Class: Antipsychotic agent, Quinolinone derivative
- Tablets 2 mg
- Tablets 5 mg
- Tablets 10 mg
- Tablets 15 mg
- Tablets 20 mg
- Tablets 30 mg
- Solution, oral 1 mg/mL
- Injection, solution 7.5 mg/mL
- Tablets, orally disintegrating 10 mg
- Tablets, orally disintegrating 15 mg
Partial agonist at dopamine D 2 and serotonin 5-HT 1A receptors, and antagonist at serotonin 5-HT 2A receptor.
Well absorbed; steady state is attained within 14 days. T max is 3 to 5 h and bioavailability is 87%.Injection
T max is 1 to 3 h and absolute bioavailability is 100%.
More than 99% is protein bound, primarily to albumin. Vd is 404 L or 4.9 L/kg.
Hepatic metabolism (dehydrogenation, hydroxylation, N-dealkylation) involves CYP2D6 and CYP3A4. Major metabolite is dehydroaripiprazole (active).
Approximately 25% of a single oral dose is 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 PopulationsRenal Function Impairment
In severe renal 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.Hepatic Function Impairment
AUC increased by 31% in mild hepatic impairment, increased by 8% in moderate impairment, and decreased by 20% in severe impairment. No dosage adjustment required.Elderly
Cl was 20% lower. No dosage adjustment required.Children
Pharmacokinetics in children 10 to 17 yr of age are similar to those in adults.Gender
C max and AUC are 30% to 40% higher in women than in men. No dosage adjustment required.Race
No clinically significant race-related differences in pharmacokinetics were demonstrated.Smoking
No significant pharmacokinetic differences were seen between smokers and nonsmokers.
Indications and UsageOral
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 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 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 irritability associated with autistic disorder in children 6 to 17 yr of age.Injection
Treatment of agitation associated with schizophrenia or bipolar disorder, manic or mixed, in adults.
Cocaine dependence; restless leg syndrome (oral).
Known hypersensitivity to the product.
Dosage and AdministrationAgitation Associated With Schizophrenia or Bipolar Mania
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. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 h has not been adequately evaluated.Bipolar Disorder
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.Children 10 to 17 yr of age
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 up to 30 mg/day.Irritability Associated With Autistic Disorder
Children 6 to 17 yr of age
PO Start with 2 mg/day and increase to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 wk.Major Depressive Disorder
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.Schizophrenia
PO Start with 10 or 15 mg/day once a day. The effective dose range is 10 to 30 mg/day. Do not increase dosage before 2 wk.Children 13 to 17 yr of age
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 up to 30 mg/day. 30 mg/day was not shown to be more efficacious than 10 mg/day.Maintenance
No evidence is available from controlled trials. Periodically reassess patient to determine need for maintenance treatment.Concurrent Use of Strong CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, fluoxetine, quinidine) Inhibitors
PO Reduce the usual dose of aripiprazole by 50%. Increase the dose when the CYP3A4 or CYP2D6 inhibitor is discontinued.Concurrent Use of Potent CYP3A4 Inducers (eg, carbamazepine)
PO Double the usual dose of aripiprazole. Base additional increases on clinical evaluation. Decrease the dose to 10 to 15 mg when the CYP3A4 inducer is discontinued.
- Tablets may be given 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.
- Do not open the orally disintegrating tablets until ready to administer. The orally disintegrating tablet should be taken without liquid. Do not split the orally disintegrating tablet.
- Oral aripiprazole 10 to 30 mg/day should replace IM aripiprazole as soon as possible if ongoing aripiprazole therapy is clinically indicated.
Store at 59° to 86°F. Opened bottle can be used for up to 6 mo after opening. Protect injection from light by storing in carton until use.
Because of the increased risk of CNS depression, advise patients to avoid alcohol while taking aripiprazole.Antihypertensive agents
Because of its alpha-adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor the patient and adjust the dose of the antihypertensive agent as needed.Centrally acting drugs
Because of the increased risk of CNS depression, use with caution.CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine), CYP3A4 inhibitors (eg, ketoconazole)
May elevate aripiprazole plasma levels, increasing the pharmacologic effects and adverse reactions. During coadministration, reduce the aripiprazole dose to 50% of the normal dose. When the CYP2D6 inhibitor is discontinued, increase the dose of aripiprazole. In addition, coadministration increased plasma concentrations of fluoxetine and decreased paroxetine concentrations.CYP3A4 inducers (eg, carbamazepine)
May reduce aripiprazole plasma levels, decreasing the therapeutic effect and necessitating dosage adjustments. For example, when carbamazepine is added to aripiprazole therapy, double the aripiprazole dose. Additional aripiprazole dose increases should be based on clinical evaluation of the patient. When the CYP3A4 inducer is discontinued, decrease the dose of aripiprazole.CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole)
Aripiprazole plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions. With coadministration, reduce the aripiprazole dose to 50% of the normal dose. When the CYP3A4 inhibitor is discontinued, increase the dose of aripiprazole
Laboratory Test Interactions
None well documented.
