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

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Special Alerts
Atypical Antipsychotics Safety Review September 2017

Health Canada has reviewed the potential risk of sleep walking and sleep-related eating disorder with the use of atypical antipsychotics and concluded there is a link between these adverse reactions and the use of these medications. Health Canada has recommended to update the product safety information for all atypical antipsychotics to include these adverse reactions.

Further information may be found at https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/safety-reviews/atypical-antipsychotics-assessing-potential-risk-sleep-walking-sleep-related-eating-disorder.html.

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 pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for the emergence of suicidal thoughts and behaviors. The safety and efficacy of aripiprazole tablets with sensor have not been established in pediatric patients.

Brand Names: US
  • Abilify;
  • Abilify Discmelt [DSC];
  • Abilify Maintena
Brand Names: Canada
  • Abilify;
  • Abilify Maintena
Pharmacologic Category
  • Second Generation (Atypical) Antipsychotic
Dosing: Adult

Note: Abilify immediate-release injection (9.75 mg/1.3 mL) has been discontinued in the US for more than 1 year.

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). Aripiprazole tablets with an ingestible event marker sensor (Abilify Mycite) may be considered in appropriately selected patients. The smartphone app and web portal will detect the ingestion within 30 minutes to 2 hours after ingestion.

Acute agitation (schizophrenia/bipolar mania): IM, immediate release: 9.75 mg as a single dose (range: 5.25 to 15 mg; a lower dose of 5.25 mg IM may be considered when clinical factors warrant); repeated doses may be given at ≥2-hour intervals to a maximum of 30 mg/day. Note: If ongoing therapy with aripiprazole is necessary, transition to oral therapy as soon as possible.

Bipolar I disorder:

Oral: Acute manic or mixed episodes (all oral formulations) and maintenance (tablet with sensor only):

Monotherapy: Initial: 15 mg once daily. May increase to 30 mg once daily if clinically indicated (maximum 30 mg/day); safety of doses >30 mg/day has not been evaluated

Adjunct to lithium or valproic acid: Initial: 10 to 15 mg once daily. Recommended target dose: 15 mg once daily; may increase to 30 mg once daily if clinically indicated (maximum 30 mg/day); safety of doses >30 mg/day has not been evaluated.

IM, extended release: Maintenance: 400 mg once monthly (doses should be separated by ≥26 days); Note: Tolerability should be established using oral aripiprazole prior to initiation of parenteral therapy; due to the half-life of oral aripiprazole it may take up to 2 weeks to fully assess tolerability. Continue oral aripiprazole (or other oral antipsychotic) for 14 days during initiation of parenteral therapy.

Missed doses:

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

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

Dosage adjustment for adverse effects: Consider reducing dose to 300 mg once monthly

Depression (adjunctive with antidepressants): Oral: Initial: 2 to 5 mg/day (range: 2 to 15 mg/day); dose adjustments of up to 5 mg/day may be made in intervals of ≥1 week, up to a maximum of 15 mg/day. Note: Dosing based on patients already receiving antidepressant therapy.

Schizophrenia:

Oral: 10 or 15 mg once daily; may be increased to a maximum of 30 mg once daily (efficacy at dosages above 10 to 15 mg has not been shown to be increased). Dosage titration should not be more frequent than every 2 weeks.

IM, extended release: 400 mg once monthly (doses should be separated by ≥26 days); Note: Tolerability should be established using oral aripiprazole prior to initiation of parenteral therapy; due to the half-life of oral aripiprazole it may take up to 2 weeks to fully assess tolerability. Continue oral aripiprazole (or other oral antipsychotic) for 14 days during initiation of parenteral therapy.

Missed doses:

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

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

Dosage adjustment for adverse effects: Consider reducing dose to 300 mg once monthly

Dosage adjustment with concurrent CYP450 inducer or inhibitor therapy:

Oral and IM, immediate release: Note: Dose reduction does not apply when adjunctive aripiprazole is administered to patients with major depressive disorder; follow usual dosing recommendations.

