same as that for monotherapy.1

Daily dosage may be increased, if necessary, in 5-mg increments.1 In pediatric clinical studies, dosages of 10 and 30 mg daily were effective.1

Irritability Associated with Autistic Disorder Oral

Children and adolescents 6–17 years of age: Initially, 2 mg once daily, then increase dosage to 5 mg daily, with subsequent increases to 10 or 15 mg daily, if necessary.1 Increase dosage gradually, at intervals of ≥1 week.1 Efficacy established within a dosage range of 5–15 mg daily in clinical studies.1 109 110

Periodically reassess need for continued therapy.1

Tourette's Syndrome Oral

Children and adolescents 6–18 years of age weighing <50 kg: Initially, 2 mg once daily for 2 days, then increase dosage to 5 mg once daily.1 If optimal control of tics not achieved, may increase dosage to 10 mg once daily.1 Adjust dosage gradually at intervals of ≥1 week.1

Children and adolescents 6–18 years of age weighing ≥50 kg: Initially, 2 mg once daily for 2 days, then increase to 5 mg once daily for 5 days, with a recommended target dosage of 10 mg once daily on day 8.1 If optimal control of tics not achieved, may increase dosage up to 20 mg once daily.1 Adjust dosage gradually in increments of 5 mg daily at intervals of ≥1 week.1

Periodically reassess need for continued maintenance therapy.1

Adults

Schizophrenia Oral

Initial and target dosage for acute treatment is 10 or 15 mg once daily.1

Dosages ranging from 10–30 mg once daily were effective in clinical trials; dosages exceeding 10–15 mg daily did not result in greater efficacy.1

Adjust dosage at intervals of ≥2 weeks, the time needed to achieve steady-state concentrations.1

Efficacy as maintenance therapy for ≤26 weeks has been demonstrated;1 other clinical experience indicates may be effective for up to 52 weeks.2 9 10 Optimum duration of therapy is not known, but maintenance therapy with antipsychotics is well established.1 28

Periodically reassess need for continued therapy.1

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.28 Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while taking antipsychotic.28 Indefinite maintenance treatment is recommended if multiple previous psychotic episodes or 2 episodes within 5 years.28

IM, Extended-release Aripiprazole (Abilify Maintena)

For patients naive to aripiprazole, establish tolerability with oral aripiprazole prior to initiating extended-release IM aripiprazole therapy; may take up to 2 weeks to fully assess tolerability due to the half-life of oral aripiprazole.118

Usual initial and maintenance dosage: 400 mg IM every month.118 May reduce dosage to 300 mg every month in patients experiencing adverse effects.118

Administer oral aripiprazole 10–20 mg daily (or another oral antipsychotic agent in patients already stable on another oral antipsychotic and known to tolerate aripiprazole) with the first extended-release IM aripiprazole injection and continue oral therapy for 14 days thereafter to ensure adequate therapeutic plasma concentrations are maintained.118

If a dose of extended-release aripiprazole injection is missed, administer the next dose as soon as possible.118 Supplementation with oral aripiprazole may be required depending on the time elapsed (see Table 1).118

Table 1. Recommended Oral Aripiprazole Supplementation Following Missed Doses of Extended-release Aripiprazole Injection118

Dose Missed	No Oral Supplementation Required	Supplementation with Oral Aripiprazole for 14 Days Required with Next IM Dose
2nd or 3rd IM dose	≤5 weeks since last injection	>5 weeks since last injection
4th or subsequent IM doses	≤6 weeks since last injection	>6 weeks since last injection

IM, Extended-release Aripiprazole Lauroxil (Aristada)

For patients naive to aripiprazole, establish tolerability with oral aripiprazole prior to initiating extended-release IM aripiprazole lauroxil therapy; may take up to 2 weeks to fully assess tolerability due to the half-life of oral aripiprazole.119

Depending on individual patient's needs, may initiate therapy at a dosage of 441, 662, or 882 mg every month or 882 mg every 6 weeks by IM injection.119

Administer oral aripiprazole daily with the first IM aripiprazole lauroxil injection and continue oral aripiprazole therapy for 21 days thereafter.119

For patients established on oral aripiprazole 10 mg daily, recommended IM dosage of aripiprazole lauroxil is 441 mg every month.119

For patients established on oral aripiprazole 15 mg daily, recommended IM dosage of aripiprazole lauroxil is 662 mg every month.119

For patients established on oral aripiprazole ≥20 mg daily, recommended IM dosage of aripiprazole lauroxil is 882 mg every month.119

Adjust dosage as needed.119 Consider pharmacokinetics and prolonged-release characteristics of extended-release aripiprazole lauroxil injection when adjusting dose and dosing interval.119

If a dose is missed, administer the next dose as soon as possible.119 Supplementation with oral aripiprazole may be required depending on the dosage and the time elapsed (see Table 2).119

Dosage of oral aripiprazole supplementation should be same as when patient began extended-release aripiprazole lauroxil therapy.119

Table 2. Recommended Oral Aripiprazole Supplementation Following Missed Doses of Aripiprazole Lauroxil Injection119

