ARIPiprazole

General

**BEERS Drug**

Genetic Implications: Genetic Implications

Pronunciation:
a-ri-pip-ra-zole


ARIPiprazole

Trade Name(s)

  • Abilify
  • Abilify Maintena
  • Abilify Mycite
  • Aristada
  • Aristada Initio

Ther. Class.
antipsychotics
mood stabilizers

Pharm. Class.
serotonin-dopamine activity modulators (SDAM)

Indications

  • Schizophrenia (Abilify, Abilify Maintena, Abilify Mycite, and Aristada).
  • Acute treatment of manic and mixed episodes associated with bipolar I disorder (as monotherapy or with lithium or valproate) (Abilify and Abilify Mycite).
  • Maintenance treatment of bipolar I disorder (as monotherapy) (Abilify Maintena).
  • Maintenance treatment of bipolar I disorder (as monotherapy or with lithium or valproate) (Abilify Mycite).
  • Adjunctive treatment of depression (Abilify and Abilify Mycite).
  • Agitation associated with schizophrenia or bipolar disorder (Abilify only).
  • Irritability associated with autistic disorder (Abilify only).
  • Tourette's disorder (Abilify only).

Action

  • Psychotropic activity may be due to agonist activity at dopamine D2  and serotonin 5-HT1A  receptors and antagonist activity at the 5-HT2A  receptor.
  • Also has alpha1  adrenergic blocking activity.

Therapeutic Effect(s):

  • Decreased manifestations of schizophrenia.
  • Decreased mania in bipolar patients.
  • Decreased symptoms of depression.
  • Decreased agitation associated with schizophrenia or bipolar disorder.
  • Decreased emotional and behavioral symptoms of irritability.
  • Decreased incidence of tics.

Pharmacokinetics

Absorption: Well absorbed (87%) following oral administration; 100% following IM injection.

Distribution: Extensive extravascular distribution.

Protein Binding: >99%.

Metabolism and Excretion: Mostly metabolized by the liver (CYP3A4 and CYP2D6 isoenzymes); Genetic implication  the CYP2D6 enzyme system exhibits genetic polymorphism; ~7% of population may be poor metabolizers (PMs) and may have significantly ↑ aripiprazole concentrations and an ↑ risk of adverse effects (↓ dose by 50% in PMs); one metabolite (dehydro-aripiprazole) has antipsychotic activity. 18% excreted unchanged in feces; <1% excreted unchanged in urine.

Half-life: Aripiprazole– 75 hr;  dehydro-aripiprazole–94 hr ; ER injectable suspension: 30–46 days (Abilify Maintena); 29–35 days (Aristada)

TIME/ACTION PROFILE (antipsychotic effect)

ROUTEONSETPEAKDURATION
POunknown2 wkunknown
ER-IMunknownunknownunknown

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity;
  • CYP2D6 PMs or concurrent use of strong CYP3A4 inhibitors, strong CYP2D6 inhibitors, or strong CYP3A4 inducers (Aristada Initio only);

Use Cautiously in:

  • Known cardiovascular or cerebrovascular disease;
  • Conditions which cause hypotension (dehydration, treatment with antihypertensives or diuretics);
  • Diabetes (may ↑ risk of hyperglycemia);
  • Seizure disorders;
  • Patients at risk for aspiration pneumonia or falls;
  • Concurrent ketoconazole or other potential CYP3A4 inhibitors (↓ aripiprazole dose by 50%);
  • Concurrent quinidine, fluoxetine, paroxetine, or other potential CYP2D6 inhibitors;
  • Concurrent carbamazepine or other potential CYP3A4 inducers;
  • OB:  Neonates at ↑ risk for extrapyramidal symptoms and withdrawal after delivery when exposed during the 3rd trimester; use only if maternal benefit outweighs risk to fetus;
  • Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant.
  • Pedi:  May ↑ risk of suicide attempt/ideation especially during dose early treatment or dose adjustment; risk may be greater in children, adolescents, and young adults taking antidepressants (safety in children/adolescents not established);
  • Geri:  ↑ risk of mortality in elderly patients treated for psychosis related to dementia/neurocognitive disorders.

