Aripiprazole

Pronunciation

Class: Atypical Antipsychotics
Chemical Name: 3,4-dihydro-7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-2(1H)-Quinolinone
Molecular Formula: C23H27Cl2N3O2
CAS Number: 129722-12-9
Brands: Abilify

Warning(s)

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

Warning(s)

  • Increased Mortality in Geriatric Patients
  • Substantially higher mortality rate (4.5%) in geriatric patients with dementia-related psychosis receiving atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) compared with those receiving placebo (2.6%).1 73

  • Most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 73

  • Atypical antipsychotics are not approved for the treatment of dementia-related psychosis.1 73 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Introduction

Atypical antipsychotic agent.2 7

Uses for Aripiprazole

Schizophrenia

Symptomatic management of schizophrenia.1

Slideshow: Can Prescription Drugs Lead to Weight Gain?

Bipolar Disorder

Management of acute manic and mixed episodes associated with bipolar I disorder.1 67

Aripiprazole Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral solution may be given at same dose on mg-per-mg basis as the 5-, 10-, 15-, or 20-mg tablet strengths of the drug up to a dose of 25 mg.1 However, if oral solution is used in patients receiving aripiprazole 30-mg tablets, use a dose of 25 mg of the oral solution.1

Adults

Schizophrenia
Oral

Initial and target dosage is 10 or 15 mg once daily.1

Dosages ranging from 10–30 mg daily were effective in clinical trials; dosages exceeding 10–15 mg daily did not result in greater efficacy.1

Adjust dosage at intervals of not less than 2 weeks, the time needed to achieve steady-state concentrations.1

In patients responding to aripiprazole therapy, continue the drug as long as clinically necessary and tolerated, but at lowest possible effective dosage; periodically reassess need for continued therapy.1

Long-term efficacy of aripiprazole has not been established, and optimum duration of therapy currently is not known.1 However, aripiprazole has been used as maintenance therapy for up to 26 weeks in clinical trials, and maintenance therapy with antipsychotic agents is well established.1

Bipolar Disorder
Acute Mania and Mixed Episodes
Oral

Initial dosage of 30 mg once daily as tablets was used in clinical trials.1 67

Dosage was decreased to 15 mg once daily in clinical trials if initial 30-mg dosage was not well tolerated.1 67

Safety of dosages >30 mg daily has not been established.1

Long-term efficacy (i.e., >6 weeks) of aripiprazole has not been established, and optimum duration of therapy currently is not known.1 Periodically reevaluate the long-term risks and benefits of the drug for the individual patient.1

Special Populations

Patients Receiving CYP3A4 or CYP2D6 Inhibitors

Reduce aripiprazole dosage to one-half the usual dosage in patients receiving concomitant therapy with inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine, quinidine)1 ; increase aripiprazole dosage to the usual dosage after discontinuance of the CYP3A4 or CYP2D6 inhibitor.1

Patients Receiving CYP3A4 Inducers

Increase aripiprazole dosage to 20–30 mg daily upon initiation of concomitant therapy with drugs that induce CYP3A4 (e.g., carbamazepine);1 additional dosage escalation should be based on clinical evaluation.1 Decrease aripiprazole dosage to 10–15 mg daily if the CYP3A4 inducer is discontinued.1

Cautions for Aripiprazole

Contraindications

  • Known hypersensitivity to aripiprazole or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with use of atypical antipsychotics in geriatric patients with dementia-related psychosis.1 73

Increased incidence of adverse cerebrovascular effects (e.g., stroke, TIA), including fatalities, observed in geriatric patients (78–88 years of age) with dementia-related psychosis treated with aripiprazole in several placebo-controlled studies.1 A statistically significant dose-response relationship for adverse cerebrovascular effects was observed in patients receiving the drug in a fixed-dose study.1

Safety and efficacy not established in patients with dementia-related psychosis;1 exercise caution if used.1 (See Boxed Warning and see Geriatric Use under Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported.1