Dosage of Patient's Last Injection	No Oral Supplementation Required	Supplement with Oral Aripiprazole for 7 Days	Supplement with Oral Aripiprazole for 21 Days
441 mg monthly	≤6 weeks since last injection	>6 and ≤7 weeks since last injection	>7 weeks since last injection
662 mg monthly	≤8 weeks since last injection	>8 and ≤12 weeks since last injection	>12 weeks since last injection
882 mg monthly	≤8 weeks since last injection	>8 and ≤12 weeks since last injection	>12 weeks since last injection
882 mg every 6 weeks	≤8 weeks since last injection	>8 and ≤12 weeks since last injection	>12 weeks since last injection

Bipolar Disorder Manic or Mixed Episodes: Monotherapy or Combination Therapy Oral

Monotherapy: Initially, 15 mg once daily.1

Adjunctive therapy to lithium or valproate: Initial dosage of 10–15 mg once daily.1

Recommended target dosage is 15 mg once daily whether the drug is given as monotherapy or as adjunctive therapy with lithium or valproate.1 Based on patient response, may increase dosage to 30 mg once daily.1

Safety of dosages >30 mg daily not established.1

Major Depressive Disorder Oral

Initially, 2–5 mg once daily as adjunctive acute therapy.1

Gradually adjust dosage in increments of ≤5 mg daily at ≥1-week intervals; the recommended dosage is 5–10 mg once daily.1 Dosages of 2–15 mg daily were effective in clinical trials.1

Periodically reassess need for continued therapy.1

Manufacturer does not recommend aripiprazole dosage adjustment when administered as adjunctive therapy for major depressive disorder concurrently with CYP2D6 inhibitors.1 (See Interactions.)

Acute Agitation in Schizophrenia and Bipolar Mania IM, Immediate-release Aripiprazole

Initially, 9.75 mg as a single dose.1 Consider lower dose of 5.25 mg when clinically warranted.1

In clinical trials, efficacy was demonstrated with doses of 5.25–15 mg.1 86 87 88 Additional benefit not demonstrated with 15-mg dose compared with 9.75-mg dose.1

Efficacy of repeated doses not systematically evaluated.1 If agitation persists following the initial dose, may administer subsequent doses up to a cumulative daily dose of 30 mg.1 Safety of total doses >30 mg daily or administration more frequently than every 2 hours not systematically evaluated in controlled trials.1

If continued aripiprazole therapy is clinically indicated, oral therapy should replace IM therapy as soon as possible.1

Prescribing Limits

Pediatric Patients

Schizophrenia Oral

Safety and efficacy of dosages >30 mg daily not established.1 91

Bipolar Disorder Manic or Mixed Episodes Oral

Safety and efficacy of dosages >30 mg daily not established.1

Irritability Associated with Autistic Disorder Oral

Safety and efficacy of dosages >15 mg daily not established.1

Tourette's Syndrome Oral

Weight <50 kg: Maximum 10 mg daily.1

Weight ≥50 kg: Maximum 20 mg daily.1

Adults

Schizophrenia Oral

Safety and efficacy of dosages >30 mg daily not established.1

IM, Extended-release Aripiprazole (Abilify Maintena)

Safety and efficacy of dosages >400 mg every month not established.118

IM, Extended-release Aripiprazole Lauroxil (Aristada)

Safety and efficacy of dosages >882 mg every month not established.119

Bipolar Disorder Manic or Mixed Episodes Oral

Safety and efficacy of dosages >30 mg daily not established.1

Adjunctive Therapy of Major Depressive Disorder Oral

Safety and efficacy of dosages >15 mg daily not established.1

Acute Agitation in Schizophrenia and Bipolar Mania IM

Safety of total dosages >30 mg daily or IM doses given more frequently than every 2 hours not established.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.1 95 118 119

Renal Impairment

Dosage adjustment not required.1 95 118 119

Geriatric Patients

Dosage adjustment not required.1 118 119

Gender, Race, or Smoking Status

Dosage adjustment not required.1 118 119

Poor CYP2D6 Metabolizer Phenotype

For dosage adjustments related to CYP-mediated interactions in populations other than patients with poor CYP2D6 metabolizer phenotype, see Interactions.

Oral Aripiprazole

Reduce oral dosage to 50% of the usual dosage; dosage adjustment not required when used as adjunctive treatment of major depressive disorder.1

If patients who are poor CYP2D6 metabolizers are concomitantly receiving a potent CYP3A4 inhibitor, reduce oral aripiprazole dosage to 25% of the usual dosage.1 (See Interactions.)

Extended-release IM Aripiprazole Injection (Abilify Maintena)

Reduce dosage to 300 mg every month.118

If patients who are poor CYP2D6 metabolizers are concomitantly receiving a potent CYP3A4 inhibitor, reduce dosage of extended-release IM aripiprazole injection to 200 mg every month.118 Dosage adjustment not required for concomitant use <2 weeks.118 (See Interactions.)

