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Aripiprazole (oral and long-acting injectable [Abilify Maintena]): Drug information

Aripiprazole (oral and long-acting injectable [Abilify Maintena]): Drug information
(For additional information see "Aripiprazole (oral and long-acting injectable [Abilify Maintena]): Patient drug information" and see "Aripiprazole (oral and long-acting injectable [Abilify Maintena]): Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Increased mortality in elderly patients with dementia-related psychosis:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.

Suicidality and antidepressant drugs:

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years of age; there was a reduction in risk with antidepressant use in patients 65 years of age and older. Closely monitor all antidepressant-treated patients for clinical worsening and for the emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. The safety and efficacy of aripiprazole tablets with sensor have not been established in pediatric patients.

Brand Names: US
  • Abilify;
  • Abilify Maintena;
  • Abilify MyCite Maintenance Kit;
  • Abilify MyCite Starter Kit;
  • Abilify MyCite [DSC]
Brand Names: Canada
  • Abilify;
  • Abilify Maintena;
  • APO-ARIPiprazole;
  • Auro-ARIPiprazole;
  • MINT-Aripiprazole;
  • PMS-ARIPiprazole;
  • RIVA-ARIPiprazole;
  • SANDOZ ARIPiprazole;
  • TEVA-ARIPiprazole [DSC]
Pharmacologic Category
  • Antimanic Agent;
  • Second Generation (Atypical) Antipsychotic
Dosing: Adult

Note: Formulations: Available formulations include oral tablets and oral solution supplied as aripiprazole (base) and 2 ER IM injections: aripiprazole monohydrate and aripiprazole lauroxil (see Aripiprazole Lauroxil monograph). All doses are expressed as the equivalent amounts of aripiprazole (base).

Aripiprazole tablets are also available with an embedded device that tracks drug ingestion using a smartphone app (Abilify Mycite). Titration: Although the manufacturer’s labeling recommends waiting ≥2 weeks before increasing dose due to long half-life of aripiprazole, it may be appropriate to increase dose at 1 week for some patients (Ref).

Agitation/Aggression associated with psychiatric disorders, substance intoxication, or other organic causes

Agitation/Aggression (acute, severe) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder), substance intoxication, or other organic causes (alternative agent) (off-label use):

Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression. Other agents are used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal. Depending on presentation, may combine with a benzodiazepine (Ref).

Oral: Initial: 10 to 15 mg; may repeat based on response and tolerability every 2 hours up to 30 mg/day (Ref).

Agitation/Aggression and psychosis associated with dementia, severe or refractory

Agitation/Aggression and psychosis associated with dementia, severe or refractory (alternative agent) (off-label use):

Note: For short-term adjunctive use while addressing underlying causes of severe symptoms (Ref).

Oral: Initial: 2 to 5 mg once daily; may increase dose based on response and tolerability in 5 mg increments at intervals ≥1 week up to 15 mg once daily. In patients without a clinically significant response after an adequate trial (eg, up to 4 weeks), taper and withdraw therapy. Only continue in patients with a demonstrated benefit and attempt to taper and withdraw at regular intervals; first taper attempt should occur ≤4 months of initiation (Ref).

Note: Patients with dementia with Lewy bodies are at increased risk for severe adverse reactions; caution is required even with low doses (Ref).

Bipolar disorder

Bipolar disorder:

Oral: Acute mania or episodes with mixed features (labeled use), acute hypomania (off-label use), and maintenance treatment (labeled use, formulation specific) as monotherapy or adjunctive therapy: Initial: 10 to 15 mg once daily; may increase dose based on response and tolerability in 5 to 10 mg/day increments at intervals of ≥1 week up to a maximum of 30 mg/day (Ref). Note: Some experts suggest higher initial doses of up to 30 mg/day (Ref). For maintenance treatment, continue dose and combination regimen that was used to achieve control of the acute episode (Ref).

IM, ER injectable suspension (aripiprazole monohydrate) (alternative agent): Note: Establish tolerability with oral aripiprazole prior to initiation of ER injection; due to the prolonged half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

Single injection start: 400 mg once monthly (doses should be separated by ≥26 days). Continue (overlap) oral aripiprazole or other oral antipsychotic for 14 days during initiation of the ER injection.

Double injection start: Initial: Administer a single oral aripiprazole 20 mg dose, plus two 400 mg injections in separate injection sites (eg, right deltoid and left gluteal muscle). Maintenance: 400 mg once monthly (doses should be separated by ≥ 26 days) (Canadian product monograph).

Dosage adjustment of ER injection for adverse effects: Consider reducing dose to 300 mg once monthly.

Missed doses of ER injection:

Second or third doses missed:

>4 weeks but <5 weeks since last dose: Administer next dose as soon as possible.

>5 weeks since last dose: Administer oral aripiprazole for 14 days with next injection or administer 1 oral aripiprazole dose of 20 mg plus 2 aripiprazole 400 mg IM injections in separate injection sites (eg, right deltoid and left gluteal muscle) (Canadian product monograph); adjust oral dose as needed based on response and tolerability.

Fourth or subsequent doses missed:

>4 weeks but <6 weeks since last dose: Administer next dose as soon as possible.

>6 weeks since last dose: Administer oral aripiprazole for 14 days with next injection or administer 1 oral aripiprazole dose of 20 mg plus 2 aripiprazole 400 mg IM injections in separate injection sites (eg, right deltoid and left gluteal muscle) (Canadian product monograph); adjust oral dose as needed based on response and tolerability.

Delusional disorder

Delusional disorder (off-label use):

Note: Dosing based on expert opinion:

Oral: Initial: 2 to 5 mg once daily; gradually increase to 10 mg/day; if needed, may further increase dose at intervals of ≥1 week based upon response and tolerability up to 30 mg/day (Ref).

Delusional infestation

Delusional infestation (delusional parasitosis) (off-label use):

Note: Dosing based on expert opinion:

Oral: Initial: 2 mg once daily; may increase dose gradually based on response and tolerability in 2 mg increments at intervals ≥2 weeks up to 12 mg/day (Ref). Some patients may require doses up to 30 mg/day for optimal response. After achieving adequate response, maintain for ≥1 to 3 months before attempting to taper and discontinue (Ref).

Huntington disease-associated chorea

Huntington disease-associated chorea (alternative agent) (off-label use):

Oral: Initial: 2 mg once daily; may increase dose gradually based on response and tolerability up to a usual range of 7.5 to 15 mg/day (Ref).

Major depressive disorder, treatment resistant

Major depressive disorder (unipolar), treatment resistant (adjunctive therapy with antidepressant):

Oral: Initial: 2 to 5 mg/day; may increase dose based on response and tolerability in 5 mg increments at intervals ≥1 week up to a manufacturer's maximum of 15 mg/day. A further increase up to 20 mg/day may be necessary in some patients for optimal response (Ref).

Obsessive-compulsive disorder, treatment resistant

Obsessive-compulsive disorder, treatment resistant (adjunctive therapy to antidepressants) (off-label use):

Oral: Initial: 5 mg once daily; may increase dose gradually based on response and tolerability in 5 mg increments at intervals ≥1 week up to 15 mg/day (Ref).

Schizophrenia

Schizophrenia:

Oral: Initial: 5 to 15 mg once daily; may increase dose based on response and tolerability in 5 mg increments at an interval of ≥4 days with initial low dose (eg, 5 mg) and at intervals ≥1 week thereafter up to a maximum of 30 mg/day (Ref).

IM, ER injectable suspension (aripiprazole monohydrate): Note: Establish tolerability with oral aripiprazole prior to initiation of the ER injection; due to the prolonged half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

Single injection start: 400 mg once monthly (doses should be separated by ≥26 days). Continue (overlap) oral aripiprazole or other oral antipsychotic for 14 days during initiation of the ER injection.