Adverse Reactions/Side Effects

CV: bradycardia, chest pain, edema, hypertension, orthostatic hypotension, tachycardia

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), dry skin, ecchymosis, skin ulcer, sweating

EENT: blurred vision, conjunctivitis, ear pain

GI: constipation, anorexia, ↑ salivation, nausea, vomiting, weight gain, weight loss

GU: urinary incontinence

Hemat: AGRANULOCYTOSIS, anemia, leukopenia, neutropenia

Metabolic: dyslipidemia, hyperglycemia

MS: muscle cramps, neck pain

Neuro: tremor, abnormal gait, SUICIDAL THOUGHTS, drowsiness, extrapyramidal reactions, akathisia, confusion, depression, fatigue, hostility, impaired cognitive function, impulse control disorders (eating/binge eating, gambling, sexual, shopping), insomnia, lightheadedness, manic reactions, nervousness, restlessness, sedation, seizures, tardive dyskinesia

Resp: dyspnea

Misc: HYPERSENSITIVITY REACTIONS, NEUROLEPTIC MALIGNANT SYNDROME, ↓ heat regulation, injection site reactions

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Ketoconazole,  clarithromycin, or other  strong CYP3A4 inhibitors  ↓ metabolism and ↑ effects (↓ aripiprazole dose by 50%).
  •  Quinidine,  fluoxetine,  paroxetine, or  other strong CYP2D6 inhibitors  ↓ metabolism and ↑ effects (↓ aripiprazole dose by at least 50%).
  • Concurrent  carbamazepine  or  other potential CYP3A4 inducers  ↑ metabolism and ↓ effects (double aripiprazole dose).

Route/Dosage

If used concurrently with combination of strong, moderate, or weak CYP3A4 and CYP2D6 inhibitors, ↓ oral aripiprazole dose by 75%. Aripiprazole dose should be ↓ by 75% in CYP2D6 PMs who are concomitantly receiving a strong CYP3A4 inhibitor. Do NOT substitute Aristada Initio for Aristada.

Schizophrenia

PO (Adults): 10 or 15 mg once daily; doses up to 30 mg/day have been used; increments in dosing should not be made before 2 wk at a given dose.

PO (Children 13–17 yr): 2 mg once daily; ↑ to 5 mg once daily after 2 days, and then to target dose of 10 mg once daily after another 2 days; may further ↑ dose in 5-mg increments if needed (max: 30 mg/day).

IM (Adults): Abilify Maintena– 400 mg every mo; after 1st injection, continue treatment with oral aripiprazole (10–20 mg/day) for 14 days; if no adverse reactions to 400 mg/mo dose, may ↓ dose to 300 mg every mo.  CYP2D6 PMs– ↓ dose to 300 mg monthly;  CYP2D6 PMs concomitantly receiving strong CYP3A4 inhibitor– ↓ dose to 200 mg monthly;  Concomitant therapy with strong CYP2D6 or CYP3A4 inhibitor– ↓ dose to 300 mg monthly (if originally receiving 400 mg monthly) or 200 mg monthly (if originally receiving 300 mg monthly);  Concomitant therapy with strong CYP2D6 and CYP3A4 inhibitor– ↓ dose to 200 mg monthly (if originally receiving 400 mg monthly) or 160 mg monthly (if originally receiving 300 mg monthly);  Concomitant therapy with CYP3A4 inducer– Avoid use.

IM (Adults): Aristada with Aristada Initio– administer 675–mg injection of Aristada Initio with first injection of Aristada (dose is based on total daily dose of oral aripiprazole; if patient receiving 10 mg/day of oral aripiprazole, administer 441 mg every mo; if patient receiving 15 mg/day of oral aripiprazole, administer 662 mg every mo, 882 mg every 6 wk, or 1064 mg every 2 mo; if patient receiving ≥20 mg/day of oral aripiprazole, administer 882 mg every mo) (initial Aristada dose can be given on same day as or within 10 days of Aristada Initio) AND one dose of oral aripiprazole 30 mg;  Aristada without Aristada Initio– Dose is based on total daily dose of oral aripiprazole; if patient receiving 10 mg/day of oral aripiprazole, administer 441 mg every mo; if patient receiving 15 mg/day of oral aripiprazole, administer 662 mg every mo, 882 mg every 6 wk, or 1064 mg every 2 mo; if patient receiving ≥20 mg/day of oral aripiprazole, administer 882 mg every mo; after 1st injection; continue treatment with oral aripiprazole for 21 days;  Concomitant therapy with strong CYP2D6 or CYP3A4 inhibitor for >2 wk– ↓ dose of Aristada to 441 mg monthly (if originally receiving 662 mg monthly) or 662 mg monthly (if originally receiving 882 mg monthly); no dose adjustment necessary if originally receiving 441 mg monthly; avoid use of Aristada Initio;  CYP2D6 PMs concomitantly receiving strong CYP3A4 inhibitor for >2 wk– ↓ dose of Aristada to 441 mg monthly (if originally receiving 662 mg or 882 mg monthly); no dose adjustment necessary if originally receiving 441 mg monthly; avoid use of Aristada Initio;  Concomitant therapy with strong CYP2D6 and CYP3A4 inhibitor– avoid use of Aristada in patients requiring 662 mg or 882 mg monthly dose; no dose adjustment of Aristada necessary if originally receiving 441 mg monthly; avoid use of Aristada Initio;  Concomitant therapy with CYP3A4 inducer– ↑ dose of Aristada to 662 mg monthly (if originally receiving 441 mg monthly); no dose adjustment if Aristada necessary if originally receiving 662 mg or 882 mg monthly; avoid use of Aristada Initio.