Extended-release IM Aripiprazole Lauroxil Injection (Aristada)

Reduce dosage based on patient's established oral dosage.119

If patients who are poor CYP2D6 metabolizers are concomitantly receiving a potent CYP3A4 inhibitor, reduce dosage of extended-release IM aripiprazole lauroxil injection from 662 or 882 mg to 441 mg every month.119 Dosage adjustment not necessary in patients already receiving 441 mg every month, if tolerated.119 Dosage adjustment not required for concomitant use <2 weeks.119 (See Interactions.)

No further dosage adjustment required in patients who are poor CYP2D6 metabolizers receiving a concomitant potent CYP2D6 inhibitor.119 (See Interactions.)

Contraindications

• Known hypersensitivity to aripiprazole; hypersensitivity reactions have ranged from pruritus/urticaria to anaphylaxis.1 118 119 (See Sensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.1 28 73 113 114 118 119

Antipsychotic agents, including aripiprazole, are not approved for the treatment of dementia-related psychosis.1 73 113 118 119 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia under Cautions.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.1 76 77 78 79 (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 76 77 78

Appropriately monitor and closely observe patients receiving aripiprazole for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 76 77 78

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 77 78 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.1 76 77 78

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 77

Sensitivity Reactions

Allergic and sensitivity reactions (e.g., anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, photosensitivity, rash, oropharyngeal spasm) reported in aripiprazole-treated patients.1 118 119 (See Contraindications under Cautions.)

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with aripiprazole in several placebo-controlled studies.1 118 Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.1 118 119 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Impulse Control/Compulsive Behaviors

Serious impulse-control and compulsive behaviors, particularly pathological gambling, reported in adult and pediatric patients treated with aripiprazole.123 132 134 135 136 137 138 In May 2016, FDA reported that 184 cases of impulse-control problems associated with aripiprazole therapy had been identified since November 2002; 89% of the cases involved pathological gambling.123 Other impulse-control and compulsive behaviors (e.g., compulsive or binge eating, compulsive spending or shopping, compulsive sexual behaviors) reported less frequently.123 136 138 Most of the patients had no history of compulsive behaviors and experienced the uncontrollable urges only after beginning aripiprazole treatment.123 137 These urges stopped within days to weeks following aripiprazole dosage reduction or discontinuance; recurrence of compulsive behaviors following rechallenge reported.123 134 136 137 138

Advise patients and caregivers of the risk of uncontrollable urges with aripiprazole and specifically ask patients whether they have developed any new or increased urges while receiving the drug.123 If an aripiprazole-treated patient develops new or increased impulsive or compulsive behaviors, consider reducing the dosage or discontinuing the drug.123 137 (See Advice to Patients.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including some rare cases in patients treated with aripiprazole.1 99 100 101 118 119

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs.1 118 119 Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.1 118 119

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including aripiprazole.1 96 97 118 119

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 118 119 In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.1 118 119

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.28 Consider discontinuance of aripiprazole if signs and symptoms of tardive dyskinesia appear.1 118 119 However, some patients may require treatment despite the presence of the syndrome.1 118 119

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain.1 118 119 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1 118 119 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.1 In short- and longer-term clinical studies in adult and pediatric patients, clinically important differences between oral aripiprazole and placebo in mean change from baseline to end point in serum glucose concentrations not observed.1

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).1 If manifestations of hyperglycemia occur in any aripiprazole-treated patient, perform fasting blood glucose testing.1 (See Advice to Patients.)

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.1

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with some atypical antipsychotics.1 However, aripiprazole generally does not appear to adversely affect the lipid profile.1

Weight Gain

Weight gain observed with atypical antipsychotic therapy.1 Monitoring of weight recommended during aripiprazole therapy.1 (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Orthostatic Hypotension

Risk of orthostatic hypotension associated with adverse effects, including postural dizziness, syncope, and tachycardia, perhaps because of aripiprazole's α1-adrenergic blocking activity.1 118 119 Risk generally appears greatest during initiation of therapy and dosage titration.119

Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose them to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in antipsychotic-naive patients.1 119 In such patients who are receiving extended-release IM aripiprazole lauroxil therapy, consider a lower initial dosage and monitoring of orthostatic vital signs.119

If parenteral benzodiazepine therapy is necessary in patients receiving short-acting IM aripiprazole, monitor patients for possible excessive sedation and orthostatic hypotension.1 (See Specific Drugs under Interactions.)

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents, including aripiprazole, reported during clinical trial and/or postmarketing experience.1 102 103 118 119 Agranulocytosis also reported.1 118 119

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.1 102 103 118 119 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 118 119 Discontinue aripiprazole at the first sign of a decline in WBC count in the absence of other causative factors.1 118 119

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.1 118 119 Discontinue aripiprazole if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.1 118 119

Seizures

Seizures/convulsions reported in 0.1% of adult and pediatric patients (6–18 years of age) treated with oral aripiprazole and in 0.2% of adults treated with short-acting IM aripiprazole.1

Use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold; such conditions may be more prevalent in patients ≥65 years of age.1 118 119

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired.1 118 119

Somnolence (including sedation) reported in 11 and 9% of adults treated with oral or short-acting parenteral aripiprazole, respectively, compared with 6% of those receiving placebo in short-term clinical trials.1 Somnolence (including sedation) reported in 24% of pediatric patients (6–17 years of age) receiving aripiprazole compared with 6% of those receiving placebo.1 (See Advice to Patients.)