Double injection start: Initial: Administer a single oral aripiprazole 20 mg dose, plus two 400 mg injections in separate injection sites (eg, right deltoid and left gluteal muscle). Maintenance: 400 mg once monthly (doses should be separated by ≥26 days) (Canadian product monograph).

Dosage adjustment of ER injection for adverse effects: Consider reducing dose to 300 mg once monthly.

Missed doses of ER injection:

Second or third doses missed:

>4 weeks but <5 weeks since last dose: Administer next dose as soon as possible.

>5 weeks since last dose: Administer oral aripiprazole for 14 days with next injection or administer 1 oral aripiprazole dose of 20 mg plus 2 aripiprazole 400 mg IM injections in separate injection sites (eg, right deltoid and left gluteal muscle) (Canadian product monograph); adjust oral dose as needed based on response and tolerability.

Fourth or subsequent doses missed:

>4 weeks but <6 weeks since last dose: Administer next dose as soon as possible.

>6 weeks since last dose: Administer oral aripiprazole for 14 days with next injection or [Canadian dosing] administer 1 oral aripiprazole dose of 20 mg plus 2 aripiprazole 400 mg IM injections in separate injection sites (eg, right deltoid and left gluteal muscle) (Canadian product monograph); adjust oral dose as needed based on response and tolerability.

Tourette syndrome

Tourette syndrome (off-label use): Oral: Initial: 2.5 mg once daily; may increase dose based on response and tolerability in 2.5 mg increments at intervals ≥3 days up to 30 mg/day (Ref).

Dosing conversions:

Orally disintegrating tablets to oral tablet: Orally disintegrating tablets may be substituted for the oral tablet on a mg-per-mg basis.

Oral solution to oral tablet: Oral solution may be substituted for the oral tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should be given 25 mg oral solution.

Dosage adjustment based on CYP2D6 metabolizer status:

Oral: Aripiprazole dose should be reduced to 50% of the usual dose in known CYP2D6 poor metabolizers; subsequently adjust dose for favorable response and tolerability.

IM, ER injectable suspension (aripiprazole monohydrate):

Single injection start: Reduce aripiprazole dose to 300 mg once monthly in known CYP2D6 poor metabolizers; subsequently adjust dose according to response and tolerability.

Double injection start: Reduce initial 2 aripiprazole doses to 300 mg each and reduce monthly aripiprazole dose to 300 mg once monthly in known CYP2D6 poor metabolizers; subsequently adjust dose according to response and tolerability (Canadian product monograph).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Discontinuation of therapy:

Oral: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).

Long-acting injection: Switching to other treatments is generally advised if side effects are intolerable or treatment is not effective. However, if a patient insists on stopping treatment, gradual dose reduction to avoid withdrawal reactions is generally not needed with long-acting injectable antipsychotics. The risk of withdrawal symptoms from discontinuation of long-acting injectables is low because the rate of drug elimination is slow. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (Ref).

Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Ref). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Ref).

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).

Hemodialysis, intermittent (thrice weekly): Unlikely to be dialyzed (highly protein bound; large Vd): No supplemental dose or dosage adjustment necessary (Ref).

Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound; large Vd): No dosage adjustment necessary (Ref).

CRRT: No dosage adjustment necessary (Ref).

PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Pediatric

(For additional information see "Aripiprazole (oral and long-acting injectable [Abilify Maintena]): Pediatric drug information")

Note: Oral solution may be substituted for the oral tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should be given 25 mg oral solution. Orally disintegrating tablets (Abilify Discmelt) are bioequivalent to the immediate release tablets (Abilify). Immediate release and extended release parenteral products are not interchangeable.

Autism; treatment of associated irritability

Autism; treatment of associated irritability (including aggression, deliberate self-injurious behavior, temper tantrums, and quickly changing moods): Children and Adolescents 6 to 17 years: Oral: Initial: 2 mg daily for 7 days, followed by 5 mg daily; subsequent dose increases may be made in 5 mg increments every ≥7 days, up to a maximum daily dose of 15 mg/day.

Bipolar I disorder

Bipolar I disorder (acute mania or episodes with mixed features): Children and Adolescents 10 to 17 years: Oral: Initial: 2 mg daily for 2 days, followed by 5 mg daily for 2 days with a further increase to target dose of 10 mg daily; subsequent dose increases may be made in 5 mg increments, up to a maximum daily dose of 30 mg/day. Note: The safety of doses >30 mg/day has not been evaluated.

Conduct disorder; aggression

Conduct disorder (CD); aggression: Limited data available: Children ≥6 years and Adolescents: Oral: Initial: Patient weight <25 kg: 1 mg/day; 25 to 50 kg: 2 mg/day; 51 to 70 kg: 5 mg/day; >70 kg: 10 mg/day; may titrate after 2 weeks to clinical effectiveness; maximum daily dose: 15 mg/day. Dosing based on an open-label, prospective study (n=23; age: 6 to 17 years) which evaluated pharmacokinetics and effectiveness in patients with a primary diagnosis of CD (with or without comorbid ADHD); results showed improvement in CD symptom scores with only minor improvements in cognition (Ref).

Pervasive Developmental Disorder Not Otherwise Specified or Asperger Disorder; treatment of associated irritability

Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) or Asperger Disorder; treatment of associated irritability (aggression, self-injury, tantrums): Limited data available: Children ≥4 years and Adolescents: Oral:

Preschool age: Initial dose: 1.25 mg/day with titration every ≥5 days in 1.25 mg/day increments as tolerated or clinically indicated (Ref).

Prepubertal children: Initial dose: 1.25 to 2.5 mg/day with titration every 3 to 5 days in 1.25 to 2.5 mg/day increments as tolerated or clinically indicated; maximum daily dose: 15 mg/day (Ref).

Adolescents: Initial dose: 2.5 to 5 mg/day with titration every 5 days in 2.5 to 5 mg/day increments as tolerated or clinically indicated; doses >5 mg/day were divided twice daily; if sleep disorder was reported, the dose was given in morning and/or at lunchtime (Ref); maximum daily dose: 15 mg/day (Ref).

An open-labeled, pilot study (n=25; mean age: 8.6 years; range: 5 to 17 years) reported an 88% response with a mean final dose of 7.8 mg/day (range: 2.5 to 15 mg/day) (Ref). A retrospective, noncontrolled, open-label study of 34 patients with PDD (mean age: 10.2 years; range: 4 to 15 years) included 10 patients with autistic disorder and 24 patients with PDD-NOS reported a mean final dose: 8.1 ± 4.9 mg/day and an overall response rate of 32.4% (29.2% in patients with PDD-NOS) (Ref). In a retrospective chart review of children and adolescents with developmental disability and a wide range of psychiatric disorders (n=32; age: 5 to 19 years), a mean starting dose of aripiprazole of 7.1 ± 0.32 mg/day and a mean maintenance dose of 10.55 ± 6.9 mg/day was used; a response rate of 56% was reported for the overall population (Ref).

Schizophrenia

Schizophrenia: Adolescents 13 to 17 years: Oral: Initial: 2 mg daily for 2 days, followed by 5 mg daily for 2 days with a further increase to target dose of 10 mg daily; subsequent dose increases may be made in 5 mg increments up to a maximum daily dose of 30 mg/day. Note: 30 mg/day was not found to be more effective than the 10 mg/day dose.

Tourette syndrome, tic disorders

Tourette syndrome, tic disorders: Children ≥6 years and Adolescents: Oral:

Patient weight <50 kg: Initial: 2 mg daily for 2 days, then increase to target dose of 5 mg/day; in patients not achieving optimal control, dose may be further titrated at weekly intervals up to 10 mg/day.

Patient weight ≥50 kg: Initial: 2 mg daily for 2 days, then increase to 5 mg/day for 5 days, then increase to target dose of 10 mg/day on day 8 of therapy; in patients not achieving optimal control, dose may be further titrated at weekly intervals in 5 mg/day increments up to 20 mg/day.