CYP3A4 inducers (eg, carbamazepine, rifampin): Aripiprazole dose should be doubled over 1 to 2 weeks; dose should be subsequently reduced to the original level over 1 to 2 weeks if concurrent inducer agent is discontinued.

Strong CYP3A4 inhibitors (eg, itraconazole, clarithromycin): Aripiprazole dose should be reduced to 50% of the usual dose, and proportionally increased upon discontinuation of the inhibitor agent.

Strong CYP2D6 inhibitors (eg, quinidine, fluoxetine, paroxetine): Aripiprazole dose should be reduced to 50% of the usual dose, and proportionally increased upon discontinuation of the inhibitor agent.

CYP3A4 and CYP2D6 inhibitors: Aripiprazole dose should be reduced to 25% of the usual dose. In patients receiving inhibitors of differing (eg, moderate 3A4/strong 2D6) or same (eg, moderate 3A4/moderate 2D6) potencies (excluding concurrent strong inhibitors), further dosage adjustments can be made to achieve the desired clinical response. In patients receiving strong CYP3A4 and 2D6 inhibitors, aripiprazole dose is proportionally increased upon discontinuation of one or both inhibitor agents.

IM, extended release: Note: Dosage adjustments are not recommended for concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for <14 days. In patients who had their aripiprazole dose adjusted for concomitant therapy, the aripiprazole dose may need to be increased if the CYP3A4 and/or CYP2D6 inhibitor is withdrawn.

CYP3A4 inducers: Avoid use; aripiprazole serum concentrations may fall below effective levels.

Strong CYP3A4 or CYP2D6 inhibitors:

Current aripiprazole dose of 300 mg once monthly: Reduce aripiprazole dose to 200 mg once monthly

Current aripiprazole dose of 400 mg once monthly: Reduce aripiprazole dose to 300 mg once monthly

Strong CYP3A4 inhibitors and CYPD2D6 inhibitors:

Current aripiprazole dose of 300 mg once monthly: Reduce aripiprazole dose to 160 mg once monthly

Current aripiprazole dose of 400 mg once monthly: Reduce aripiprazole dose to 200 mg once monthly

Dosage adjustment based on CYP2D6 metabolizer status:

Oral and IM, immediate release: 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 (eg, itraconazole, clarithromycin); subsequently adjust dose for favorable clinical response.

IM, extended release: Reduce aripiprazole dose to 300 mg once monthly in CYP2D6 poor metabolizers; reduce dose to 200 mg once monthly in CYP2D6 poor metabolizers receiving a concurrent CYP3A4 inhibitor for >14 days.

Discontinuation of therapy: American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). 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 (APA [Lehman 2004]; CPA [Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). 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 (Cerovecki 2013; Remington 2005).

Dosing: Pediatric

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

Note: Abilify immediate-release injection (9.75 mg/1.3 mL) has been discontinued in the US for more than 1 year.

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).

Bipolar I disorder (acute manic or mixed episodes): Children ≥10 years and Adolescents: Oral: Tablet, orally disintegrating tablet, and oral solution only: Initial: 2 mg once daily for 2 days, followed by 5 mg once daily for 2 days with a further increase to target dose of 10 mg once daily as monotherapy or as adjunct to lithium or valproic acid; subsequent dose increases may be made in 5 mg increments, up to a maximum of 30 mg/day.

Irritability associated with autistic disorder: Children ≥6 years and Adolescents: Oral: Tablet, orally disintegrating tablet, and oral solution only: Initial: 2 mg once daily for 7 days, followed by an increase to 5 mg once daily; subsequent dose increases may be made in 5 mg increments at intervals of ≥1 week, up to a maximum of 15 mg/day. The need for ongoing treatment should be assessed periodically.

