aripiprazole (Abilify, Abilify Maintena, Aristada)
Dosing and uses of Abilify Maintena, Aristada (aripiprazole)
Adult dosage forms and strengths
tablet
- 2mg
- 5mg
- 10mg
- 15mg
- 20mg
- 30mg
oral disintegrating tablet
- 10mg
- 15mg
oral solution
- 1mg/mL
extended-release injectable IM suspension (Abilify Maintena)
- 300mg/vial or prefilled dual chamber syringe
- 400mg/vial or prefilled dual chamber syringe
extended-release injectable IM suspension (aripiprazole lauroxil [Aristada])
- 441mg/prefilled syringe
- 662mg/prefilled syringe
- 882mg/prefilled syringe
injectable IM solution
- 7.5mg/mL (9.75mg/1.3mL)
Schizophrenia
10-15 mg/day PO initially; may be increased to 30 mg/day PO after 2 weeks
Maintenance with Abilify Maintena
- Abilify Maintena: 400 mg IM once monthly; continue treatment with aripiprazole PO (10-20 mg/day) or other oral antipsychotic for 14 consecutive days following first injection
- Only to be administered by deep IM injection into deltoid or gluteal muscle by healthcare professional
- Establish tolerability with oral aripiprazole prior to initiating if patient has never taken aripiprazole
- Administer monthly dose no sooner than 26 days after previous injection (also see Dosage modifications)
- Consider dose reduction to 300 mg/month if adverse reaction occurs
Treatment of relapse with Abilify Maintena
- 400 mg IM plus oral aripiprazole 10-20 mg x2 weeks
Aristada
- Establish tolerability to aripiprazole with oral dosing, then in conjunction with the first Aristada dose, administer treatment with PO aripiprazole for 21 consecutive days
- Depending on individual patient’s needs, treatment can be initiated with 441 mg, 662 mg, or 882 mg IM once monthly of Aristada, which corresponds to 300 mg, 450 mg, and 600 mg of aripiprazole base, respectively
- Treatment may also be initiated with 882 mg IM q6wk
- Adjust dose and dosing interval as needed; take into consideration the pharmacokinetics and prolonged-release characteristics of Aristada
- In the event of early dosing, Aristada should not be given earlier than 14 days after the previous injection
- Aristada dose based on total PO dose
- 10 mg/day PO: 441 mg IM once monthly
- 15 mg/day PO: 662 mg IM once monthly
- ≥20 mg/day: 882 mg IM once monthly
Bipolar Mania
Acute and maintenance treatment of manic or mixed episodes associated with bipolar I disorder, either as monotherapy or as adjunct to lithium or valproate
Monotherapy: 15 mg/day PO initially; may be increased gradually; not to exceed 30 mg/day
Adjunct to lithium or valproate: 10-15 mg/day PO initially; recommended daily dose is 15 mg/day; may be gradually increased; not to exceed 30 mg/day
Continue stabilization dose for up to 6 weeks; treatment >6 weeks not studied
Major Depressive Disorder
2-5 mg/day PO initially; increased weekly PRN by ≤5 mg/day to dose range of 2-15 mg/day
Used adjunctively with other antidepressants
Dosage modifications (Oral)
Coadministration with potent CYP2D6 or CYP3A4 inhibitors: Decrease dose by 50%
Coadministration with potent CYP2D6 inhibitor PLUS a potent CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%)
Coadministration with any CYP2D6 inhibitor PLUS any CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response
Poor CYP2D6 metabolizers: Decrease dose by 50% initially, and then adjust to a favorable clinical response
Poor CYP3A4 metabolizers: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response
Coadministration with potent CYP3A4 inducer: The usual dose should be doubled
Dosage modifications (Abilify Maintena)
CYP2D6 poor metabolizers: 300 mg Im
CYP2D6 poor metabolizers taking concomitant CYP3A4 inhibitor: 200 mg Im
Patients taking 400 mg Im
- Strong CYP2D6 OR CYP3A4 inhibitors: 300 mg IM
- CYP2D6 AND CYP 3A4 inhibitors: 200 mg IM
- CYP3A4 inducers: Avoid use
Patients taking 300 mg Im
- Strong CYP2D6 OR CYP3A4 inhibitors: 200 mg IM
- CYP2D6 AND CYP 3A4 inhibitors: 160 mg IM
- CYP3A4 inducers: Avoid use
Missed doses