Discontinuation of therapy: Children and Adolescents: American Academy of Child and Adolescent Psychiatry (AACAP), American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), National Institute for Health and Care Excellence (NICE), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (Ref); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Ref). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months and the APA guidelines recommend reducing the dose by 10% each month (Ref). Continuing antiparkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Ref). When switching antipsychotics, three strategies have been suggested: Cross titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited and results are conflicting (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment based on CYP2D6 metabolizer status:

Oral: Children and Adolescents: Aripiprazole dose should be reduced to 50% of the usual dose in CYP2D6 poor metabolizers and to 25% of the usual dose in poor metabolizers receiving a concurrent strong CYP3A4 inhibitor; subsequently adjust dose for favorable clinical response.

Dosing: Kidney Impairment: Pediatric

No dosage adjustment required.

Dosing: Hepatic Impairment: Pediatric

No dosage adjustment required.

Dosing: Older Adult

Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient with late-onset schizophrenia or psychosis. Titrate dosage slowly and monitor carefully (Ref).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Prefilled Syringe, Intramuscular:

Abilify Maintena: 300 mg (1 ea); 400 mg (1 ea)

Solution, Oral:

Generic: 1 mg/mL (150 mL)

Suspension Reconstituted ER, Intramuscular:

Abilify Maintena: 300 mg (1 ea); 400 mg (1 ea)

Tablet, Oral:

Abilify: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Abilify MyCite: 2 mg [DSC], 5 mg [DSC], 10 mg [DSC], 15 mg [DSC], 20 mg [DSC], 30 mg [DSC] [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Generic: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Tablet Disintegrating, Oral:

Generic: 10 mg, 15 mg

Tablet Therapy Pack, Oral:

Abilify MyCite Maintenance Kit: 2 mg (30 ea); 5 mg (30 ea); 10 mg (30 ea); 15 mg (30 ea); 20 mg (30 ea); 30 mg (30 ea) [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Abilify MyCite Starter Kit: 2 mg (30 ea); 5 mg (30 ea); 10 mg (30 ea); 15 mg (30 ea); 20 mg (30 ea); 30 mg (30 ea) [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Generic Equivalent Available: US

May be product dependent

Dosage Forms Considerations

Oral solution contains fructose 200 mg and sucrose 400 mg per mL.

Abilify MyCite is a drug-device combination product comprised of aripiprazole tablets embedded with an Ingestible Event Marker (IEM) sensor and packaged with a wearable sensor patch intended to track drug ingestion.

Abilify MyCite Kit is packaged with seven 1-component patches (electronic recording component is contained in each patch).

Abilify MyCite Starter Kit is packaged with 1 sensor pod and 7 adhesive patches (electronic recording component is contained in the pod).

Abilify MyCite Maintenance Kit is packaged with 7 adhesive patches (for use with the sensor pod supplied separately).

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension Reconstituted ER, Intramuscular:

Abilify Maintena: 300 mg (1 ea); 400 mg (1 ea)

Tablet, Oral:

Abilify: 2 mg, 5 mg [contains corn starch, fd&c blue #2 (indigo carm) aluminum lake]

Abilify: 10 mg, 15 mg, 20 mg, 30 mg [contains corn starch]

Generic: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Abilify: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021436s044s045,021713s035s036,021729s027s028,021866s029s030lbl.pdf#page=77

Abilify Maintena: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202971s013lbl.pdf#page=52

Abilify MyCite: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207202s002s004lbl.pdf#page=48

Administration: Adult

IM: Extended release: For IM use only; do not administer SubQ or IV. Inject slowly into deltoid or gluteal muscle using the appropriate provided needle; for nonobese patients, use the 1-inch (25 mm) needle with deltoid administration or the 1.5-inch (38 mm) needle with gluteal administration; for obese patients, use the 1.5-inch (38 mm) needle with deltoid administration or the 2-inch (51 mm) needle with gluteal administration. Do not massage muscle after administration. Rotate injection sites between the 2 deltoid or gluteal muscles. Administer monthly (doses should be separated by ≥26 days).

Oral: Administer with or without food.

Orally disintegrating tablet: Remove from foil blister by peeling back (do not push tablet through the foil). Place tablet in mouth immediately upon removal. Tablet dissolves rapidly in saliva and may be swallowed without liquid. If needed, can be taken with liquid. Do not split tablet.

Tablet with sensor: Swallow tablets whole; do not divide, crush, or chew. Each tablet is embedded with an ingestible event marker (IEM). The patch that accompanies the tablets is a wearable sensor that detects a signal from the IEM sensor after the tablet is ingested and transmits data to a smartphone within 30 minutes to 2 hours of ingestion. If the detection system fails (ie, tablet is not detected after ingestion), do not repeat the dose. Before use, ensure that the patient is capable and willing to use smartphones and apps, that the app is compatible with the patient's specific smartphone, and that the smartphone is paired with the patch prior to use. There are 2 types of patches; refer to corresponding instructions for use within the app. Apply the 1-component patch only when instructed by the app to the left side of the body just above the lower edge of the rib cage. Apply the 2-component patch only when instructed by the app to the left or right side of the body just above the lower edge of the rib cage. Do not place the patch in areas where the skin is scraped, cracked, inflamed, or irritated, or in a location that overlaps the area of the most recently removed patch. Instruct patients to keep the patch on when showering, swimming, or exercising. The patch should be changed weekly or sooner as needed. The app will prompt patient to change the patch and will direct patient to apply and remove the patch correctly. Patients undergoing an MRI need to remove their patch and replace with a new one as soon as possible. If there is skin irritation, instruct patients to remove the patch. Refer to the information provided in the product packaging and electronic instructions for use with the Mycite app.

Administration: Pediatric

Oral (all dosage forms): May be administered with or without food.

Orally disintegrating tablet: Do not remove tablet from blister pack until ready to administer; do not push tablet through foil (tablet may become damaged); peel back foil to expose tablet; use dry hands to remove tablet and place immediately on tongue. Tablet dissolves rapidly in saliva and may be swallowed without liquid; if needed, tablet can be taken with liquid. Do not split tablet.

Use: Labeled Indications

Oral:

Bipolar disorder: As monotherapy or as an adjunct to lithium or valproate for acute treatment of mania or episodes with mixed features associated with bipolar disorder and maintenance treatment (tablet with sensor only) of bipolar disorder.

Irritability associated with autistic disorder: Treatment of irritability associated with autistic disorder (tablet, orally disintegrating tablet, and oral solution only) in children and adolescents.

Major depressive disorder (unipolar), treatment resistant: Adjunctive treatment of unipolar major depressive disorder in patients with an inadequate response to prior antidepressant therapy.

Schizophrenia: Treatment of schizophrenia.

Tourette disorder: Treatment of Tourette disorder (tablet, orally disintegrating tablet, and oral solution only) in children and adolescents.

Injection: Extended release:

Bipolar disorder: Maintenance monotherapy treatment of bipolar disorder.

Schizophrenia: Treatment of schizophrenia.

Use: Off-Label: Adult

Agitation/aggression (acute, severe) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder), substance intoxication, or other organic causes; Agitation/aggression and psychosis associated with dementia, severe or refractory; Delusional disorder; Delusional infestation (delusional parasitosis); Huntington disease-associated chorea; Obsessive-compulsive disorder, treatment resistant; Tourette syndrome

Medication Safety Issues
Sound-alike/look-alike issues:

Abilify may be confused with Ambien

ARIPiprazole may be confused with proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, RABEprazole)

Older Adult: High-Risk Medication:

Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Use may be appropriate in geriatric patients with schizophrenia, bipolar disorder, other mental health conditions, or for short-term use as an antiemetic during chemotherapy, but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).

Other safety issues:

There are two ER formulations available for IM administration: Aripiprazole monohydrate (Abilify Maintena) and aripiprazole lauroxil (Aristada and Aristada Initio).