Body Temperature Regulation

Antipsychotic agents may disrupt ability to reduce core body temperature.1 118 119

Use appropriate caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).1 118 119

Suicide

Attendant risk with psychotic illnesses, bipolar disorder, and major depressive disorder; closely supervise high-risk patients.1 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents, including aripiprazole.1 118 119

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer’s dementia.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.) Use with caution in patients at risk for aspiration pneumonia.1 118 119

Phenylketonuria

Each 10- or 15-mg Abilify Discmelt orally disintegrating tablet contains aspartame (NutraSweet), which is metabolized in the GI tract to provide about 1.12 or 1.68 mg of phenylalanine, respectively.1 80 81 82 83 84

Specific Populations

Pregnancy

Category C.1

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.1 106 107 108 111 118 119 Symptoms varied in severity; some neonates recovered within hours to days without specific treatment, while others have required intensive care unit support and prolonged hospitalization.1 106 107 108 118 119

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and .1 118 119

Lactation

Distributed into milk in humans.1 111 118 119 However, data are insufficient to determine the amount present in human milk, the effects of the drug on breast-fed infants, or the effects on milk production.118 119

Because of the potential for serious adverse reactions to aripiprazole in nursing infants, the manufacturer of aripiprazole tablets, oral solution, and the short-acting IM injection states that a decision should be made whether to discontinue nursing or the drug, taking into consideration the importance of the drug to the woman.1

The manufacturers of extended-release IM formulations of aripiprazole state that the benefit of aripiprazole therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant from exposure to the drug or from the underlying maternal condition.118 119

Pediatric Use

Safety and efficacy of oral aripiprazole not established in pediatric patients with major depressive disorder.1 Safety and efficacy of immediate-release IM aripiprazole not established for agitation associated with schizophrenia or bipolar mania in pediatric patients.1 Safety and efficacy of extended-release IM aripiprazole and aripiprazole lauroxil not evaluated in pediatric patients <18 years of age.118 119

Safety and efficacy of oral aripiprazole for acute management of schizophrenia in pediatric patients 13–17 years of age established in a placebo-controlled study of 6 weeks' duration.1 91 Efficacy for maintenance treatment not established, but can be extrapolated from adult data and pharmacokinetic comparisons between adult and pediatric populations.1

Safety and efficacy of oral aripiprazole monotherapy for acute management of bipolar mania in pediatric patients 10–17 years of age established in a placebo-controlled study of 4 weeks' duration.1

Efficacy of oral aripiprazole as adjunctive therapy to lithium or valproate for management of manic or mixed episodes associated with bipolar disorder in pediatric patients not systematically evaluated.1 However, efficacy can be extrapolated from adult data and pharmacokinetic comparisons between adult and pediatric populations.1

Safety and efficacy of oral aripiprazole for treatment of irritability associated with autistic disorder in pediatric patients 6–17 years of age established in 2 placebo-controlled clinical studies of 8 weeks’ duration.1 109 110 Efficacy as maintenance treatment not established in a longer-term, placebo-controlled relapse prevention trial in pediatric patients 6–17 years of age.1 133

Safety and efficacy of oral aripiprazole for treatment of Tourette's syndrome in pediatric patients 6–18 years of age established in 2 short-term, placebo-controlled trials of 8 and 10 weeks' duration.1 Efficacy as maintenance therapy not systematically evaluated.1

Mean weight gain of 1.6 kg reported in pediatric patients with schizophrenia or bipolar disorder receiving oral aripiprazole compared with a gain of 0.3 kg in those receiving placebo in 2 short-term studies; from baseline to 24 weeks, mean weight gain was 5.8 kg in aripiprazole-treated patients compared with 1.4 kg in placebo recipients.1 Similar weight gain observed in short-term studies in pediatric patients with Tourette's syndrome or with irritability associated with autistic disorder.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).1 77 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.79 No suicides occurred in these pediatric trials.1 77 79

Geriatric Use

Insufficient experience with oral, short-acting IM, and extended-release IM formulations of aripiprazole in patients ≥65 years of age to determine whether they respond differently than younger adults.1 118 Manufacturer states that dosage adjustment of oral and IM aripiprazole formulations based on age alone in geriatric patients is not necessary.1 118

Safety and efficacy of extended-release IM aripiprazole lauroxil not evaluated in patients >65 years of age; manufacturer makes no specific dosage recommendations for geriatric patients.119

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death;1 28 73 113 114 118 119 increased incidence of cerebrovascular events also observed with aripiprazole.1 Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.1 118 119 (See Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 76 77 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Poor CYP2D6 Metabolizers

Because higher plasma concentrations of aripiprazole are likely, dosage adjustment recommended for patients known to be poor metabolizers of CYP2D6.1 118 119 Approximately 8% of Caucasians and 3–8% of Blacks/African Americans cannot metabolize CYP2D6 substrates and are classified as poor CYP2D6 metabolizers.1 118 119 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.)