- 2nd or 3rd dose missed (>4 wk but <5 wk since last injection): Administer injection as soon as possible
- 2nd or 3rd dose missed (>5 wk since last injection): Restart concomitant oral aripiprazole for 14 days with next administered injection
- 4th or subsequent doses missed (>4 wk but <6 wk since last injection): Administer injection as soon as possible
- 4th or subsequent doses missed (>6 wk since last injection): Restart concomitant oral aripiprazole for 14 days with next administered injection
Dosage modifications (Aristada)
No dosage changes if CYP450 modulators are added for <2 wk
Strong CYP3A4 inhibitor for >2 wk
- Reduce the dose to the next lower strength No dosage adjustment necessary in patients taking 441 mg, if tolerated
- Poor CYP2D6 metabolizers: Reduce dose to 441 mg from 662 mg or 882 mg; no dosage adjustment necessary in patients taking 441 mg, if tolerated
Strong CYP2D6 inhibitor for >2 wk
- Reduce the dose to the next lower strength
- No dosage adjustment necessary in patients taking 441 mg, if tolerated
- Poor CYP2D6 metabolizers: No dose adjustment required
Both strong CYP3A4 & CYP2D6 inhibitors for >2 wk
- Avoid use for patients taking 662 mg or 882 mg
- No dosage adjustment necessary in patients taking 441 mg, if tolerated
CYP3A4 inducers for >2 wk
- No dose adjustment for 662 mg and 882 mg dose
- Increase the 441 mg dose to 662 mg
Missed doses
- When a dose is missed, administer the next injection as soon as possible, unless the time has exceed 6-8 wk
- See the following for recommendations for missed doses based on last injection dose
- Monthly 441 mg
- ≤6 wk: No PO supplementation required
- >6 wk and ≤7 wk: Supplement with 7 days of PO aripiprazole
- >7 wk: Supplement with 21 days of PO aripiprazole
- Monthly 662 mg, monthly 882 mg, or 882 mg q6wk
- ≤8 wk: No PO supplementation required
- >8 wk and ≤12 wk: Supplement with 7 days of PO aripiprazole
- >12 wk: Supplement with 21 days of PO aripiprazole
Dosing Considerations
Dosing for oral disintegrating tablets is the same as for oral tablets
Pediatric dosage forms and strengths
tablet
- 2mg
- 5mg
- 10mg
- 15mg
- 20mg
- 30mg
tablet, orally disintegrating
- 10mg
- 15mg
oral solution
- 1mg/mL
Schizophrenia
13-17 years: 2 mg/day PO initially; increased to 5 mg/day after 2 days; increased to recommended dosage of 10 mg/day after additional 2 days; may subsequently be increased by 5 mg/day; maintenance: 10-30 mg/day
Bipolar Mania
Acute manic or mixed episodes, either as monotherapy or as adjunct to lithium or valproate
10-17 years: 2 mg/day PO initially; increased to 5 mg/day after 2 days; increased to recommended dosage of 10 mg/day after additional 2 days; may subsequently be increased by 5 mg/day; maintenance: 10-30 mg/day
Autism
Irritability associated with autistic disorder
<6 years: Safety and efficacy not established
6-17 years: 2 mg/day PO initially; increased gradually at intervals ≥1 week to target dosage of 5 mg/day; may gradually be further increased PRN to 10 mg/day or higher; not to exceed 15 mg/day
Tourette Disorder
Indicated for treatment of Tourette disorder
<6 years: Safety and efficacy not established
6-18 years (<50 kg)
- Initiate at 2 mg/day PO with a target dose of 5 mg/day after 2 days
- The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics
- Dosage adjustments should occur gradually at intervals of no less than 1 week
6-18 years (≥50 kg)
- Initiate at 2 mg/day PO for 2 days, and then increase to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8
- The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics
- Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than 1 week
Dosage modifications (Oral)
Coadministration with potent CYP2D6 or CYP3A4 inhibitors: Decrease dose by 50%
Coadministration with potent CYP2D6 inhibitor PLUS a potent CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%)
Coadministration with any CYP2D6 inhibitor PLUS any CYP3A4 inhibitor: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response