The following adverse reactions were reported with aripiprazole monotherapy.
Tachycardia (2%); hypertension (at least 1%); orthostatic hypotension (1%).
Headache (27%); somnolence (26%); sedation (21%); extrapyramidal disorder (20%); agitation (19%); insomnia (18%); anxiety, fatigue (17%); akathisia (13%); tremor (12%); dizziness (10%); restlessness (6%); lethargy (5%); dystonia (2%); abnormal coordination, asthenia, suicidal ideation (at least 1%); dyskinesia, dystonia, hypersomnia, irritability (1%).
Rash (2%); hyperhidrosis, rash (including acneform, allergic, contact, drug eruption, erythematous, exfoliative, generalized, macular, maculopapular, neurodermatitis, papular rash, and seborrheic dermatitis) (at least 1%).
Blurred vision (8%); nasopharyngitis (6%); rhinorrhea (2%); nasal congestion (at least 1%).
Nausea (15%); vomiting (14%); constipation (11%); drooling, dyspepsia (9%); salivary hypersecretion (8%); diarrhea, dry mouth (5%); toothache (4%); abdominal discomfort, abdominal pain, stomach discomfort (3%).
Increased CPK (at least 1%).
Injection-site reaction (at least 1%).
Decreased appetite, increased appetite (7%); weight increase (2%); increased blood insulin, weight decrease (at least 1%).
Musculoskeletal stiffness, pain in extremities (4%); muscle spasm, myalgia (2%); arthralgia (1%).
Cough, pharyngolaryngeal pain (3%); aspiration pneumonia, dyspnea (at least 1%).
Pyrexia (9%); pain (3%); chest pain, fall, peripheral edema (at least 1%); thirst (1%); blood glucose fluctuation, rare occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm) (postmarketing).
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Over the course of a 10-wk controlled trial, the rate of death in drug-treated patients was about 4.5% compared with 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Aripiprazole is not approved for the treatment of patients with dementia-related psychosis.Suicidality
Compared with placebo, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorders and other psychiatric disorders. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Aripiprazole is not approved for use in children with depression.
Closely observe all patients who are being treated with antidepressants for clinical worsening, suicidality, or unusual changes in behavior. Ensure fasting blood glucose is evaluated before starting therapy and periodically thereafter during therapy in patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes). Monitor patients with established diagnosis of diabetes mellitus regularly for worsening of glucose control. Frequently monitor CBC in patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia during the first few months of therapy. Carefully monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection.
Assess baseline neurologic status; during treatment, observe for agitation, aggressive reaction, anxiety, drowsiness, involuntary body and facial movements, or seizure activity.
If parenteral benzodiazepine therapy is necessary in addition to aripiprazole injection, monitor patients for excessive sedation and orthostatic hypotension.
Ensure therapy is periodically reviewed to determine if it needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated.
Evaluate patients for a history of drug abuse and closely observe such patients for signs of aripiprazole misuse or abuse.
Category C .
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. Safety and efficacy not established for the treatment of irritability associated with autistic disorder in children younger than 6 yr of age.
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.
Use with caution in patients with CV disease (history of MI or ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (eg, dehydration, hypovolemia, treatment with antihypertensive medications).
Leukopenia, neutropenia, and agranulocytosis have been reported.
Hyperglycemia and diabetes mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, may occur.
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.
Orally disintegrating tablets contain phenylalanine; use with caution in patients with phenylketonuria.
Seizures may occur; use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
Closely supervise high-risk patients. Prescribe the smallest quantity consistent with good patient management in order to reduce the risk of overdose.
A potentially irreversible syndrome of involuntary body and facial movements may occur.
Antipsychotics can disrupt the body's ability to reduce core temperature.
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.
- Advise patient, family, or caregiver to read the Medication Guide before starting therapy and with each refill, especially if the patient is a child or adolescent.
- 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.
- Advise women not to breast-feed while taking aripiprazole.
Copyright © 2009 Wolters Kluwer Health.