Common Adverse Effects

Oral aripiprazole (adults): Nausea,1 vomiting,1 constipation,1 sedation,1 fatigue,1 headache,1 dizziness,1 akathisia,1 anxiety,1 insomnia,1 restlessness,1 tremor,1 extrapyramidal disorder,1 blurred vision.1

Oral aripiprazole (pediatric patients): Somnolence or sedation,1 headache,1 nausea,1 vomiting,1 tremor,1 extrapyramidal disorder,1 increased appetite,1 fatigue,1 insomnia,1 akathisia,1 nasopharyngitis,1 blurred vision,1 salivary hypersecretion,1 dizziness,1 increased weight.1

IM aripiprazole, immediate-release: Nausea.1

IM aripiprazole, extended-release: Increased weight,118 akathisia,118 injection site pain,118 sedation.118

IM aripiprazole lauroxil, extended-release: Akathisia,119 122 extrapyramidal symptoms (e.g., parkinsonism, dystonia),119 injection site reactions (e.g., pain).119 122

Aripiprazole is extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors and/or potent CYP2D6 inhibitors: Potential pharmacokinetic interaction.1

Combination of potent, moderate, and weak CYP3A4 and CYP2D6 inhibitors (e.g., potent CYP3A4 inhibitor with moderate CYP2D6 inhibitor; moderate CYP3A4 inhibitor with moderate CYP2D6 inhibitor): Potential pharmacokinetic interaction.1

Potent CYP3A4 inducers: Decreased systemic exposure to aripiprazole.1

Inhibitors or inducers of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1: Pharmacokinetic interaction unlikely.1

Concomitant Drug	Recommended Dosage Adjustment
Potent CYP3A4 inhibitors	Oral aripiprazole: Reduce aripiprazole dosage to 50% of usual dosage; dosage adjustment not required when used as adjunctive treatment of major depressive disorder.1 Increase back to original dosage when the CYP3A4 inhibitor is discontinued.1 Further reduce dosage in patients with poor CYP2D6 metabolizer phenotype.1 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.) Extended-release IM aripiprazole injection (Abilify Maintena): Dosage adjustment not necessary if potent CYP3A4 inhibitor is added for <2 weeks.118 For concomitant therapy >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg every month.118 Further dosage reduction in patients with poor CYP2D6 metabolizer phenotype may be necessary.118 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.) Extended-release IM aripiprazole lauroxil injection (Aristada): Dosage adjustment not necessary if potent CYP3A4 inhibitor is added for <2 weeks.119 For concomitant therapy >14 days, reduce aripiprazole lauroxil dosage to next available lower strength.119 Dosage reduction not necessary in patients receiving the 441-mg dosage, if tolerated.119 Reduce 882 mg every 6 weeks to 441 mg every 4 weeks.119 Further dosage reduction in patients with poor CYP2D6 metabolizer phenotype may be necessary.119 (See Poor CYP2D6 Metabolizer Phenotype under Dosage and Administration.)
Potent CYP2D6 inhibitors	Oral aripiprazole: Reduce aripiprazole dosage to 50% of usual dosage; dosage adjustment not required when used as adjunctive treatment of major depressive disorder.1 Increase back to original dosage when the CYP2D6 inhibitor is discontinued.1 Extended-release IM aripiprazole injection (Abilify Maintena): Dosage adjustment not necessary if potent CYP2D6 inhibitor is added for <2 weeks.118 For concomitant therapy >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg every month.118 Extended-release IM aripiprazole lauroxil injection (Aristada): Dosage adjustment not necessary if potent CYP2D6 inhibitor is added for <2 weeks.119 For concomitant therapy >14 days, reduce aripiprazole lauroxil dosage to next available lower strength.119 Dosage reduction not necessary in patients receiving 441-mg dosage, if tolerated.119 Reduce 882 mg every 6 weeks to 441 mg every 4 weeks.119
Potent CYP3A4 inhibitors and potent CYP2D6 inhibitors	Oral aripiprazole: Reduce aripiprazole dosage to 25% of usual dosage; dosage adjustment not required when used as adjunctive treatment of major depressive disorder.1 Increase back to original dosage when the CYP3A4 and/or CYP2D6 inhibitor is discontinued.1 Extended-release IM aripiprazole injection (Abilify Maintena): Reduce aripiprazole dosage from 400 to 200 mg every month, or from 300 to 160 mg every month for concomitant therapy >14 days.118 Extended-release IM aripiprazole lauroxil injection (Aristada): Dosage adjustment not required for patients tolerating the 441-mg dosage; however, avoid concomitant use of potent CYP2D6 inhibitors and potent CYP3A4 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosage.119 Dosage adjustment not required for concomitant use <2 weeks.119
Combination of potent, moderate, or weak CYP3A4 and CYP2D6 inhibitors (e.g., potent CYP3A4 inhibitor with moderate CYP2D6 inhibitor; moderate CYP3A4 inhibitor with moderate CYP2D6 inhibitor)	Oral aripiprazole: Reduce aripiprazole dosage to 25% of usual dosage, then adjust dosage to achieve clinical response.1 Increase back to original dosage when the CYP3A4 and/or CYP2D6 inhibitor is discontinued.1
Potent CYP3A4 inducers	Oral aripiprazole: Double dosage of aripiprazole over 1–2 weeks of concomitant therapy.1 Reduce back to original dosage over 1–2 weeks when the CYP3A4 inducer is discontinued.1 Extended-release IM aripiprazole injection (Abilify Maintena): Avoid use of potent CYP3A4 inducers for >14 days.118 Extended-release IM aripiprazole lauroxil injection (Aristada): Increase monthly aripiprazole dosage from 441 to 662 mg when used concomitantly for >2 weeks; dosage adjustment not required in patients receiving 662 or 882 mg every month.119 Dosage adjustment not required for concomitant use <2 weeks.119