Adverse Reactions (Significant): Considerations
Activating/sedating effects

Activating/sedating effects: Both activating effects (eg, akathisia, restlessness) and sedating effects (eg, sedated state, drowsiness) may occur with aripiprazole and may lead to nonadherence or discontinuation. Individual patient experience can vary depending on the person's sensitivity toward activation or sedation and the dose used (Ref).

Mechanism: Dose related; sedation is believed to be due to H1 antagonism leading to potential CNS depressant effects; aripiprazole is considered to display modest antagonism at H1 receptors (Ref).

Risk factors:

• Young age (in general, children and adolescents appear to be at higher risk for sedation due to antipsychotics compared to adults (Ref); in studies that included aripiprazole in children and adolescents, younger age has been associated with activating symptoms and higher age has been associated with sedating symptoms) (Ref).

• Specific antipsychotic (aripiprazole is generally considered to be minimally sedating at usual therapeutic doses in comparison with other antipsychotics) (Ref).

Dyslipidemia

Antipsychotics are associated with dyslipidemia in adult and pediatric patients, which is a component of the metabolic syndrome observed with this pharmacologic class. Aripiprazole is associated with a low risk of causing lipid abnormalities; however, hypertriglyceridemia and hypercholesterolemia have been observed (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; metabolic alterations from antipsychotics can develop in as short as 3 months after initiation (Ref).

Risk factors:

• Schizophrenia (regardless of medication use) is associated with a higher rate of morbidity/mortality compared to the general population, primarily due to cardiovascular disease (Ref).

• Specific antipsychotic: Clozapine and olanzapine are associated with a high risk of hyperlipidemia while aripiprazole and ziprasidone are associated with the lowest risk (Ref).

Extrapyramidal symptoms

Aripiprazole may cause extrapyramidal symptoms (EPS), also known as drug-induced movement disorders, particularly akathisia in all ages (Ref). Antipsychotics can cause 4 main EPS: Drug-induced parkinsonism, akathisia, acute dystonia, and tardive dyskinesia (Ref). EPS presenting as dysphagia, esophageal dysmotility, or aspiration have also been reported with antipsychotics, which may not be recognized as EPS (Ref).

Mechanism: EPS: Dose related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways (as either antagonists or as a partial agonist, such as aripiprazole) (Ref). Akathisia: Mechanism not completely understood, but possibly associated with the low activity of dopaminergic projections from the midbrain to the ventral striatum and imbalance between the dopamine and serotonin neurotransmitter system (Ref). Tardive dyskinesia: Time-related (delayed); results from chronic exposure to dopamine 2 receptor antagonists leading to up-regulation of these receptors over time; aripiprazole has partial agonistic activity at the D2 receptor; however, it has one of the highest D2 receptor affinities among the antipsychotic agents (Ref).

Onset:

Antipsychotics in general:

Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (and even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).

Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).

Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases and within 3 months in 90% of cases (Ref).

Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a dopamine 2 receptor antagonist, and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom stabilization and then a chronic waxing and waning of symptoms (Ref).

Esophageal dysfunction (associated with EPS): Varied; ranges from weeks to months following initiation (Ref).

Risk factors:

EPS (in general):

• Prior history of EPS (Ref)

• Higher doses (Ref)

• Younger age (in general, children and adolescents are usually at higher risk for EPS compared to adults) (Ref)

• Specific antipsychotic: Aripiprazole is usually associated with a lower risk of EPS, with the possible exception of akathisia (Ref).

Acute dystonia:

• Males (Ref)

• Young age (Ref)

Drug-induced parkinsonism:

• Females (Ref)

• Older patients (Ref)

Akathisia:

• Higher antipsychotic dosages (Ref)

• Polypharmacy (Ref)

• Mood disorders (Ref)

• Females (Ref)

• Older patients (Ref)

Tardive dyskinesia:

• Age >55 year (Ref)

• Cognitive impairment (Ref)

• Concomitant treatment with anticholinergic medications (Ref)

• Diabetes (Ref)

• Diagnosis of schizophrenia or affective disorders (Ref)

• Female sex (Ref)

• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)

• History of extrapyramidal symptoms (Ref)

• Substance misuse or dependence (Ref)

• Race (White or African descent). Note: Although early literature supported race as a potential risk factor for tardive dyskinesia (Morgenstern 1993), newer studies have challenged this assertion (Ref).

Esophageal dysfunction (associated with EPS):

• Certain comorbidities such as neurologic degenerative disease, dementia, stroke, Parkinson disease, or myasthenia gravis (Ref)

• Older adults >75 years of age (may be risk factor due to age related muscle atrophy, cognitive impairment, reduced esophageal peristalsis) (Ref)

Hematologic abnormalities

Leukopenia and neutropenia have been reported with aripiprazole (Ref). Agranulocytosis has been reported with other atypical antipsychotics and, per the manufacturer's labeling, has also been reported with aripiprazole.

Mechanism: Non-dose-related; likely idiosyncratic (Ref).

Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be insidious (Ref).

Risk factors:

• History of drug-induced leukopenia/neutropenia and preexisting low white blood cell count/absolute neutrophil count

• Older adults (Ref)

Hyperglycemia

Antipsychotics are associated with hyperglycemia, to varying degrees, which is a component of the metabolic syndrome observed with this pharmacologic class. Aripiprazole is associated with a low risk of causing metabolic alterations; however, glycemic abnormalities ranging from mild insulin resistance or hyperglycemia to new-onset diabetes mellitus, diabetes mellitus with hyperosmolar coma, and diabetic ketoacidosis, including fatal cases, have been observed very rarely (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; new-onset diabetes has been observed within first 3 months to a median onset of 3.9 years (Ref).

Risk factors:

Antipsychotics in general:

• African American race (Ref)

• Males (Ref)

• Age <35 years (Ref)

• Preexisting obesity, poor exercise habits, or other risk factors for diabetes, including family history of diabetes (Ref)

• Exposure to other agents that also increase the risk of hyperglycemia (Ref)

• Type 2 diabetes mellitus: Extended exposure (mean: 17.2 months) in pediatric patients 10 to 18 years (Ref)

• Specific antipsychotic: Metabolic disturbances appear to be the greatest with clozapine and olanzapine and lowest with aripiprazole (Ref)

Impulse control disorders

Aripiprazole has been associated with an increased risk of developing impulse control disorders, which primarily manifests as pathological gambling, although other reported behaviors include hypersexuality, compulsive buying, compulsive eating, and/or other intense urges (Ref).

Mechanism: Non-dose-related; may be due to aripiprazole’s partial dopamine agonist activity in brain circuits regulating reward pathways such as the mesolimbic circuitry (Ref).

Onset: Varied; case reports and case series of aripiprazole-associated pathological gambling suggest that the onset occurs between a few days and a few months after initiation, with some cases occurring only after an increase in dosage (Ref).

Risk factors:

• History of impulse control disorders and gambling behaviors (Ref)

• The depot formulation (aripiprazole lauroxil) may be associated with an increased risk compared to oral aripiprazole (Ref)

Mortality in older adults

Older adults with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo (Ref). In addition, an increased incidence of cerebrovascular effects (eg, cerebrovascular accident, transient ischemic attacks), including fatalities, have been reported in placebo-controlled aripiprazole trials in older adults with dementia-related psychosis, per the manufacturer's labeling. Of note, aripiprazole is not approved for the treatment of dementia-related psychosis.

Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, and extrapyramidal effects that may increase the risk of falls, aspirations, and pneumonia (Ref).

Risk factors:

Antipsychotics in general:

• Higher antipsychotic dosage (Ref)

• Dementia-related psychosis (eg, Lewy body dementia, Parkinson disease dementia)

• Older adults

Neuroleptic malignant syndrome

All antipsychotics have been associated with neuroleptic malignant syndrome (NMS), although the incidence is less with second-generation (atypical) antipsychotics compared to first-generation (typical) antipsychotics. There are case reports of NMS with aripiprazole, including monotherapy. Some data suggest that NMS induced by certain second-generation antipsychotics, including aripiprazole, may present with milder or atypical features more frequently compared to NMS induced by other agents; these atypical features include less intense extrapyramidal symptoms or less extreme fever (Ref).