Schizophrenia: Adolescents ≥13 years: Oral: Tablet, orally disintegrating tablet, and oral solution only: Initial: 2 mg once daily for 2 days, followed by 5 mg once daily for 2 days with a further increase to target dose of 10 mg once daily; subsequent dose increases may be made in 5 mg increments up to a maximum of 30 mg/day (30 mg/day not shown to be more efficacious than 10 mg/day)

Tourette syndrome: Children ≥6 years and Adolescents: Oral: Tablet, orally disintegrating tablet, and oral solution only:

<50 kg: Initial: 2 mg/day for 2 days then increase to a target dose of 5 mg/day; may increase dose up to a maximum of 10 mg/day based on response and tolerability; dosage adjustments should occur gradually at intervals of no less than 1 week. Assess the need for ongoing treatment periodically.

≥50 kg: Initial: 2 mg/day for 2 days, then increase to 5 mg/day for 5 days with a target dose of 10 mg/day on day 8; may increase dose up to a maximum of 20 mg/day, based on response and tolerability, in 5 mg/day increments at intervals no less than 1 week. Assess the need for ongoing treatment periodically.

Dosage adjustment with concurrent CYP450 inducer or inhibitor therapy, or adjustment based on CYP2D6 metabolizer status: Refer to adult dosing.

Dosing: Geriatric

Refer to adult dosing.

Psychosis/agitation associated with dementia (off-label use):

IM, immediate release: Initial: 2.5 to 10 mg once; a repeat dose of 2.5 to 5 mg may be given at ≥2-hour intervals not to exceed 15 mg/day (Rappaport 2009).

Oral: Initial: 2 to 5 mg once daily; if necessary gradually increase based on response and tolerability not to exceed 15 mg daily. In patients without a clinically significant response after 4 weeks, taper and withdraw therapy. In patients with an adequate response, attempt to taper and withdraw therapy within 4 months, unless symptoms recurred with a previous taper attempt. Assess symptoms at least monthly during taper and for at least 4 months after withdrawal of therapy (APA [Reus 2016]); De Deyn 2005; Mintzer 2007; Streim 2008).

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Dosage Forms

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, Intramuscular:

Abilify: 9.75 mg/1.3 mL (1.3 mL [DSC])

Solution, Oral:

Abilify: 1 mg/mL (150 mL [DSC]) [contains methylparaben, propylene glycol, propylparaben; orange cream flavor]

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 aluminum lake]

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

Tablet Disintegrating, Oral:

Abilify Discmelt: 10 mg [DSC], 15 mg [DSC] [contains aspartame, fd&c blue #2 aluminum lake]

Generic: 10 mg, 15 mg

Generic Equivalent Available (US)

May be product dependent

Dosage Forms Considerations

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

Product Availability

Abilify immediate-release injection (9.75 mg/1.3 mL) has been discontinued in the US for more than 1 year.

Abilify Mycite: FDA approved November 2017; availability anticipated in 2018. Information pertaining to this product within the monograph is pending revision. Abilify Mycite is a drug-device combination product comprised of aripiprazole tablets embedded with an Ingestible Event Marker (IEM) sensor intended to track drug ingestion. Consult the prescribing information for additional information.

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: http://www.fda.gov/downloads/Drugs/DrugSafety/ucm085804.pdf

Abilify Maintena: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM342207.pdf

Administration

Injection: For IM use only; do not administer SubQ or IV; Note: Immediate-release and extended-release parenteral products are not interchangeable.

Immediate release: Inject slowly into deep muscle mass

Extended release: Inject slowly into deltoid or gluteal muscle using the appropriate provided needle; for non-obese 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 two deltoid or gluteal muscles. Administer monthly (doses should be separated by ≥26 days).

Oral: Administer with or without food. Tablet and oral solution may be interchanged on a mg-per-mg basis, up to 25 mg. Doses using 30 mg tablets should be exchanged for 25 mg oral solution. Orally disintegrating tablets (Abilify Discmelt) are bioequivalent to the immediate-release tablets (Abilify).

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, and that the app is compatible with the patient’s specific smartphone. Apply patch only when instructed by the app to the left 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.