Poor CYP2D6 metabolizers: Decrease dose by 50% initially, and then adjust to a favorable clinical response
Poor CYP3A4 metabolizers: Decrease dose to 25% of the usual dose (ie, decrease dose by 75%) initially, and then adjust to a favorable clinical response
Coadministration with potent CYP3A4 inducer: The usual dose should be doubled
Dosing Considerations
Dosing for oral disintegrating tablets is the same as for oral tablets
Abilify Maintena, Aristada (aripiprazole) adverse (side) effects
>10%
Weight gain (8-30%)
Headache (27%)
Agitation (19%)
Insomnia (18%)
Anxiety (17%)
Nausea and vomiting (11-15%)
Akathisia (10-13%)
Lightheadedness (11%)
Constipation (10-11%)
1-10%
Dizziness (10%)
Dyspepsia (9%)
Somnolence (5-8%)
Fatigue (6%)
Restlessness (6%)
Tremor (6%)
Dry mouth/xerostomia (5%)
Extrapyramidal disorder (5%)
Orthostatic hypotension (1-5%)
Musculoskeletal stiffness (4%)
Abdominal discomfort (3%)
Blurred vision (3%)
Cough (3%)
Pain (3%)
Myalgia (2%)
Rash
Rhinitis
<1%
Altered mental status
Autonomic instability
Dysphagia
Hyperpyrexia
Muscle rigidity
Neuroleptic malignant syndrome (NMS)
Seizure
Tardive dyskinesia
Postmarketing Reports
Pathological gambling
Hiccups
Warnings
Black box warnings
Not approved for dementia-related psychosis; patients with dementia-related psychosis who are treated with antipsychotic drugs are at increased risk of death, as shown in short-term controlled trials; deaths reported in trials appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
In short-term studies, antidepressants increased risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses
Contraindications
Documented hypersensitivity
Cautions
Risk of NMS and extrapyramidal symptoms (EPS)
Tardive dyskinesia may occur; may consider discontinuation of therapy if clinically indicated
Use caution in patients with known cardiovascular disease, cerebrovascular disease, or predisposition to hypotension; may increase incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack, including fatalities)
Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope
Use caution in patients with Parkinson disease; may aggravate motor disturbances
May increase risk of suicidal tendencies in children and adolescents
FDA warning regarding off-label use for dementia in elderly
Patients may act on dangerous impulses
Leukopenia/neutropenia and agranulocytosis reported; possible risk factors for leukopenia/neutropenia include preexisting low white blood cell (WBC) count and history of drug-induced leukopenia/neutropenia
If patient has history of clinically significant low WBC count or drug-induced leukopenia/neutropenia, monitor complete blood count (CBC) frequently during first few months of therapy; discontinue drug at first sign of clinically significant WBC decline <1000/mcL in absence of other causative factors, and continue monitoring WBC count until recovery
Monitor for orthostatic hypertension
May cause seizures or convulsions; use cautiously in patients with history of seizures or with conditions that lower the seizure threshold
May cause CNS depression, which may impair physical or mental abilities; use caution when operating heavy machinery
Use caution in patients at risk of pneumonia; antipsychotic therapy has been associated with esophageal dysmotility and aspiration
Impairment of core body temperature regulation possible; use caution in dehydration, heat exposure, strenuous exercise, and concomitant medication possessing anticholinergic effects
Metabolic changes
- Atypical antipsychotics have been associated with metabolic changes that may increase cardiovascular or cerebrovascular risk, including dyslipidemia and body weight gain
- Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics has been associated with ketoacidosis, hyperosmolar coma, or death; monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness; monitor glucose regularly in patients with and at risk for diabetes