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, has been reported.1 Consider discontinuance of aripiprazole.1

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.1 11 12 14 15 16 17 18 20 21 22 23 25 40 41 42 46 65 Although there have been few reports of hyperglycemia in patients receiving aripiprazole, it is not known whether the paucity of such reports is due to relatively limited experience with the drug.1 8 18 59 60 61 62 63

Closely monitor patients with preexisting diabetes mellitus for worsening of glucose control and perform fasting glucose tests at baseline and periodically for patients with risk factors for diabetes (e.g., obesity, family history of diabetes).11 12 If manifestations of hyperglycemia occur, perform fasting blood glucose testing.1 11 12 14 15 16 17 18 19 20 21 22 23

General Precautions

Cardiovascular Effects

Orthostatic hypotension reported.1 Use with caution in patients with known cardiovascular or cerebrovascular disease and/or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1

Nervous System Effects

Possible risk of seizures;1 use with caution in patients with a history of seizures or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer’s type, geriatric patients).1

Disruption of ability to reduce core body temperature possible; use caution in patients exposed to conditions that may contribute to an elevation in core body temperature (e.g., dehydration, extreme heat, strenuous exercise, concomitant use of anticholinergic agents).1

Somnolence reported;1 most prominent in patients with schizophrenia receiving the aripiprazole 30-mg daily dosage during clinical trials.1 Potential impairment of judgment, thinking, or motor skills.1

GI Effects

Esophageal dysmotility and aspiration possible;1 use with caution in patients at risk for aspiration pneumonia (e.g., geriatric patients, those with advanced Alzheimer’s dementia).1

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients.1 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Metabolic Effects

Weight gain possible.1

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.

Lactation

Distributed into milk in rats.1 Not known whether aripiprazole or its metabolites are distributed into milk in humans.1 Women receiving aripiprazole should not breast-feed.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 8

Geriatric Use

Experience in those ≥65 years of age is insufficient to determine whether they respond differently from younger adults.1

Tolerability profile may differ in patients ≥65 years of age with dementia-related psychosis, including psychosis in association with dementia of the Alzheimer’s type, compared with that in younger patients with schizophrenia.1 Possible increased risk of death.1 73 (See Boxed Warning and see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Common Adverse Effects

In short-term studies, headache, agitation, anxiety, insomnia, nausea, dyspepsia, somnolence, akathisia, vomiting, constipation, lightheadedness, asthenia, extrapyramidal syndrome, accidental injury.1

With longer-term (e.g., 26 weeks) use, adverse effects generally were consistent with those reported in short-term trials, except for a higher incidence of tremor.1

Interactions for Aripiprazole

Unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by CYP isoenzymes.1

Extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4 isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inducers or inhibitors of CYP3A4 or CYP2D6: Potential pharmacokinetic interaction (altered aripiprazole metabolism and plasma concentrations); dosage adjustment recommended.1 (See Special Populations under Dosage and Administration and see Specific Drugs under Interactions.)

Inhibitors or inducers of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1: Pharmacokinetic interaction unlikely.1

Substrates of Hepatic Microsomal Enzymes

Substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4: Pharmacokinetic interaction unlikely.1

Specific Drugs1

Drug

Interaction

Comments

Carbamazepine

Possible decrease in plasma aripiprazole concentrations1

Increased aripiprazole dosage recommended1

CNS agents or alcohol

Possible additive CNS effects1

Use with caution1

Dextromethorphan

No change in dextromethorphan metabolism observed1

Famotidine

Potential decreased aripiprazole absorption; not clinically important1

No dosage adjustment necessary1

Fluoxetine

Possible increase in plasma aripiprazole concentrations1

Reduction of aripiprazole dosage recommended1

Hypotensive agents

Possible additive hypotensive effects1

Use with caution1

Ketoconazole

Possible increase in plasma aripiprazole concentrations1

Reduction of aripiprazole dosage recommended1

Lithium

Pharmacokinetic interaction unlikely1

Omeprazole

Pharmacokinetic interaction unlikely1

Paroxetine

Possible increase in plasma aripiprazole concentrations1

Reduction of aripiprazole dosage recommended1

Quinidine

Possible increase in plasma aripiprazole concentrations1

Reduction of aripiprazole dosage recommended1

Valproate

Potential decreased plasma aripiprazole concentrations; not clinically important1

