Aripiprazole

Trade Names:Abilify- Tablets 2 mg- Tablets 5 mg- Tablets 10 mg- Tablets 15 mg- Tablets 20 mg- Tablets 30 mg- Solution, oral 1 mg/mL- Injection 7.5 mg/mL

Trade Names:Abilify Discmelt- Tablets, orally disintegrating 10 mg- Tablets, orally disintegrating 15 mg

Pharmacology

Partial agonist at dopamine D ₂ and serotonin 5-HT _1A receptors, and antagonist at serotonin 5-HT _2A receptor.

Pharmacokinetics

Absorption

Well absorbed; steady state is attained within 14 days. T _max is 3 to 5 h and bioavailability is 87%.

T _max is 1 to 3 h and absolute bioavailability is 100%.

Distribution

More than 99% is protein bound, primarily to albumin. Vd is 404 L or 4.9 L/kg.

Metabolism

Hepatic metabolism (dehydrogenation, hydroxylation, N-dealkylation) involves CYP2D6 and CYP3A4. Major metabolite is dehydroaripiprazole (active).

Elimination

Approximately 25% excreted in urine (less than 1% unchanged) and 55% in feces (approximately 18% as unchanged drug). Elimination half-life is 75 h (aripiprazole) and 94 h (dehydroaripiprazole).

Special Populations

In severe renal function impairment (CrCl less than 30 mL/min), C _max increased by 36% (parent drug) and 53% (metabolite), but AUC was 15% lower for aripiprazole and 7% higher for metabolite. No dosage adjustment needed.

AUC increased by 31% in mild hepatic function impairment, increased by 8% in moderate impairment, and decreased by 20% in severe impairment. No dosage adjustment required.

Cl was 20% lower. No dosage adjustment required.

C _max and AUC are 30% to 40% higher in women than in men. No dosage adjustment required.

No dosage adjustment is recommended.

No dosage adjustment is recommended.

Indications and Usage

Acute and maintenance treatment of schizophrenia in adults and adolescents 13 to 17 yr of age; acute and maintenance treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults and children 10 to 17 yr of age; adjunctive therapy to either lithium or valproate for the acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in adults and children 10 to 17 yr of age; adjunctive therapy to antidepressants for the acute treatment of major depressive disorder in adults.

Treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed.

Unlabeled Uses

Limited evidence suggests that aripiprazole may be a reasonable alternative in patients with restless leg syndrome.

Contraindications

Standard considerations.

Dosage and Administration

IM Recommended dose is 9.75 mg. A lower dose of 5.25 mg may be considered based on clinical factors. If agitation persists, cumulative dosages of up to 30 mg/day may be given.

PO Recommended starting and target dose is 15 mg as monotherapy or adjunctive therapy with lithium or valproate given once daily. The dosage can be increased to 30 mg/day based on clinical response.

PO Start with 2 mg/day, then titrate to 5 mg/day after 2 days and to the target dosage of 10 mg/day after 2 additional days. Subsequent dose increases should be in 5 mg/day increments.

PO Recommended starting dosage for patients already receiving an antidepressant is 2 to 5 mg/day. Gradually make dose adjustments of up to 5 mg/day at intervals of no less than 1 wk. Efficacy of adjunctive therapy was established within the range of 2 to 15 mg/day. Long-term efficacy has not been established.

PO Start with 10 or 15 mg/day once a day. The effective dosage range is 10 to 30 mg/day. Do not increase dosage before 2 wk.

PO Start with 2 mg/day, then titrate to 5 mg/day after 2 days, and to a target dose of 10 mg after 2 additional days. Subsequent dose increases should be in 5 mg/day increments. 30 mg/day was not shown to be more efficacious than 10 mg/day.

No evidence is available from controlled trials. Periodically reassess patient to determine need for maintenance treatment.

PO Reduce the usual dose of aripiprazole by 50%. Increase the dose when the CYP3A4 or CYP2D6 inhibitor is discontinued.

PO Double the usual dose of aripiprazole (to 20 to 30 mg). Base additional increases on clinical evaluation. Decrease the dose (to 10 to 15 mg) when the CYP3A4 inducer is discontinued.

General Advice

• May be given orally without regard to meals.
• Parenteral administration is intended for IM use only; inject slowly, deep into muscle mass. Do not give IV or subcutaneously.
• Oral solution may be substituted for tablets on a mg-per-mg basis up to a 25 mg dose. Patients receiving 30 mg tablets should receive 25 mg of the solution.
• Dosing for the orally disintegrating tablet is the same as the oral tablet.
• IM injection has not been evaluated in children.

Storage/Stability

Store at 59° to 86°F.

Store at 59° to 86°F. Opened bottle can be used for up to 6 mo after opening.

Store at 59° to 86°F. Protect from light by storing in carton until use.

Drug Interactions

Patients should avoid alcohol while taking aripiprazole.

Because of its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

Use with caution.

May elevate aripiprazole plasma levels, increasing the adverse reactions.

May reduce aripiprazole plasma levels, decreasing the therapeutic effect.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions were reported with aripiprazole monotherapy.