- Significant weight gain reported with therapy; monitor waist circumference and BMI
Pregnancy and lactation
Pregnancy category: C
Neonates exposed to antipsychotic drugs during 3rd trimester of pregnancy are at risk for EPS or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization
Lactation: Excreted in human breast milk; a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Abilify Maintena, Aristada (aripiprazole)
Mechanism of action
Atypical antipsychotic; partial agonist at dopamine D2 and serotonin type 1 (5-HT1A) receptors; antagonist at serotonin type 2 (5-HT2A) receptor; also has alpha-blocking activity
Absorption
Bioavailability: 87% (tablet); 100% (IM)
Peak plasma time: 1-3 hr (IR); 5-7 hr (ER); 3-5 hr (tablet)
Distribution
Protein bound: 99%
Vd: 404 L (4.9 L/kg)
Metabolism
Metabolized by CYP2D6 and CYP3A4
Metabolites: Dehydroaripiprazole (40%)
Elimination
Half-life: 75 hr (parent drug); 94 hr (metabolite); 30-47 days (IM); 146 hr (poor metabolizers)
Excretion: Feces (55%), urine (25%)
Administration
IM Preparation (Abilify Maintena)
Do not confuse IM long-acting depot suspension for maintenance of schizophrenia with the IM solution for acute agitation in patients with schizophrenia or mania
Reconstitute lyophilized power with sterile water for injection (SWI); discard any unused portion of diluent
400 mg/vial: 1.9 mL SWI
300 mg/vial: 1.5 mL SWI
Final concentration for either vial is 200 mg/mL following reconstitution
Slowly inject SWI into vial, and then withdraw air from vial to equalize the pressure
Shake the vial vigorously for 30 seconds until the reconstituted suspension appears uniform
Visually inspect for particulate matter and discoloration; should appear as a uniform, homogeneous suspension that is opaque and milky-white in color
Do not store reconstituted suspension in syringe
Use BD Leur-Lok syringe (provided in kit) to remove the vial adapter from the package and discard the vial adapter package
Determine recommended volume for injection to provide appropriate dose
Attach adapter-syringe to vial and pushing adapter’s spike firmly through the rubber stopper until it snaps in place
Slowly withdraw the dosage volume into the syringe
Remove BD Leur-Lok syringe and select appropriate size hypodermic needle
Needle for gluteal injection
- Nonobese patient: 22-ga, 1.5-in
- Obese patient: 21-ga, 2-in
Needle for deltoid injection
- Nonobese patient: 23-ga, 1-in
- Obese patient: 22-ga, 1.5-in
IM Preparation (Aristada)
Tap the syringe on your palm at least 10 times to dislodge any material which may have settled, and then shake the syringe vigorously for a minimum of 30 seconds to ensure a uniform suspension; if the syringe is not used within 15 minutes, shake again for 30 seconds
Select injection need according to injection site
- 441 mg dose (deltoid): 21-ga, 1-in or 20-ga, 1.5-in
- 441 mg, 662 mg, or 882 mg doses (gluteal): 20-ga, 1.5-in or 20-ga 2-in
Attach appropriate needle with a clockwise twisting motion; do not overtighten (could lead to needle hub cracking)
Prime syringe to remove air by bringing the syringe into upright position and tap the syringe to bring air to the top; remove air by depressing the plunger rod; a few drops of suspension will be released
Administer the entire content IM; inject in a rapid and continuous manner in <10 seconds
Cover the needle by pressing the safety device, then dispose the needle, and used and unused items in proper waste container
IM Administration
Must be administered by a healthcare professionaL
For IM use only; do not administer IV or SC
Abilfy Maintena
- Slowly inject dosage volume as a single IM injection into the deltoid or gluteal muscle
- Do not massage the injection site
Aristada
- Administer the entire syringe content IM; inject in a rapid and continuous manner in <10 seconds
- 441 mg once monthly: Administer in deltoid or gluteal muscle
- 662 mg monthly, 882 mg monthly or q6wk: Administer in gluteal muscle