Acute Manic or Mixed Episodes Associated with Bipolar I Disorder

PO (Adults): 15 mg once daily as monotherapy or 10–15 mg once daily with lithium or valproate; target dose is 15 mg once daily; may ↑ to 30 mg once daily, if needed.

PO (Children 10–17 yr): 2 mg once daily; ↑ to 5 mg once daily after 2 days, and then to target dose of 10 mg once daily after another 2 days; may further ↑ dose in 5-mg increments if needed (max: 30 mg/day).

Maintenance Treatment of Bipolar I Disorder

PO (Adults): Abilify Mycite– 15 mg once daily as monotherapy or 10–15 mg once daily with lithium or valproate; target dose is 15 mg once daily; may ↑ to 30 mg once daily, if needed.

IM (Adults): 400 mg every mo; after 1st injection, continue treatment with oral aripiprazole (10–20 mg/day) for 14 days; if no adverse reactions to 400 mg/mo dose, may ↓ dose to 300 mg every mo.  CYP2D6 PMs– ↓ dose to 300 mg monthly;  CYP2D6 PMs concomitantly receiving strong CYP3A4 inhibitor– ↓ dose to 200 mg monthly;  Concomitant therapy with strong CYP2D6 or CYP3A4 inhibitor– ↓ dose to 300 mg monthly (if originally receiving 400 mg monthly) or 200 mg monthly (if originally receiving 300 mg monthly);  Concomitant therapy with strong CYP2D6 and CYP3A4 inhibitor– ↓ dose to 200 mg monthly (if originally receiving 400 mg monthly) or 160 mg monthly (if originally receiving 300 mg monthly);  Concomitant therapy with CYP3A4 inducer– Avoid use.

Depression

PO (Adults): 2–5 mg once daily, may titrate upward at 1-wk intervals to 5–10 mg once daily (max: 15 mg/day).

Irritability Associated with Autistic Disorder

PO (Children 6–17 yr): 2 mg once daily; ↑ to 5 mg once daily after at least 1 wk; may further ↑ dose in 5-mg increments if needed at ≥1-wk intervals (max: 15 mg/day).

Tourette's Disorder

PO (Children 6–18 yr and ≥50 kg): 2 mg once daily; ↑ to target dose of 5 mg once daily after 2 days; may further ↑ dose if needed at ≥1-wk intervals (max: 10 mg/day).

PO (Children 6–18 yr and <50 kg): 2 mg once daily; ↑ to 5 mg once daily after 2 days, and then to target dose of 10 mg once daily after 5 days; may further ↑ dose in 5-mg increments if needed at ≥1-wk intervals (max: 20 mg/day).

Availability (generic available)

Extended-release suspension for injection (Abilify Maintena) (prefilled syringes or vials): 300 mg, 400 mg

Extended-release suspension for injection (Aristada) (prefilled syringes): 441 mg/1.6 mL, 662 mg/2.4 mL, 882 mg/3.2 mL, 1064 mg/3.9 mL

Extended-release suspension for injection (Aristada Initio) (prefilled syringes): 675 mg/2.4 mL

Immediate-release tablets: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Cost: 2 mg $2,208.52/90, 5 mg $2,208.52/90, 10 mg $2,208.52/90, 15 mg $2,208.52/90, 20 mg $3,107.38/90, 30 mg $3,107.38/90

Immediate-release tablets with sensor (Abilify Mycite): 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg

Oral solution (orange cream): 1 mg/mL

Orally disintegrating tablets (vanilla flavor): 10 mg, 15 mg

Cost: All strengths $955.82/30

Assessment

  • Assess mental status (orientation, mood, behavior) before and periodically during therapy. Assess for suicidal tendencies, especially during early therapy for depression. Restrict amount of drug available to patient. Risk may be increased in children, adolescents, and adults ≤24 yrs.
  • Assess weight and BMI initially and throughout therapy. Compare weight of children and adolescents with that expected during normal growth.
  • Monitor BP (sitting, standing, lying), pulse, and respiratory rate before and periodically during therapy.
  • Observe patient carefully when administering medication to ensure that medication is actually taken and not hoarded or cheeked.
  • Monitor patient for onset of akathisia (restlessness or desire to keep moving) and extrapyramidal side effects ( parkinsonian– difficulty speaking or swallowing, loss of balance control, pill rolling of hands, masklike face, shuffling gait, rigidity, tremors; and  dystonic– muscle spasms, twisting motions, twitching, inability to move eyes, weakness of arms or legs) periodically throughout therapy. Report these symptoms.
  • Monitor for tardive dyskinesia (uncontrolled rhythmic movement of mouth, face, and extremities; lip smacking or puckering; puffing of cheeks; uncontrolled chewing; rapid or worm-like movements of tongue). Notify health care professional immediately if these symptoms occur, as these side effects may be irreversible.
  • Monitor for development of neuroleptic malignant syndrome (fever, muscle rigidity, altered mental status, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness, loss of bladder control). Notify health care professional immediately if these symptoms occur.
  • Assess for falls risk. Drowsiness, orthostatic hypotension, and motor and sensory instability increase risk. Institute prevention if indicated.

Lab Test Considerations:

May cause ↑ creatine kinase.

  • Monitor CBC frequently during initial mo of therapy in patients with pre-existing or history of low WBC. May cause leukopenia, neutropenia, or agranulocytosis. Discontinue therapy if this occurs.
  • Monitor blood glucose and cholesterol levels prior to starting and periodically during therapy.

Potential Diagnoses

Implementation

  • Do not confuse aripiprazole with rabeprazole.
  • Aristada Initio  is only used as a one-time dose to initiate  Aristada  therapy or if doses of  Aristada  are missed. Administer missed doses as soon as possible, may supplement next  Aristada  injection with  Aristada Initio.   If last Aristada injection 441 mg and time since last injection ≤6 wk,  do not supplement if >6 wk and ≤ 7 wk since last dose,  supplement with single dose of  Aristada Initio  if >7 wk since last dose,  re-initiate with a single dose of  Aristada Initio  and a single dose of oral aripiprazole 30 mg.  If last Aristada injection 662 mg or 882 mg and time since last injection ≤8 wk,  do not supplement if >8 wk and ≤12 wk since last dose,  supplement with single dose of  Aristada Initio  if ≥12 wk since last dose,  re-initiate with a single dose of  Aristada Initio  and a single dose of oral aripiprazole 30 mg.  If last Aristada injection 1064 mg and time since last injection ≤10 wk,  do not supplement if >8 wk and ≤12 wk since last dose,  supplement with single dose of  Aristada Initio  if ≥12 wk since last dose,  re-initiate with a single dose of  Aristada Initio  and a single dose of oral aripiprazole 30 mg.
  • PO 

    Administer once daily without regard to meals.

    • Orally disintegrating tablets:  Do not open blister until ready to administer. For single tablet removal, open package and peel back foil on blister to expose tablet. Do not push tablet through foil; may damage tablet. Immediately upon opening blister, using dry hands, remove tablet and place entire orally disintegrating tablet on tongue. Tablet disintegration occurs rapidly in saliva. Take tablet without liquid; but if needed, it can be taken with liquid. Do not attempt to split tablet.
  • Abilify Mycite: Comprised of aripiprazole tablets embedded with an ingestible event marker (IEM) sensor to track drug ingestion. Kit includes tablets, a wearable sensor (Mycite patch) that detects signal from IEM after ingestion and transmits to a smartphone, a smartphone app (Mycite app) to display information for patient, and a web-based portal for health care professionals and caregivers. Ensure patient is capable and willing before use. Download app, follow instructions, ensure app is compatible with smartphone and paired with patch. When instructed by app, apply patch to left side of body just above lower edge of rib cage for  1-component patch  or to right or left side for  2–component patch. Avoid applying patch in areas where skin is scraped, cracked, inflamed, or irritated, or in a location that overlaps area of most recently removed patch; if skin irritation occurs remove patch. Change patch at least weekly; do not remove for showering, swimming, or exercising. Ingestion is usually detected within 30 min, but may take up to 2 hr. If ingestion is not detected, do not repeat dose. Administer tablet without regard to food. Swallow tablet whole; do not divide, crush, or chew.
  • Extended-Release IM:

    Abilify Maintena  is available in vials or dual chamber prefilled syringes.  For vials,  reconstitute 300 mg dose with 1.5 mL and 400 mg dose with 1.9 mL of sterile water for injection; discard extra sterile water. Withdraw air to equalize pressure in vial. Shake vial vigorously for 30 sec until suspension is uniform; suspension is opaque and milky white. If injection is not given immediately, shake vial vigorously to resuspend prior to injection. Do not store suspension in syringe. Determine volume needed for dose: from 400 mg vial: 400 mg = 2 mL, 300 mg = 1.5 mL, 200 mg = 1.0, and 160 mg = 0.8 mL. From 300 mg vial: 300 mg = 1.5 mL, 200 mg = 1 mL, and 160 mg = 0.8 mL.  For prefilled syringes,  push plunger rod slightly to engage threads. Rotate plunger rod until rod stops rotating to release diluent; middle stopper will be at indicator line. Vertically shake syringe vigorously for 20 sec until drug is uniformly milky-white.  For deltoid site,  use 23 gauge needle, 1 inch in length for non-obese patients and 22 gauge 1.5 inch for obese patients.  For gluteal site,  use 22 gauge needle, 1.5 inches in length for non-obese patients and 22 gauge, 2 inch for obese patients. Inject deep into deltoid or gluteal site; do not massage. Continue oral dosing of aripiprazole for 2 wk after first dose of  Abilify Maintena 

    • If 2nd or 3rd doses of  Abilify Maintena  are missed and >4 wk and <5 wk since last injection, administer injection as soon as possible. If >5 wk since last injection, restart concomitant oral aripiprazole for 14 days with next administered injection. If fourth or subsequent doses are missed and >4 wk and <6 wk since last injection, administer injection as soon as possible. If >6 wk since last injection, restart concomitant oral aripiprazole for 14 days with next administered injection.
    • Aristada  comes in a kit with several needle sizes. Tap syringe at least 10 times to dislodge settled material and shake syringe vigorously for at least 30 sec to ensure suspension is uniform. Shake again if syringe not used within 15 min. Select needle and injection site. Deltoid may be used for 441 mg dose only. May use gluteal site for all doses. Remove air from syringe. Inject entire contents rapidly and continuously over <10 sec.

Patient/Family Teaching

  • Advise patient to take medication as directed and not to skip doses or double up on missed doses. Take missed doses as soon as remembered unless almost time for the next dose. Emphasize importance of maintaining regular scheduled injections when taking  Abilify Maintena or Aristada. 
  • Inform patient of possibility of extrapyramidal symptoms and tardive dyskinesia. Instruct patient to report these symptoms immediately.
  • Advise patient to make position changes slowly to minimize orthostatic hypotension.
  • Medication may cause drowsiness and lightheadedness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide; new or worse depression; new or worse anxiety; feeling very agitated or restless; panic attacks; trouble sleeping; new or worse irritability; acting aggressive; being angry or violent; acting on dangerous impulses; an extreme increase in activity and talking; other unusual changes in behavior or mood or if signs and symptoms of high blood sugar (feel very thirsty, urinating more than usual, feel very hungry, feel weak or tired, nausea, confusion, breath smells fruity) occur.
  • Inform patient that aripiprazole may cause weight gain. Advise patient to monitor weight periodically. Notify health care professional of significant weight gain.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any new medications. Caution patient to avoid taking alcohol or other CNS depressants concurrently with this medication.
  • Advise patient that extremes in temperature should be avoided, because this drug impairs body temperature regulation.
  • Advise patient to notify health care professional if new or increased eating/binge eating, gambling, sexual, shopping, or other impulse control disorders occur.
  • Advise patient to notify health care professional of medication regimen prior to treatment or surgery.
  • Rep:  Advise female patients to notify health care professional if pregnancy is planned or suspected and or if breast feeding. Encourage pregnant patients to enroll in pregnancy exposure registry that monitors outcomes of women exposed to aripiprazole during pregnancy by contacting National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi....
  • Emphasize the importance of routine follow-up exams and continued participation in psychotherapy as indicated.
  • Abilify Mycite: Advise patient referred for MRI test to remove patch and replace with a new patch as soon as possible.

Evaluation/Desired Outcomes

  • Decrease in excitable, paranoid, or withdrawn behavior.
  • Decrease incidence of mood swings in patients with bipolar disorders.
  • Increased sense of well-being in patients with depression.
  • Decreased agitation associated with schizophrenia or bipolar disorder.
  • Decreased emotional and behavioral symptoms of irritability.
  • Decrease in tics.
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