Use

Oral:

Bipolar I disorder: As monotherapy or as adjunctive therapy to lithium or valproate for acute treatment of manic or mixed episodes and maintenance (tablet with sensor only) associated with bipolar I disorder

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

Major depressive disorder: Adjunctive treatment of major depressive disorder

Schizophrenia: Treatment of schizophrenia

Tourette disorder: Treatment of Tourette disorder (tablet, orally disintegrating tablet and oral solution only)

Injection:

Agitation associated with schizophrenia or bipolar mania (immediate-release injection only): Treatment of agitation associated with schizophrenia or bipolar mania

Bipolar I disorder (extended -release injection only): Maintenance monotherapy treatment of bipolar I disorder

Schizophrenia (extended-release injection only): Treatment of schizophrenia

Use: Off-Label

Psychosis/agitation associated with dementia

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)

Geriatric Patients: 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 with dementia due to an increased risk of mortality, cerebrovascular accidents (stroke), and a greater rate of cognitive decline with use; avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. Use may be appropriate in geriatric patients with schizophrenia, bipolar disorder, or for short-term use as an antiemetic during chemotherapy. 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 2015]).

Other safety issues:

There are two formulations available for intramuscular administration: Abilify is an immediate release short-acting formulation and Abilify Maintena is an extended-release formulation. These products are not interchangeable.

Adverse Reactions

Unless otherwise noted, frequency of adverse reactions is shown as reported for adult patients receiving aripiprazole monotherapy with oral administration. Spectrum and incidence of adverse effects similar in children; exceptions noted when incidence much higher in children.

>10%:

Central nervous system: Headache (adults 27%; children and adolescents 10% to 12%; injection 12%), extrapyramidal reaction (dose-related; children and adolescents 6% to 27%; adults 5% to 13% ), drowsiness (children and adolescents 10% to 26%; adults 8% to 13%), akathisia (dose-related; adults 2% to 25%; children and adolescents 6% to 11%), fatigue (dose-related; children and adolescents 4% to 22%; adults 6%; injection 1% to 2%), sedation (dose-related; children and adolescents 9% to 21%; adults 3% to 8%), agitation (oral 19%; injection <1%), insomnia (18%; injection ≥1%), anxiety (oral 17%; injection ≥1%)

Endocrine & metabolic: Weight gain (children and adolescents 3% to 26%; injection 17% to 22%; adults 2% to 8%), increased serum cholesterol (injection 4% to 22%; oral 1%), increased serum triglycerides (adults 7% to 10%; children and adolescents 5%; injection 7% to 20%; oral 5% to 10%), increased serum glucose (adults 8% to 18%; children and adolescents 3% to 5%), decreased HDL cholesterol (adults 14%; children and adolescents 4%), increased LDL cholesterol (injection 10% to 14%)

Gastrointestinal: Nausea (≤15%), vomiting (oral 8% to 14%; injection: 3%), constipation (10% to 11%; children and adolescents 2% to 3%)

Local: Application site rash (Mycite patch: 12%)

Neuromuscular & skeletal: Tremor (dose-related; oral 5% to 12%; injection 3%)

1% to 10%:

Cardiovascular: Tachycardia (injection ≤2%), peripheral edema (≥1%), orthostatic hypotension (including injection; ≤1%)

Central nervous system: Dizziness (3% to 10%), drooling (children and adolescents 3% to 9%), restlessness (oral 5% to 6%; injection ≥1%), lethargy (older adults 5%; children 3% to 5%; injection <1%), pain (3%), dystonia (2%), irritability (children and adolescents 2%; injection <1%), ataxia (≥1%), hypersomnia (≤1%)

Dermatologic: Skin rash (≤2%)

Endocrine & metabolic: Weight loss (injection 4%; oral ≥1%)

Gastrointestinal: Dyspepsia (oral 9%; injection <1%), sialorrhea (dose-related; 3% to 8%), decreased appetite (children and adolescents 5% to 7%; injection <1%), increased appetite (children and adolescents 7%), xerostomia (5%; injection: 4%; children and adolescents 1%), toothache (4%), diarrhea (3% to 4%), gastric distress (3%), stomach discomfort (3%), upper abdominal pain (children and adolescents 3%; injection <1%), abdominal distress (2% to 3%), anorexia (≥1%)