Mechanism: Non-dose-related; idiosyncratic. Believed to be due to a reduction in CNS dopaminergic tone, along with the dysregulation of autonomic nervous system activity (Ref).

Onset: Varied; in general, most patients develop NMS within 2 weeks of initiating an antipsychotic, and in some patients, prodromal symptoms emerge within hours of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref). However, there are many cases of NMS occurring months after stable therapy, including a report of NMS developing 1 year after treatment with aripiprazole (Ref).

Risk factors:

Antipsychotics in general:

• Males (twice as likely to develop NMS compared to females) (Ref)

• Dehydration (Ref)

• High-dose antipsychotic treatment (Ref)

• Concomitant lithium or benzodiazepine (potential risk factors) (Ref)

• Catatonia (Ref)

• Polypharmacy (Ref)

• Pharmacokinetic interactions (Ref)

• Intramuscular administration (Ref)

• Rapid dosage escalation (Ref)

• Psychomotor agitation (Ref)

Sexual dysfunction

Antipsychotics have been associated with sexual disorder in both males and females. Antipsychotic treatment has been associated with effects on all phases of sexual activity (libido, arousal, and orgasm); however, many patients with schizophrenia experience more frequent sexual dysfunction, with or without antipsychotic treatment. Conversely, there are also case reports of hypersexuality,related to impulse control disorders, occurring with use (Ref).

Mechanism: Antipsychotic-induced sexual dysfunction has been attributed to many potential mechanisms, including dopamine receptor antagonism, dopamine D2 receptor antagonism in the hypothalamic infundibular system causing hyperprolactinemia, histamine receptor antagonism, cholinergic receptor antagonism, and alpha-adrenergic receptor antagonism. Of note, in adults, aripiprazole is associated with a minimal risk of causing hyperprolactinemia (Ref).

Risk factors:

• Hyperprolactinemia (although a correlation with sexual dysfunction has been observed, a relationship has not been confirmed) (Ref).

• Schizophrenia (the prevalence of antipsychotic-induced sexual dysfunction in patients with schizophrenia is high [~50% to 60% compared with 31% of males in the general population]) (Ref).

• Specific antipsychotic: Aripiprazole is associated with lower rates of sexual dysfunction relative to other antipsychotics (Ref).

Temperature dysregulation

Antipsychotics may impair the body's ability to regulate core body temperature, which may cause a potentially life-threatening heatstroke during predisposing conditions such as a heat wave or strenuous exercise. There are also several case reports of potentially life-threatening hypothermia associated with aripiprazole use (Ref).

Mechanism: Non-dose-related; idiosyncratic. Exact mechanism is unknown; however, body temperature is regulated by the hypothalamus with complex involvement of the dopamine, serotonin, and norepinephrine neurotransmitters. D2 antagonism may cause an increase in body temperature, while 5-HT2A (serotonin) receptor antagonism and 5-HT1 receptor agonism may cause a decrease in body temperature. Aripiprazole is a partial agonist at D2 receptors, an antagonist at 5-HT2A receptor, and a partial agonist at 5-HT1A receptor. In addition, antagonism of peripheral alpha-adrenergic receptors has also been suggested as a factor in the hypothermic effect, by inhibiting peripheral responses to cooling (vasoconstriction and shivering) (Ref).

Onset: Hypothermia: Varied; antipsychotic-induced hypothermia cases indicate a typical onset in the period shortly after initiation of therapy or a dosage increase (first 7 to 10 days) (Ref).

Risk factors:

Heat stroke:

• Psychiatric illness (regardless of medication use) (Ref)

• Dehydration (Ref)

• Strenuous exercise (Ref)

• Heat exposure (Ref)

• Concomitant medications possessing anticholinergic effects (Ref)

Hypothermia:

• In general, predisposing risk factors include: Older adults, cerebrovascular accident, preexisting brain damage, hypothyroidism, malnutrition, shock, sepsis, adrenal insufficiency, diabetes, disability, burns, exfoliative dermatitis, benzodiazepine use, alcohol intoxication, kidney or liver failure (Ref).

• Schizophrenia (regardless of antipsychotic use) (Ref)

Weight gain

Aripiprazole may cause significant weight gain (increase of >7% from baseline), particularly in pediatric patients, which is a component of the metabolic syndrome observed with this pharmacologic class (Ref).

Mechanism: Multiple proposed mechanisms, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects explained by differing affinity of antipsychotics at these receptors (Ref). Aripiprazole displays a low affinity for histamine H1 receptors, which may account for the relatively low risk of weight gain associated with aripiprazole (Ref).

Onset: Varied; antipsychotic-induced weight gain usually occurs rapidly in the initial period following initiation, then gradually decreases and flattens over several months with patients continuing to gain weight in the long term (Ref).

Risk factors:

• Family history of obesity (Ref)

• Parental BMI (Ref)

• Children and adolescents (Ref)

• Rapid weight gain in the initial period: Younger age, lower baseline BMI, more robust response to antipsychotic, and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)

• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)

• Schizophrenia (regardless of medication) is associated with a higher prevalence of obesity compared to the general population due to components of the illness such as negative symptoms, sedentary lifestyles, and unhealthy diets (Ref)

• Specific antipsychotic: In adults, aripiprazole is considered to have a minimal or low risk for weight gain; clozapine and olanzapine are considered to have high propensity (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Unless otherwise noted, frequency of adverse reactions is shown as reported for adult patients receiving aripiprazole monotherapy. Spectrum and incidence of adverse effects similar in children; exceptions noted when incidence is much higher in children.

IM:

>10%:

Endocrine & metabolic: Decreased HDL cholesterol (14%), increased LDL cholesterol (10% to 14%), increased serum cholesterol (4% to 22%), increased serum triglycerides (7% to 27%), weight gain (17% to 22%) (table 1)

Aripiprazole: Adverse Reaction: Weight Gain (IM)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

Comments

22%

9%

Adults

IM injection

Schizophrenia

144

141

≥7% of body weight

17%

7%

Adults

IM injection

Schizophrenia

167

172

≥7% of body weight

Nervous system: Akathisia (dose-related; 2% to 12%) (table 2), headache (12%)

Aripiprazole: Adverse Reaction: Akathisia (IM)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

2%

0%

Adults

IM injection

Agitation associated with schizophrenia or bipolar mania

501

220

12%

4%

Adults

IM injection

Schizophrenia

N/A

N/A

11%

4%

Adults

IM injection

Schizophrenia

167

172

1% to 10%:

Cardiovascular: Orthostatic hypotension (3%), tachycardia (≤2%)

Endocrine & metabolic: Increased serum glucose (8%), weight loss (4%)

Gastrointestinal: Abdominal distress (2%), constipation (10%), diarrhea (3%), nausea (9%), vomiting (3%), xerostomia (4%)

Hematologic & oncologic: Neutropenia (6%) (table 3)

Aripiprazole: Adverse Reaction: Neutropenia (IM)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

6%

2%

Adults

IM injection

Schizophrenia

Local: Injection-site reaction (≤1%; including erythema, induration, inflammation, hemorrhage, pruritus, rash, swelling), pain at injection site (5%)

Nervous system: Anxiety (≥1%), dizziness (4% to 8%), drowsiness (7%) (table 4), extrapyramidal reaction (10%), fatigue (dose-related; 1% to 2%), insomnia (≥1%), sedated state (3% to 5%), restlessness (≥1%), tremor (dose-related; 3%)

Aripiprazole: Adverse Reaction: Drowsiness (IM)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

7%

4%

Adults

IM injection

Agitation associated with schizophrenia or bipolar mania

501

220

Neuromuscular & skeletal: Arthralgia (4%), back pain (4%), dystonia (2%), musculoskeletal pain (3%), myalgia (4%)

Respiratory: Nasal congestion (2%), upper respiratory tract infection (4%)