No dosage adjustment necessary1

Warfarin

Pharmacokinetic interaction unlikely1

Aripiprazole Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability of tablets is 87%.1

Peak plasma concentrations for tablets are achieved within 3–5 hours; steady-state concentrations achieved within 14 days.1

Well absorbed when administered as oral solution with higher plasma aripiprazole concentrations after administration of oral solution than with tablets at equivalent doses.1 (See Dosage under Dosage and Administration.)

Oral solution-to-tablet ratios of geometric mean maximum plasma concentrations and AUC were 122 and 114%, respectively.1

Food

Administration of aripiprazole with a high-fat meal affected rate but not extent of absorption.1

Distribution

Extent

Large volume of distribution following IV administration indicates extensive extravascular distribution.1

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

Aripiprazole and its major metabolite, dehydro-aripiprazole, are >99% bound, principally to albumin.1

Elimination

Metabolism

Extensively metabolized in the liver principally via dehydrogenation, hydroxylation, and N-dealkylation by CYP2D6 and CYP3A4 isoenzymes.1

Elimination Route

Approximately 18% and <1% excreted unchanged in feces and urine, respectively.1

Half-life

75 hours and 94 hours, for aripiprazole and dehydro-aripiprazole, respectively.1

Special Populations

In patients with the poor metabolizer CYP2D6 phenotype (approximately 8% of Caucasians), exposure to aripiprazole is increased by about 80%, while exposure to its active metabolite is decreased by approximately 30%.1 The elimination half-life for aripiprazole in poor metabolizers of the drug is approximately 146 hours.1

Stability

Storage

Oral

Oral Solution

2–8°C.1 After opening, store containers at 2–8°C; can use for up to 6 months.1

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Exact mechanism of antipsychotic action has not been fully elucidated; may involve the drug’s activity at dopamine D2 and serotonin type 1 (5-HT1A) and type 2 (5-HT2A) receptors.1 2 3 4 5 6 7

  • Unlike other atypical antipsychotic agents, aripiprazole demonstrates partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors.1 2 3 4 5 6 7 The major active metabolite, dehydro-aripiprazole, exhibits affinity for D2 receptors similar to that of the parent compound.1

  • Antagonism at other receptors (e.g., α1-adrenergic receptors, histamine H1 receptors) may contribute to other therapeutic and adverse effects (e.g., orthostatic hypotension, somnolence).1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Risk of somnolence and impairment of judgment, thinking, or motor skills; avoid driving, operating machinery, or performing hazardous tasks until effects on the individual are known.1

  • Importance of avoiding alcohol during aripiprazole therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., diabetes mellitus, seizures, dementia).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of avoiding overheating or dehydration.1

  • Importance of being aware that aripiprazole oral solution contains 400 mg of sucrose and 200 mg of fructose per mL.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Aripiprazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

5 mg/5 mL

Abilify (with parabens and propylene glycol)

Otsuka (also promoted by Bristol-Myers Squibb)

Tablets

5 mg

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

10 mg

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

15 mg

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

20 mg

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

30 mg

Abilify

Otsuka (also promoted by Bristol-Myers Squibb)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Abilify 10MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$584.00 or 90/$1,710.95

Abilify 15MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$560.01 or 90/$1,652.89

Abilify 2MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$570.01 or 90/$1,680.02

Abilify 20MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$793.98 or 90/$2,323.88

Abilify 30MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$815.98 or 90/$2,368.90

Abilify 5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$558.02 or 90/$1,646.02

Abilify Discmelt 10MG Dispersible Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$631.30 or 90/$1,842.24

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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