Genitourinary: Urinary incontinence (older adults ≤5%; injection <1%), dysmenorrhea (children and adolescents 2%)

Hematologic & oncologic: Neutropenia (injection 6%)

Local: Pain at injection site (5%), injection site reaction (injection ≥1%; including erythema, induration, inflammation, hemorrhage, pruritus, swelling, rash)

Neuromuscular & skeletal: Arthralgia (injection 4%; children and adolescents 1%), back pain (injection 4%), limb pain (4%), myalgia (2% to 4%), stiffness (2% to 4%), musculoskeletal pain (injection 3%), muscle cramps (2%), muscle rigidity (children and adolescents 2%), muscle spasm (2%), weakness (1% to 2%), dyskinesia (children and adolescents 1%)

Ophthalmic: Blurred vision (oral 3% to 8%; injection <1%)

Respiratory: Nasopharyngitis (children and adolescents 6% to 9%; injection <1%), upper respiratory tract infection (4%), cough (3%), pharyngolaryngeal pain (3%), epistaxis (children and adolescents 2%), nasal congestion (injection: 2%; oral <1%), aspiration pneumonia (≥1%), dyspnea (≥1%)

Miscellaneous: Fever (children and adolescents 4% to 9%; injection <1%)

<1%, postmarketing, and/or case reports: Abnormal bilirubin levels, abnormal gait, abnormal hepatic function tests, aggressive behavior, agranulocytosis, akinesia, alopecia, altered serum glucose, amenorrhea, anaphylaxis, angina pectoris, angioedema, anorgasmia, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, bradykinesia, bruxism, cardiac arrhythmia, catatonia, cerebrovascular accident, change in libido, chest discomfort, chest pain, choreoathetosis, cogwheel rigidity, decreased serum cholesterol, decreased serum triglycerides, delayed ejaculation, delirium, depression, diabetes mellitus, diabetic ketoacidosis, diplopia, disruption of body temperature regulation, drug-induced Parkinson disease, dysgeusia, dysphagia, dystonia (oromandibular), edema, elevated glycosylated hemoglobin, erectile dysfunction, esophagitis, extrasystoles, eyelid edema, facial edema, falling, gastroesophageal reflux disease, glycosuria, gynecomastia, heatstroke, hepatic failure, hepatitis, hepatotoxicity, hirsutism, homicidal ideation, hostility, hyperglycemia, hyperhidrosis, hyperinsulinism, hyperlipidemia, hypersensitivity reaction, hypertension, hypertonia, hypoglycemia, hypokalemia, hypokinesia, hyponatremia, hypothermia, hypotonia, impulse control disorder (including pathologic gambling and hypersexuality), increased blood urea nitrogen, increased creatinine clearance, increased creatine phosphokinase, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased liver enzymes, increased serum bilirubin, increased serum prolactin, inhibition of prolactin secretion, intentional injury, ischemic heart disease, jaundice, joint stiffness, laryngospasm, leukopenia, mastalgia, memory impairment, menstrual disease, mobility disorder, muscle twitching, myasthenia, myocardial infarction, myoclonus, neuroleptic malignant syndrome, nocturia, obesity, oculogyric crisis, oropharyngeal spasm, palpitations, pancreatitis, panic attack, photophobia, photopsia, pollakiuria, polydipsia, polyuria, presyncope, priapism, prolonged Q-T interval on ECG, pruritus, psychosis, rhabdomyolysis, seizure (including injection), skin photosensitivity, sleep apnea syndrome (obstructive) (Health Canada, August 16, 2016; Shirani 2011), sleep talking, somnambulism, speech disturbance, suicidal ideation, suicidal tendencies, supraventricular tachycardia, swollen tongue, syncope, tardive dyskinesia, thrombocytopenia, tics, tongue spasm, tonic-clonic seizures, torsades de pointes, transient ischemic attacks, trismus, uncontrolled diabetes mellitus, urinary retention, urticaria, venous thromboembolism, ventricular tachycardia

Contraindications

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

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Aripiprazole is not FDA approved for adjunctive treatment of depression in children.