<1%:

Cardiovascular: Abnormal T waves on ECG, bradycardia, chest discomfort, hypertension, increased blood pressure, presyncope, prolonged QT interval on ECG, sinus tachycardia, syncope

Endocrine & metabolic: Decreased serum cholesterol, decreased serum triglycerides, hyperinsulinism, hyperprolactinemia, increased libido, obesity

Gastrointestinal: Bruxism, decreased appetite, dysgeusia, dyspepsia, upper abdominal pain

Genitourinary: Delayed ejaculation, glycosuria, pollakiuria, urinary incontinence

Hematologic & oncologic: Thrombocytopenia

Hepatic: Abnormal hepatic function tests, hepatotoxicity

Hypersensitivity: Hypersensitivity reaction, swollen tongue

Nervous system: Abnormal gait, aggressive behavior, agitation, hypersomnia, irritability, lethargy, memory impairment, panic attack, psychotic reaction, seizure, suicidal ideation, trismus

Neuromuscular & skeletal: Bradykinesia, dystonia (oromandibular), increased creatinine phosphokinase in blood specimen, joint stiffness, muscle twitching, rhabdomyolysis

Ophthalmic: Blurred vision, oculogyric crisis

Respiratory: Nasopharyngitis

Miscellaneous: Fever

Oral:

>10%:

Endocrine & metabolic: Increased serum glucose (children and adolescents: 3% to 5%; adults: 18%), weight gain (children and adolescents: 3% to 26%; adults: 2% to 8%) (table 5)

Aripiprazole: Adverse Reaction: Weight Gain (Oral)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

Comments

26%

7%

Children and adolescents

Oral

Irritability associated with autistic disorder

209

98

≥7% of body weight

5%

2%

Children and adolescents

Oral

Schizophrenia or bipolar mania

381

187

≥7% of body weight

3%

1%

Children and adolescents

Oral

Schizophrenia, bipolar mania, autistic disorder, or Tourette disorder

732

370

N/A

20%

8%

Children and adolescents

Oral

Tourette disorder

105

66

≥7% of body weight

2%

3%

Adults

Oral

Bipolar mania

719

598

≥7% of body weight

8%

3%

Adults

Oral

Schizophrenia

852

379

≥7% of body weight

Gastrointestinal: Constipation (children and adolescents: 2%; adults: 11%), nausea (8% to 15%), vomiting (8% to 14%)

Local: Application-site rash (MyCite patch: 12%)

Nervous system: Agitation (19%), akathisia (dose-related; 3% to 13%) (table 6), anxiety (17%), drowsiness (dose-related; children and adolescents: 10% to 26%; adults: 5% to 13%) (table 7), extrapyramidal reaction (dose-related; children and adolescents: 6% to 27%; adults: 5% to 16%), fatigue (dose-related; children and adolescents: 4% to 22%; adults: 6%), headache (children and adolescents: 10% to 12%; adults: 27%), insomnia (18%), sedated state (dose-related; children and adolescents: 9% to 21%; adults: 3% to 11%), tremor (dose-related; 5% to 12%)

Aripiprazole: Adverse Reaction: Akathisia (Oral)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

3%

9%

Children and adolescents

Oral

Autistic disorder

N/A

N/A

10%

2%

Children and adolescents

Oral

Bipolar mania

197

97

6%

4%

Children and adolescents

Oral

Schizophrenia, bipolar mania, autistic disorder, or Tourette disorder

732

370

4%

6%

Children and adolescents

Oral

Tourette disorder

N/A

N/A

9%

6%

Adolescents

Oral

Schizophrenia

N/A

N/A

13%

4%

Adults

Oral

Bipolar mania

917

753

8%

4%

Adults

Oral

Schizophrenia

N/A

N/A

10%

4%

Adults

Oral

Schizophrenia or bipolar mania

1,843

1,166

Aripiprazole: Adverse Reaction: Drowsiness (Oral)

Drug (Aripiprazole)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

Comments

10%

4%

Children and adolescents

N/A

Oral

Autistic disorder

212

101

N/A

26%

3%

Children and adolescents

30 mg

Oral

Bipolar mania

N/A

N/A

N/A

23%

3%

Children and adolescents

N/A

Oral

Bipolar mania

197

97

N/A

19%

3%

Children and adolescents

10 mg

Oral

Bipolar mania

N/A

N/A

N/A

16%

4%

Children and adolescents

N/A

Oral

Schizophrenia, bipolar mania, autistic disorder, or Tourette disorder

732

370

N/A

13%

1%

Children and adolescents

N/A

Oral

Tourette disorder

121

72

N/A

22%

6%

Adolescents

30 mg

Oral

Schizophrenia

N/A

N/A

N/A

11%

6%

Adolescents

10 mg

Oral

Schizophrenia

N/A

N/A

N/A

13%

7%

Adults

30 mg

Oral

Schizophrenia

N/A

N/A

Including sedation

9%

7%

Adults

10 mg

Oral

Schizophrenia

N/A

N/A

Including sedation

9%

7%

Adults

15 mg

Oral

Schizophrenia

N/A

N/A

Including sedation

8%

7%

Adults

20 mg

Oral

Schizophrenia

N/A

N/A

Including sedation

5%

3%

Adults

N/A

Oral

Schizophrenia or bipolar mania

1,843

1,166

N/A

1% to 10%:

Cardiovascular: Orthostatic hypotension (≤4%)

Dermatologic: Skin rash (children and adolescents: ≤2%)

Endocrine & metabolic: Decreased HDL cholesterol (children and adolescents: 4%), increased serum cholesterol (children and adolescents: 1%), increased serum triglycerides (5% to 10%), weight loss (≥1%)

Gastrointestinal: Abdominal distress (2% to 3%), anorexia, decreased appetite (children and adolescents: 5% to 7%), diarrhea (children and adolescents: 4%), dyspepsia (9%), increased appetite (children and adolescents: 7%), sialorrhea (dose-related; children and adolescents; 4% to 8%), stomach discomfort (3%), upper abdominal pain (children and adolescents: 3%), xerostomia (5%)

Genitourinary: Urinary incontinence (≥1%)

Nervous system: Asthenia (≥1%), dizziness (3% to 10%), drooling (children and adolescents: 3% to 9%), irritability (children and adolescents: 2%), lethargy (3% to 5%), pain (3%), restlessness (5% to 6%) (table 8)

Aripiprazole: Adverse Reaction: Restlessness (Oral)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

6%

3%

Adults

Oral

Bipolar mania

917

753

5%

3%

Adults

Oral

Schizophrenia or bipolar mania

1,843

1,166

Neuromuscular & skeletal: Dystonia (children and adolescents: 2%) (table 9), limb pain (4%), muscle rigidity (children and adolescents: 2%), muscle spasm (2%), myalgia (2%), stiffness (2% to 4%)

Aripiprazole: Adverse Reaction: Dystonia (Oral)

Drug (Aripiprazole)

Placebo

Population

Dosage Form

Indication

Number of Patients (Aripiprazole)

Number of Patients (Placebo)

2%

1%

Children and adolescents

Oral

Schizophrenia, bipolar mania, autistic disorder, or Tourette disorder

732

370

Ophthalmic: Blurred vision (3% to 8%)

Respiratory: Cough (3%), epistaxis (children and adolescents: 2%), nasopharyngitis (children and adolescents: 6% to 9%), pharyngolaryngeal pain (3%)

Miscellaneous: Fever (children and adolescents: 4% to 9%)

<1%:

Cardiovascular: Acute myocardial infarction, angina pectoris, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, chest pain, hypertension, hypotension, ischemic heart disease, palpitations, peripheral edema, prolonged QT interval on ECG

Dermatologic: Alopecia, hyperhidrosis, pruritus, skin photosensitivity, urticaria