Substrates of Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 2C9, 2C19, 2D6, and 3A4: Clinically important pharmacokinetic interaction unlikely; dosage adjustment not necessary.1 118 119

Specific Drugs

Drug	Interaction	Comments
Alcohol	Possible additive CNS effects118 Oral aripiprazole: No clinically important effects on gross motor skills or stimulus response118	Extended-release IM aripiprazole (Abilify Maintena): Manufacturer recommends avoiding concomitant use118 Specific recommendations concerning alcohol use not provided in the prescribing information for other oral and parenteral formulations of aripiprazole (e.g., Abilify, Aristada)1 119
Anticholinergic agents	Possible disruption of body temperature regulation1 118 119	Use with caution1 118 119
Benzodiazepines (e.g., lorazepam)	Possible increased sedative and orthostatic hypotensive effects1 118 119 Lorazepam: No clinically important effects on pharmacokinetics of either aripiprazole or lorazepam1 118 119	If concomitant use of aripiprazole and benzodiazepines considered necessary, monitor for excessive sedation and orthostatic hypotension; adjust dosages if needed1 118 119 Lorazepam: Routine dosage adjustment of aripiprazole and lorazepam not necessary1 118
Carbamazepine	Carbamazepine (potent CYP3A4 inducer) decreased peak plasma concentrations and AUCs of aripiprazole and dehydro-aripiprazole1 105 118 119	Oral aripiprazole: Double aripiprazole dosage over 1–2 weeks when carbamazepine is added; decrease back to original dosage over 1–2 weeks when carbamazepine is discontinued1 Extended-release aripiprazole (Abilify Maintena): Avoid concomitant use >14 days118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, increase aripiprazole lauroxil dosage from 441 to 662 mg monthly; no dosage adjustment necessary for 662- or 882-mg dosages119
Clarithromycin	Clarithromycin (potent CYP3A4 inhibitor) may increase AUCs of aripiprazole and its active metabolite1	Reduce oral aripiprazole to 50% of usual dosage; if used in combination with potent CYP2D6 inhibitors, reduce oral aripiprazole dosage to 25% of usual dosage1 If used in combination with potent, moderate, and weak CYP3A4 and CYP2D6 inhibitors, initially reduce oral aripiprazole dosage to 25% of usual dosage then adjust dosage based on clinical response1 Dosage adjustment not necessary when aripiprazole used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly;118 if used in combination with potent CYP2D6 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; dosage reduction not necessary in patients tolerating 441-mg dosage.119 Reduce 882 mg every 6 weeks to 441 mg every 4 weeks.119 Avoid concomitant use of potent CYP3A4 inhibitors (e.g., clarithromycin) and potent CYP2D6 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosages; no dosage adjustment necessary for 441-mg dosage, if tolerated119 Increase aripiprazole dosage when the CYP3A4 and/or CYP2D6 inhibitor is discontinued1
Dextromethorphan	No clinically important change in dextromethorphan (CYP2D6 and CYP3A4 substrate) pharmacokinetics observed1 118 119	Dextromethorphan dosage adjustment not necessary1 118 119
Escitalopram	No substantial effect on pharmacokinetics of escitalopram (CYP2C19 and CYP3A4 substrate)1 104	Escitalopram dosage adjustment not necessary1
Famotidine	Possible decreased peak concentration and AUC of aripiprazole; unlikely to be clinically important1	Aripiprazole dosage adjustment not necessary1
Fluoxetine	Fluoxetine (potent CYP2D6 inhibitor) expected to increase aripiprazole AUC1 Aripiprazole did not substantially affect fluoxetine pharmacokinetics1 104	Oral aripiprazole: Reduce aripiprazole to 50% of usual dosage; if used in combination with potent CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage; if used in combination with potent, moderate, or weak CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage then adjust to achieve clinical response; dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly; in combination with potent CYP3A4 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; no dosage adjustment necessary in patients tolerating 441-mg dosage; reduce 882 mg every 6 weeks to 441 mg every 4 weeks; dosage adjustment not necessary for concomitant use <2 weeks; avoid concomitant use of potent CYP2D6 inhibitors (e.g., fluoxetine) and potent CYP3A4 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosage119 Increase aripiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitor is discontinued1
Hypotensive agents	Possible additive hypotensive effects1 118 119	Use with caution; monitor BP and adjust dosage of antihypertensive agent(s), if necessary1 118 119
Itraconazole	Potent CYP3A4 inhibitors (e.g., itraconazole) may increase AUCs of aripiprazole and its active metabolite1	Reduce oral aripiprazole to 50% of usual dosage; if used in combination with potent CYP2D6 inhibitors, reduce oral aripiprazole dosage to 25% of usual dosage1 If used in combination with potent, moderate, and weak CYP3A4 and CYP2D6 inhibitors, initially reduce oral aripiprazole dosage to 25% of usual dosage then adjust dosage based on clinical response1 Dosage adjustment not necessary when aripiprazole used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly; if used in combination with potent CYP2D6 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; dosage reduction not necessary in patients tolerating 441-mg dosage.119 Reduce 882 mg every 6 weeks to 441 mg every 4 weeks.119 Avoid concomitant use of potent CYP3A4 inhibitors (e.g., itraconazole) and potent CYP2D6 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosages; no dosage adjustment necessary for 441-mg dosage, if tolerated119 Increase aripiprazole dosage when the CYP3A4 and/or CYP2D6 inhibitor is discontinued1