-The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Patients should be screened for bipolar disorder prior to initiation of treatment of major depression.

- Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.

Concerns related to adverse reactions:

• Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.

• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC/ANC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.

• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of aripiprazole for the unapproved use in elderly patients with dementia-related psychosis.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents. In clinical trials, lipid changes observed with aripiprazole monotherapy were similar to those observed with placebo.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer dementia).

• Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension and motor or sensory instability. Complete fall risk assessments at baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk.

• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation. Reports of hyperglycemia with aripiprazole therapy have been few and specific risk associated with this agent is not known.

• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating, and/or other intense urges. Patients with prior history of impulse control issues may be at increased risk. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in most, but not all, cases (Gaboriau 2014; Moore 2014; Smith 2011).

• Neuroleptic malignant syndrome (NMS): Use may be associated with neuroleptic malignant syndrome (NMS); monitor for mental status changes, fever, muscle rigidity and/or autonomic instability.

• 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).

• Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Weight gain: Significant weight gain (>7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Monitor waist circumference and BMI.

Disease-related concerns:

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

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death (APA [Reus 2016]). Aripiprazole is not approved for the treatment of dementia-related psychosis.

• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotics may aggravate motor disturbances (APA [Lehman 2004; 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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 two formulations available for intramuscular administration: Abilify is an immediate-release short-acting formulation and Abilify Maintena is an extended-release formulation. These products are not interchangeable.

• 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: When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness and vomiting (APA [Lehman 2004]; CPA [Addington 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or two episodes within 5 years (APA [Lehman 2004]).

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

(For additional information: Launch drug interactions program)

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

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

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

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

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 using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Risk D: Consider therapy modification

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

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

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

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

Blonanserin: CNS Depressants may enhance the CNS depressant effect of 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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Risk D: Consider therapy modification

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

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

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. 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

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

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

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 and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Risk D: Consider therapy modification

CYP2D6 Inhibitors (Weak): 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 and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. 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 and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Weak): 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 and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. 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 (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

DULoxetine: ARIPiprazole may enhance the adverse/toxic effect of DULoxetine. ARIPiprazole may enhance the serotonergic effect of DULoxetine. This could result in serotonin syndrome. DULoxetine may increase the serum concentration of ARIPiprazole. Risk C: Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Risk D: Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

FLUoxetine: May enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of neuroleptic malignant syndrome may be increased. ARIPiprazole may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose should be reduced by at least half, except when used adjunctively for depression. Consult full interaction monograph or aripiprazole prescribing information for complete details. Risk D: Consider therapy modification

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

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

Haloperidol: ARIPiprazole may enhance the QTc-prolonging effect of Haloperidol. ARIPiprazole may diminish the therapeutic effect of Haloperidol. Haloperidol may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph. Aripiprazole dose adjustment may not be required when used as adjunctive therapy for major depressive disorder. Risk D: Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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

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

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

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

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 anticonvulsants. 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 anticonvulsants. 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 anticonvulsants. Risk D: Consider therapy modification

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

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

Methadone: May enhance the CNS depressant effect of ARIPiprazole. ARIPiprazole may enhance the QTc-prolonging effect of Methadone. Risk C: Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

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

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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Risk D: Consider therapy modification

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

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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Risk D: Consider therapy modification

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

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

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics 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

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

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

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Risk D: Consider therapy modification

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

PARoxetine: May enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of neuroleptic malignant syndrome may be increased. ARIPiprazole may enhance the serotonergic effect of PARoxetine. This could result in serotonin syndrome. PARoxetine may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose adjustment is recommended, except when used adjunctively for depression. Consult full interaction monograph or aripiprazole prescribing information for complete details. Risk D: Consider therapy modification

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. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). 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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Risk C: Monitor therapy

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

Ritonavir: ARIPiprazole may enhance the adverse/toxic effect of Ritonavir. The risk of metabolic disturbances (e.g. hyperglycemia, weight gain, hyperlipidemia) may be increased. Ritonavir may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph. Aripiprazole dose adjustment may not be required when used as adjunctive therapy for major depressive disorder. 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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Risk C: Monitor therapy

Sertraline: May enhance the adverse/toxic effect of ARIPiprazole. Sertraline may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph. Aripiprazole dose adjustment may not be required when used as adjunctive therapy for major depressive disorder. Risk D: Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy modification

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol 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

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

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Trimeprazine: May increase the serum concentration of ARIPiprazole. 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.