Cardiovascular

Tachycardia (2%); hypertension (at least 1%); orthostatic hypotension (1%).

CNS

Headache (27%); somnolence (26%); extrapyramidal disorder (20%); agitation (19%); insomnia (18%); anxiety (17%); akathisia (13%); tremor (12%); fatigue (11%); dizziness (10%); sedation (8%); restlessness (6%); increased appetite (4%); pyrexia (3%); dystonia (2%); abnormal coordination, asthenia, decreased appetite, irritability, suicidal ideation (at least 1%); dyskinesia (1%).

Dermatologic

Rash (2%); hyperhidrosis, rash including acneform, allergic, contact, drug eruption, erythematous, exfoliative, generalized, macular, maculopapular, neurodermatitis, papular rash, and seborrheic dermatitis (at least 1%).

EENT

Blurred vision (8%); nasopharyngitis (4%); nasal congestion (at least 1%).

GI

Nausea (15%); constipation, vomiting (11%); dyspepsia (9%); salivary hypersecretion (8%); dry mouth (5%); toothache (4%); abdominal pain, diarrhea, stomach discomfort (3%).

Lab Tests

Increased CPK (at least 1%).

Metabolic-Nutritional

Weight increase (3%); increased blood insulin, weight decrease (at least 1%).

Musculoskeletal

Musculoskeletal stiffness, pain in extremities (4%); arthralgia, muscle spasm, myalgia (2%).

Respiratory

Cough, pharyngolaryngeal pain (3%); aspiration pneumonia, dyspnea (at least 1%).

Miscellaneous

Pain (3%); chest pain, peripheral edema (at least 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established for the treatment of major depressive disorder or agitation associated with schizophrenia or bipolar mania in children. Safety and efficacy not established for the treatment of schizophrenia in children younger than 13 yr of age. Safety and efficacy not established for the treatment of bipolar mania in children younger than 10 yr of age.

Elderly

No dosage adjustment is recommended for elderly patients.

Aspiration pneumonia

Antipsychotics have been associated with esophageal dysmotility and aspiration; use with caution in patients at risk for aspiration pneumonia.

Cerebrovascular adverse reactions

The risk of cerebrovascular adverse reactions (eg, stroke, transient ischemic attack) may be increased.

Cognitive and motor skills

Cognitive and motor skills may be impaired.

Concomitant illness

Use with caution in patients with CV disease (history of MI or ischemic heart disease, heart failure, or conduction abnormalities) and cerebrovascular disease.

Dosage adjustment

Adjust dosage when aripiprazole is used concomitantly with a potential CYP3A4 inhibitor or inducer, or with a potential CYP2D6 inhibitor.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur.

NMS

NMS has occurred with antipsychotics and is potentially fatal. Signs and symptoms are altered mental status, diaphoresis, hyperpyrexia, irregular BP, irregular pulse, muscle rigidity, and tachycardia.

Orthostatic hypotension

May occur.

Phenylketonurics

Orally disintegrating tablets contain phenylalanine; use with caution in patients with phenylketonuria.

Seizures

Seizures may occur; use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

Suicide

Closely supervise high-risk patients. Prescribe the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

Tardive dyskinesia

A potentially irreversible syndrome of involuntary body and facial movements may occur.

Temperature regulation

Antipsychotics can disrupt the body's ability to reduce core temperature.

Overdosage

Symptoms

Acidosis, aggression, aspiration pneumonia, AST elevation, atrial fibrillation, blood CPK elevation, bradycardia, coma, confusional state, convulsion, depressed consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolongation, QT interval prolongation, respiratory arrest, somnolence, status epilepticus, tachycardia, tremor, vomiting.

Patient Information

• Explain name, dose, action, and potential adverse reactions of drug, including risk of developing tardive dyskinesia.
• Instruct patient to take prescribed dose once daily without regard to meals, but to take with food if stomach upset occurs.
• Instruct patient not to open blister for orally disintegrating tablet until ready to administer.
• Inform patient that orally disintegrating tablet should be placed on the tongue and that disintegration occurs rapidly in saliva. It may be taken without water.
• Advise patients with phenylketonuria that orally disintegrating tablets contain phenylalanine.
• Advise patients that oral solution contains sucrose and fructose.
• Instruct patient not to stop taking aripiprazole when feeling better.
• Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
• Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed, and to inform health care provider of significant changes in readings.
• Tell patient to immediately report high fever, muscle rigidity, altered mental status, irregular or rapid pulse, sweating, racing thoughts, mood swings, irritability, unquenchable thirst, frequent urination, seizures, or rash to health care provider.
• Advise patient to avoid strenuous activity during periods of high temperature or humidity.
• Instruct patient to avoid alcoholic beverages while taking aripiprazole.
• Instruct patient to get up slowly from lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to health care provider. Caution patient that hot tubs or hot showers or baths may make dizziness worse.
• Advise patient taking antihypertensives to monitor BP at regular intervals.
• Advise patient that drug may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness.
• Advise patient to notify health care provider of the following symptoms: constipation, excessive drowsiness, increased agitation or anxiety, involuntary body or facial movements, nausea, vomiting.

Copyright © 2009 Wolters Kluwer Health.