Ketoconazole	Ketoconazole (potent CYP3A4 inhibitor) substantially increased AUCs of aripiprazole and its active metabolite1	Reduce oral aripiprazole to 50% of usual dosage; if used in combination with potent CYP2D6 inhibitors, reduce oral aripiprazole dosage to 25% of usual dosage1 If used in combination with potent, moderate, and weak CYP3A4 and CYP2D6 inhibitors, initially reduce oral aripiprazole dosage to 25% of usual dosage then adjust dosage based on clinical response1 Dosage adjustment not necessary when aripiprazole used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly; if used in combination with potent CYP2D6 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; dosage reduction not necessary in patients tolerating 441-mg dosage.119 Reduce 882 mg every 6 weeks to 441 mg every 4 weeks.119 Avoid concomitant use of potent CYP3A4 inhibitors (e.g., ketoconazole) and potent CYP2D6 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosages; no dosage adjustment necessary for 441-mg dosage, if tolerated119 Increase aripiprazole dosage when the CYP3A4 and/or CYP2D6 inhibitor is discontinued1
Lamotrigine	Concomitant use with aripiprazole apparently well tolerated;92 pharmacokinetic interaction unlikely1 92	Lamotrigine dosage adjustment not necessary1 92
Lithium	Clinically important pharmacokinetic interaction unlikely1	Dosage adjustment of aripiprazole and lithium not necessary1
Omeprazole	No substantial effect on pharmacokinetics of omeprazole (CYP2C19 substrate)1	Omeprazole dosage adjustment not necessary1
Paroxetine	Paroxetine (potent CYP2D6 inhibitor) expected to increase aripiprazole AUC1 Aripiprazole did not substantially affect paroxetine pharmacokinetics1 104	Paroxetine dosage adjustment not necessary1 104 Oral aripiprazole: Reduce aripiprazole to 50% of usual dosage; if used in combination with potent CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage; if used in combination with potent, moderate, or weak CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage then adjust to achieve clinical response; dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly; in combination with potent CYP3A4 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; no dosage adjustment necessary in patients tolerating 441-mg dosage; reduce 882 mg every 6 weeks to 441 mg every 4 weeks; dosage adjustment not necessary for concomitant use <2 weeks; avoid concomitant use of potent CYP2D6 inhibitors (e.g., paroxetine) and potent CYP3A4 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosage119 Increase aripiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitor is discontinued1
Quinidine	Quinidine (potent CYP2D6 inhibitor) increased aripiprazole AUC but decreased AUC of dehydro-aripiprazole1	Oral aripiprazole: Reduce aripiprazole to 50% of usual dosage; if used in combination with potent CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage; if used in combination with potent, moderate, or weak CYP3A4 inhibitors, reduce aripiprazole dosage to 25% of usual dosage then adjust to achieve clinical response; dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder1 Extended-release aripiprazole (Abilify Maintena): If used concomitantly >14 days, reduce aripiprazole dosage from 400 to 300 mg or from 300 to 200 mg monthly; in combination with potent CYP3A4 inhibitors, reduce dosage from 400 to 200 mg or 300 to 160 mg monthly118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, reduce aripiprazole lauroxil dosage to next available lower strength; no dosage adjustment necessary in patients tolerating 441-mg dosage; reduce 882 mg every 6 weeks to 441 mg every 4 weeks; dosage adjustment not necessary for concomitant use <2 weeks; avoid concomitant use of potent CYP2D6 inhibitors (e.g., quinidine) and potent CYP3A4 inhibitors for >2 weeks in patients taking the 662- or 882-mg dosage119 Increase aripiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitor is discontinued1
Rifampin	Potent CYP3A4 inducers expected to decrease AUCs of aripiprazole and its active metabolite1	Oral aripiprazole: Double aripiprazole dosage over 1–2 weeks when rifampin is added; decrease back to original dosage over 1–2 weeks when rifampin is discontinued1 Extended-release aripiprazole (Abilify Maintena): Avoid concomitant use >14 days118 Extended-release aripiprazole lauroxil (Aristada): If used concomitantly >2 weeks, increase aripiprazole lauroxil dosage from 441 to 662 mg monthly; no dosage adjustment necessary for 662- or 882-mg dosages119
Sertraline	Aripiprazole did not substantially affect sertraline pharmacokinetics1 104 118 119	Dosage adjustment of aripiprazole and sertraline not necessary1 118 119
Valproate	Clinically important pharmacokinetic interaction unlikely1	Dosage adjustment of aripiprazole and valproate not necessary1
Venlafaxine	No effect on pharmacokinetics of venlafaxine (CYP2D6 substrate) or O-desmethylvenlafaxine1 104	Venlafaxine dosage adjustment not necessary1
Warfarin	No clinically important effect on warfarin (CYP2C9 and CYP2C19 substrate) pharmacokinetics1	Warfarin dosage adjustment not necessary1