Pregnancy Risk Factor

C (show table)

Pregnancy Implications

Adverse events have been observed in animal reproduction studies. 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 needed in a woman planning a pregnancy or 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/).

Breast-Feeding Considerations

Aripiprazole and dehydroaripiprazole 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 (dehydroaripiprazole), 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).

The manufacturer recommends a decision be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother. The manufacturer of the extended-release injection recommends the development and health benefits of breastfeeding be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from aripiprazole or from the underlying maternal condition. 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

Mental status; vital signs (as clinically indicated); blood pressure (baseline; repeat 3 months after antipsychotic initiation, then yearly); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain ≥5% of initial weight); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if LDL level is normal repeat at 2- to 5-year intervals or more frequently if clinical indicated); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004).

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).

Pharmacodynamics/Kinetics

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: Initial: 1 to 3 weeks

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: IM: 100%; 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:

Immediate release: 1 to 3 hours

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

Tablet: 3 to 5 hours

With high-fat meal: Aripiprazole: Delayed by 3 hours; dehydro-aripiprazole: Delayed by 12 hours

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)

Pricing: US

Prefilled Syringe (Abilify Maintena Intramuscular)

300 mg (1): $1,862.24

400 mg (1): $2,482.99

Solution (ARIPiprazole Oral)

1 mg/mL (150 mL): $1,059.95

Suspension Reconstituted ER (Abilify Maintena Intramuscular)

300 mg (1): $1,862.24

400 mg (1): $2,482.99

Tablet, orally-disintegrating (ARIPiprazole Oral)

10 mg (30): $1,143.86

15 mg (30): $1,143.86

Tablets (Abilify Oral)

2 mg (30): $1,070.36

5 mg (30): $1,070.36

10 mg (30): $1,070.36

15 mg (30): $1,070.36

20 mg (30): $1,513.62

30 mg (30): $1,513.62

Tablets (ARIPiprazole Oral)

2 mg (30): $963.25

5 mg (30): $963.25

10 mg (30): $963.25

15 mg (30): $963.25

20 mg (30): $1,360.74

30 mg (30): $1,360.74

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);
  • Abilify (AE, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CO, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, IS, IT, JO, JP, KR, KW, LB, LT, LU, MT, MX, MY, NL, NO, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, VE, VN, ZA);
  • Abilify Discmelt (PH);
  • Abilify Maintena (HK);
  • Abilify OD (JP);
  • Abilify ODT (NZ);
  • Apalife (TH);
  • Arika (TW);
  • Arilental (UA);
  • Arilex (CL);
  • Arinia (BD, ID);
  • Aripi (ID);
  • Aripizole (KR);
  • Ariple (TW);
  • Aripra (KR);
  • Ariprazol (CR, DO, GT, HN, NI, PA, SV);
  • Ariski (ID);
  • Aristab (BR);
  • Arive (IN);
  • Arixind (AR);
  • Arizol (UY);
  • Arizole (LK, TW);
  • Arlemide (AR);
  • Aryp MT (UA);
  • Azymol (PE, PY);
  • Bisoza (LK, PH);
  • Groven (AR);
  • Ilimit (CR, DO, EC, GT, HN, NI, PA, PE, PY, SV, UY);
  • Irazem (AR);
  • Lemilvo (IE);
  • Mactril (LK);
  • Pipzol (LK, UA);
  • Siblix (AR);
  • Siznil (BD);
  • Sizopra (BD, LK);
  • Viza (CL);
  • Xalipro (LB);
  • Xarip (BD);
  • Zedan (PK);
  • Zipren (ID)
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