Endocrine & metabolic: Amenorrhea, change in libido, elevated glycosylated hemoglobin, gynecomastia, hirsutism (children and adolescents), hypoglycemia, hypokalemia, hyponatremia, increased lactate dehydrogenase, increased serum prolactin, menstrual disease

Gastrointestinal: Gastroesophageal reflux disease, tongue spasm (children and adolescents)

Genitourinary: Anorgasmia, erectile dysfunction, mastalgia, nocturia, priapism, urinary retention

Hematologic & oncologic: Thrombocytopenia

Hepatic: Hepatitis, increased gamma-glutamyl transferase, increased liver enzymes, increased serum bilirubin, jaundice

Hypersensitivity: Facial edema, hypersensitivity reaction

Nervous system: Akinesia, aggressive behavior, ataxia, catatonia, choreoathetosis, cogwheel rigidity, delirium, hypertonia, impaired mobility, memory impairment, myasthenia, myoclonus, parkinsonism, seizure, sleep talking (children and adolescents), somnambulism, speech disturbance, tic disorder

Neuromuscular & skeletal: Bradykinesia, hypokinesia, rhabdomyolysis

Ophthalmic: Diplopia, oculogyric crisis, photophobia

Renal: Increased blood urea nitrogen

Respiratory: Dyspnea, nasal congestion

Postmarketing (any route):

Cardiovascular: Syncope

Endocrine & metabolic: Diabetes mellitus (new onset) (van Winkel 2008), diabetes mellitus with hyperosmolar coma (Campanella 2009), diabetic ketoacidosis (Church 2005, Makhzoumi 2008), hypercholesterolemia (Vazquez-Bourgon 2018), hyperglycemia (Church 2005, Stern 2012), hypertriglyceridemia (Vazquez-Bourgon 2018), insulin resistance (Teff 2013)

Gastrointestinal: Dysphagia (Lin 2012)

Genitourinary: Sexual disorder (La Torre 2013, Serretti 2010)

Hematologic & oncologic: Agranulocytosis, leukopenia (Qureshi 2008), neutropenia (Felin 2018, Majeed 2017), transient neutropenia (pseudoneutropenia) (Pinnaka 2016)

Hypersensitivity: Anaphylaxis, angioedema, drug reaction with eosinophilia and systemic symptoms (Taleb 2019)

Nervous system: Cerebrovascular accident, hypothermia (Szota 2019, Zonnenberg 2017), impulse control disorder (including compulsive buying, compulsive eating, hypersexuality, pathological gambling) (Bulbena-Cabré 2016; Dhillon 2017, Peterson 2017), neuroleptic malignant syndrome (Agrawal 2019, Palakurthi 2007), suicidal ideation (Padder 2006, Selvaraj 2010), suicidal tendencies, transient ischemic attacks

Neuromuscular & skeletal: Tardive dyskinesia (Aguilar 2019, She 2018)

Respiratory: Hypersensitivity pneumonitis (Gunasekaran 2017), sleep apnea (obstructive) (Health Canada 2016; Kohen 2009; Shirani 2011)

Contraindications

Hypersensitivity (eg, anaphylaxis, pruritus, urticaria) to aripiprazole or any component of the formulation.

Warnings/Precautions

Concerns related to adverse reactions:

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiac disease, cerebrovascular disease, prior myocardial infarction, ischemic heart disease, or conditions that predispose to hypotension.

• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances (APA [Keepers 2020]; APA [Reus 2016]).

• Seizures: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Dosage form specific issues:

• Lactose: Tablets may contain lactose; avoid use in patients with galactose intolerance or glucose-galactose malabsorption.

• Phenylalanine: Orally disintegrating tablets may contain phenylalanine.

• Product interchangeability: Injection There are 2 ER formulations available for IM administration: Aripiprazole monohydrate (Abilify Maintena) and aripiprazole lauroxil (Aristada and Aristada Initio).

• Tablet with sensor: The ability of aripiprazole tablets with sensor to improve patient compliance or modify aripiprazole dosage has not been established. The use of aripiprazole tablets with sensor to track drug ingestion in “real time” or during an emergency is not recommended because detection may be delayed or not occur.

Other warnings/precautions:

• Discontinuation of therapy: physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, insomnia, irritability, GI symptoms, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).

Warnings: Additional Pediatric Considerations

Pediatric psychiatric disorders are frequently serious disorders which present with variable symptoms that do not always match adult diagnostic criteria. Conduct a thorough diagnostic evaluation and carefully consider risks of psychotropic medication before initiation in pediatric patients with schizophrenia, bipolar disorder, or irritability associated with autistic disorder. Medication therapy for pediatric patients with these disorders is indicated as part of a total treatment program that frequently includes educational, psychological, and social interventions. Long-term usefulness of aripiprazole should be periodically re-evaluated in patients receiving the drug for extended periods of time.

Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP, 1997; Shehab, 2009).

Metabolism/Transport Effects

Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy

Agents With Seizure Threshold Lowering Potential: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome or increased QTc interval may be increased. Risk C: Monitor therapy

Amphetamines: Antipsychotic Agents may enhance the adverse/toxic effect of Amphetamines. Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification

Armodafinil: May decrease the serum concentration of ARIPiprazole. Risk C: Monitor therapy

Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of ARIPiprazole. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy, indication, or dosage form. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, CYP2D6 genotype, and use of CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Risk X: Avoid combination

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Trimeprazine: May enhance the CNS depressant effect of ARIPiprazole. Trimeprazine may increase the serum concentration of ARIPiprazole. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Ingestion with a high-fat meal delays time to peak plasma level. Management: Administer without regard to meals.

Reproductive Considerations

If treatment is needed in a woman planning a pregnancy, use of an agent other than aripiprazole is preferred (Larsen 2015).

Pregnancy Considerations

Aripiprazole crosses the placenta; aripiprazole and dehydro-aripiprazole can be detected in the cord blood at delivery (Nguyen 2011; Watanabe 2011).

Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.

Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers 2009). The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited, as such, routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to an agent that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008). If treatment is initiated during pregnancy, use of an agent other than aripiprazole is preferred (Larsen 2015).

Health care providers are encouraged to enroll women exposed to aripiprazole during pregnancy in the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388 or http://www.womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/).

Breastfeeding Considerations

Aripiprazole and dehydro-aripiprazole are present in breast milk. (Nordeng 2014)

The relative infant dose (RID) of aripiprazole is 8.3% when calculated using the highest mean breast milk concentration located and compared to a weight-adjusted maternal dose of 10 mg/day.

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

The RID of aripiprazole was calculated using a mean milk concentration of 56 ng/mL (aripiprazole) and 8.8 ng/mL (dehydro-aripiprazole), providing an estimated daily infant dose via breast milk of 47 mcg/day. This milk concentration was obtained following maternal administration of aripiprazole 10 mg/day during pregnancy and while breastfeeding. Milk samples were obtained at 8 and 10 weeks' postpartum. The RID was calculated by the authors of the study using the actual maternal weight. Peak milk concentrations appeared ~3 hours after the dose, but remained relatively constant throughout the dosing interval (Nordeng 2014).

Although reports of aripiprazole use in breastfeeding women are limited, lactation failure has been observed in some cases (Lutz 2010; Mendhekar 2006; Nordeng 2014). In general, infants exposed to second generation antipsychotics via breast milk should be monitored weekly for the first month of exposure for symptoms, such as appetite changes, insomnia, irritability, or lethargy (Uguz 2016).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Until additional information is available, use of agents other than aripiprazole in breastfeeding women is preferred (Pacchiarotti 2016; Uguz 2016).

Dietary Considerations

Some products may contain phenylalanine.

Monitoring Parameters

Frequency of Antipsychotic Monitoringa,b

Monitoring parameter

Frequency of monitoring

Comments

Adherence

Every visit

Blood chemistries (electrolytes, renal function, liver function, TSH)

Annually

CBC

As clinically indicated

Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia

Extrapyramidal symptoms

Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high riskc

Fall risk

Every visit

Fasting plasma glucose/HbA1c

12 weeks after initiation and dose change; annually

Check more frequently than annually if abnormal. Follow diabetes guidelines.