• Importance of providing copy of written patient information (medication guide) each time aripiprazole is dispensed.1 76 77 78 118 119 Importance of advising patients to read the patient information before taking aripiprazole and each time the prescription is refilled.1 76 118 119

• Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 28 73 98 113 118 119 Inform patients and caregivers that aripiprazole is not approved for treating geriatric patients with dementia-related psychosis.1 73 98 118 119

• Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, manic or hypomanic symptoms, irritability, agitation, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1 76 77 78

• Risk of somnolence and impairment of judgment, thinking, or motor skills; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.1 118 119

• Importance of avoiding alcohol during extended-release IM aripiprazole (Abilify Maintena) therapy.118

• Importance of informing patients and caregivers about the risk of NMS; importance of immediately contacting clinician or seeking emergency medical attention if signs and symptoms of this rare but potentially life-threatening syndrome develop (e.g., high fever, muscle stiffness, sweating, fast or irregular heart beat, change in BP, confusion, kidney damage).1 118 119

• Importance of informing patients of risk of tardive dyskinesia if chronic use is contemplated.1 98 118 119 Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.98 118 119

• Risk of leukopenia/neutropenia.1 118 119 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia of need for CBC monitoring during aripiprazole therapy.1 118 119

• Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) and the need for specific monitoring for such changes.1 118 119 Importance of patients and caregivers being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness).1 118 119

• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending or shopping, binge eating) while receiving aripiprazole.123 Advise patients or their caregivers to promptly report any such urges that seem out of the ordinary; also advise patients not to abruptly stop taking aripiprazole without first consulting their clinician.123

• Risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.1 118 119

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1 98

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 108 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1 108 Importance of advising patients not to stop taking aripiprazole if they become pregnant without consulting their clinician; abruptly discontinuing antipsychotic agents may cause complications.108 Importance of advising patients not to breast-feed during aripiprazole therapy.1

• Importance of avoiding overheating or dehydration.1 118 119

• For patients taking aripiprazole orally disintegrating tablets, importance of not removing a tablet from the blister package until just before administering a dose; importance of peeling blister open with dry hands and placing tablet on tongue to dissolve and be swallowed with saliva.1

• Importance of informing patients with phenylketonuria that aripiprazole orally disintegrating 10- and 15-mg tablets (Abilify Discmelt) contain 1.12 and 1.68 mg of phenylalanine, respectively.1

• Importance of being aware that aripiprazole oral solution contains 400 mg of sucrose and 200 mg of fructose per mL.1

• Importance of informing patients of other important precautionary information.1 118 119 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

ARIPiprazole

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	5 mg/5 mL*	Abilify	Otsuka
	Tablets	2 mg*	Abilify	Otsuka
		5 mg*	Abilify	Otsuka
		10 mg*	Abilify	Otsuka
		15 mg*	Abilify	Otsuka
		20 mg*	Abilify	Otsuka
		30 mg*	Abilify	Otsuka
	Tablets, orally disintegrating	10 mg*	Abilify Discmelt	Otsuka
		15 mg*	Abilify Discmelt	Otsuka
Parenteral	For injectable suspension, extended-release, for IM use	300 mg	Abilify Maintena (available as kit containing either a single-dose vial, sterile water for injection, needles, and syringe or a prefilled dual-chamber syringe, sterile water for injection, and needles)	Otsuka (also promoted by Lundbeck)
		400 mg	Abilify Maintena (available as kit containing either a single-dose vial, sterile water for injection, needles, and syringe or a prefilled dual-chamber syringe, sterile water for injection, and needles)	Otsuka (also promoted by Lundbeck)
	Injection, for IM use only	7.5 mg/mL (9.75 mg)	Abilify	Otsuka

ARIPiprazole Lauroxil

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injectable suspension, extended-release, for IM use	441 mg/1.6 mL	Aristada (available as kit containing prefilled syringe and needles)	Alkermes
		662 mg/2.4 mL	Aristada (available as kit containing prefilled syringe and needles)	Alkermes
		882 mg/3.2 mL	Aristada (available as kit containing prefilled syringe and needles)	Alkermes