Lipid panel

12 weeks after initiation and dose change; annually

Check more frequently than annually if abnormal. Follow lipid guidelines.

Mental status and alertness

Every visit

Metabolic syndrome history

Annually

Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease

Prolactin

Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.

Hyperprolactinemia symptoms: Changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function

Tardive dyskinesia

Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskd

Vital signs (BP, orthostatics, temperature, pulse, signs of infection)

Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change.

Weight/Height/BMI

8 and 12 weeks after initiation and dose change; quarterly

Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome.

Consider changing antipsychotic if BMI increases by ≥1 unit.

Some experts recommend checking weight and height at every visit.

a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline.

b ADA 2004; APA [Keepers 2020]; de Hert 2011; Gugger 2011; manufacturer’s labeling.

c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic.

d Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; and past or current EPS.

Reference Range

Timing of serum samples: Draw trough just before next dose (Hiemke 2018).

Therapeutic reference range: 100 to 350 ng/mL (SI: 223 to 780.5 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations, however therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).

Laboratory alert level: 1,000 ng/mL (SI: 2,230 nmol/L) (Hiemke 2018).

Mechanism of Action

Aripiprazole is a quinolinone antipsychotic which exhibits high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors; moderate affinity for D4, 5-HT2C, 5-HT7, alpha1 adrenergic, and H1 receptors. It also possesses moderate affinity for the serotonin reuptake transporter; has no affinity for muscarinic (cholinergic) receptors. Aripiprazole functions as a partial agonist at the D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptor (de Bartolomeis 2015).

Pharmacokinetics

Note: In pediatric patients 10 to 17 years of age, the pharmacokinetic parameters of aripiprazole and dehydro-aripiprazole have been shown to be similar to adult values when adjusted for weight.

Onset of action: Oral:

Bipolar disorder, acute mania: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).

Major depressive disorder, unipolar: Initial effects may be observed within 1 week with continued improvements over 6 to 12 weeks (Wen 2014).

Schizophrenia: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).

Absorption:

IM: Extended-release: Slow, prolonged.

Oral: Well absorbed.

Distribution: Vd: 4.9 L/kg.

Protein binding: ≥99%, primarily to albumin.

Metabolism: Hepatic dehydrogenation, hydroxylation and N-dealkylation via CYP2D6, CYP3A4 (dehydro-aripiprazole metabolite has affinity for D2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma) (Sheehan 2010).

Bioavailability: Tablet: 87%; Note: Orally disintegrating tablets are bioequivalent to tablets; oral solution to tablet ratio of geometric mean for peak concentration is 122% and for AUC is 114%.

Half-life elimination: Aripiprazole: 75 hours; dehydro-aripiprazole: 94 hours; IM, extended release (terminal): ~30 to 47 days (dose-dependent).

CYP2D6 poor metabolizers: Aripiprazole: 146 hours.

Time to peak, plasma:

IM: Extended release (after multiple doses): 4 days (deltoid administration); 5 to 7 days (gluteal administration).

Tablet: 3 to 5 hours; high-fat meals delay time to peak by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole.

Excretion: Feces (55%, ~18% of the total dose as unchanged drug; 37% of the total dose as changed drug); urine (25%, <1% of the total dose as unchanged drug; 25% of the total dose as changed drug) (Sheehan 2010)

Pharmacokinetics: Additional Considerations

Altered kidney function: In severe renal impairment (CrCl <30 mL/minute), Cmax increased by 36% (aripiprazole) and 53% (dehydro-aripiprazole), but AUC was 15% lower for aripiprazole and 7% higher for dehydro-aripiprazole.

Hepatic function impairment: AUC increased by 31% in mild hepatic impairment and by 8% in moderate impairment, and decreased by 20% in severe impairment.

Older adult: In patients ≥65 years of age who were administered a single oral dose, clearance was 20% lower than that observed in younger patients.

Sex: Cmax and AUC are 30% to 40% higher in women than in men.

CYP 2D6 metabolizers: 60% higher exposure to aripiprazole and active metabolites in poor CYP 2D6 metabolizers compared to extensive metabolizers (Sheehan 2010).

Pricing: US

Prefilled Syringe (Abilify Maintena Intramuscular)

300 mg (per each): $2,297.94

400 mg (per each): $3,063.92

Solution (ARIPiprazole Oral)

1 mg/mL (per mL): $2.08 - $7.07

Suspension Reconstituted ER (Abilify Maintena Intramuscular)

300 mg (per each): $2,297.94

400 mg (per each): $3,063.92

Tablet Therapy Pack (Abilify MyCite Maintenance Kit Oral)

2 mg (per each): $66.00

5 mg (per each): $66.00

10 mg (per each): $66.00

15 mg (per each): $66.00

20 mg (per each): $66.00

30 mg (per each): $66.00

Tablet Therapy Pack (Abilify MyCite Starter Kit Oral)

2 mg (per each): $66.00

5 mg (per each): $66.00

10 mg (per each): $66.00

15 mg (per each): $66.00

20 mg (per each): $66.00

30 mg (per each): $66.00

Tablet, orally-disintegrating (ARIPiprazole Oral)

10 mg (per each): $41.87 - $41.89

15 mg (per each): $41.87 - $41.89

Tablets (Abilify Oral)

2 mg (per each): $23.35

5 mg (per each): $23.35

10 mg (per each): $23.35

15 mg (per each): $23.35

20 mg (per each): $33.02

30 mg (per each): $33.02

Tablets (ARIPiprazole Oral)

2 mg (per each): $0.09 - $32.11

5 mg (per each): $0.11 - $32.11

10 mg (per each): $0.14 - $32.11

15 mg (per each): $0.18 - $32.11

20 mg (per each): $0.25 - $45.41

30 mg (per each): $0.26 - $45.41

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Abdin (PH);
  • Abilia (EG);
  • Abilify (AE, AT, AU, BB, BE, BG, BH, BR, CH, CN, CO, CY, CZ, DE, DK, EE, EG, ES, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, IS, IT, JO, JP, KR, LB, LT, LU, MT, MX, NL, NO, PH, PL, PT, PY, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, VE, VN, ZA);
  • Abilify Discmelt (PH);
  • Abilify Maintena (BE, HK, MY, RO, SG, TH);
  • Abilify OD (JP);
  • Abilify ODT (NZ);
  • Antredamin (CR, DO, GT, HN, NI, PA, SV);
  • Apalife (MY, TH);
  • Apaloz (ES);
  • Apilipex (EG);
  • Apipral (NL);
  • Apiprax (PL);
  • Arian (MY);
  • Arika (TW);
  • Arilex (CL);
  • Arilobe (EG);
  • Arinia (BD, ID);
  • Aripi (ID);
  • Aripipan (LB);
  • Aripizole (KR);
  • Ariple (TW);
  • Ariply (IL);
  • Aripra (KR);
  • Aripsan (PL);
  • Ariski (ID);
  • Aristab (BR);
  • Arive (IN);
  • Arixind (AR);
  • Arizol (ES, UY);
  • Arizole (AU, LK, TW);
  • Arizopress (PH);
  • Arlemide (AR);
  • Atfren (CR, DO, GT, HN, NI, PA, SV);
  • Atypral (LB);
  • Azymol (CL, PE, PY);
  • Bisoza (LK, PH);
  • Ilimit (EC, PE, PY, UY);
  • Irazem (AR);
  • Laprinz (MX);
  • Lemilvo (IE, SE);
  • Mactril (LK);
  • Pipzol (LK, UA);
  • Poziats (VN);
  • Ripizol (PL);
  • Siblix (AR);
  • Siznil (BD);
  • Sizopra (BD, LK);
  • Tevaripiprazole (AU);
  • Xalipro (LB);
  • Xarip (BD);
  • Zedan (PK)


For country code abbreviations (show table)
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