P&T Portfolio - Abilify

HEALTH-SYSTEM EDITION
P & T PORTFOLIO

Generic name

Aripiprazole

Proprietary name/manufacturer

Abilify/Bristol-Myers Squibb-Otsuka

FDA-approved indication

Treatment of schizophrenia

Pharmacology

Aripiprazole, a next-generation, atypical antipsychotic agent, has beenreferred to as a dopamine system stabilizer (a drug that reduces dopaminelevels in the mesolimbic pathways to exert antipsychotic effects and at thesame time prevent adverse motor effects in the nigrostriatal pathway). Itsprecise mechanism of action in schizophrenia is unknown, but it has beenproposed that the efficacy of aripiprazole is mediated through a combination ofpartial agonist activity at D₂ and 5-HT_1A receptors and antagonistactivity at 5-HT_2A receptors. These dual effects are seen at thesame dose level and are unlike those of other antipsychotic drugs (typical andatypical).

Efficacy

The effectiveness of aripiprazole for the treatment of schizophrenia hasbeen demonstrated in several relatively large (mostly short-term) controlledclinical trials. Efficacy in these studies was primarily based uponimprovements in the Positive and Negative Syndrome Scale (PANSS), the BriefPsychiatric Rating Scale (BPRS), and the Clinical Global Impression (CGI)assessment. Study results showed that aripiprazole is significantly moreeffective than placebo for the treatment of schizophrenia with improvements inboth positive and negative symptoms.

Pharmacokinetics

Protein binding 

> 99%

Volume of distribution

4.9 L/kg

Metabolism

Dehydrogenation,

 hydroxylation, and N-dealkylation in liver via P450 isoenzymes CYP2D6 and CYP3A4. Dehydro-aripiprazole is the major metabolite (active).

Excretion

Feces (55%)   
Urine (25%)

Half-life (mean terminal)

            75 hours (aripiprazole) 94 hours           (dehydro-aripiprazole)

Contraindications

• Hypersensitivity to product components

Warnings

• May cause neuroleptic malignant syndrome (NMS)

• May cause tardive dyskinesia

• Use with caution in patients with known cardiovascular disease,cerebrovascular

• Disease or conditions which would predispose patients to hypotension

• Use cautiously in patients with a history of seizure or with conditionsthat lower seizure threshold

Adverse effects

The most common adverse effects, seen in 12% to 32% of patients, wereheadache, anxiety, insomnia, nausea, and vomiting.

Less common adverse effects, occurring in 2% to 11% of patients, includedlightheadedness, somnolence, constipation, akathisia, asthenia, rash, rhinitis,coughing, tremor, blurred vision, and fever.

Dose

Usual dose: 10 or 15 mg orally every day

Dose titration: Dosage increases should not be made before two weeks, thetime needed to achieve steady state.

Dose adjustment: Reduce dose to one-half the usual dose when concomitantlyadministered with CYP3A4 inhibitors (ketoconazole) or CYP2D6 inhibitors (suchas quinidine, fluoxetine, paroxetine). Increase dose when the CYP3A4 or CYP2D6inhibitor is discontinued. Double the dose (20 to 30 mg) of aripiprazole whenused concomitantly with CYP3A4 inducers such as carbamazepine. Additional doseincreases should be based on clinical evaluation. When the CYP3A4 inducer isdiscontinued, the aripiprazole dose should be reduced to 10 or 15 mg.

Conclusion/comments

Aripiprazole is an atypical antipsychotic agent (dopamine system stabilizer)that demonstrated efficacy in the treatment of schizophrenia. Aripiprazoleappears to be similar in effectiveness to haloperidol, but clinical comparisonswith other atypical antipsychotic agents are lacking and will be needed tobetter differentiate these agents. Study results indicate that aripiprazole mayhave less potential for weight gain, extrapyramidal symptoms, and elevatedprolactin levels but additional long-term study and clinical experience isneeded. The manufacturer is also investigating the use of aripiprazole for thetreatment of other psychiatric disorders, including bipolar disorder.

Published January 2003. Content based on medical literature and productinformation available at that time.

Source: Thomson MICROMEDEX Inc., Greenwood Village, Colo. All rights reserved. P&T QUIK Reports,http://www.micromedex.com/products/ptquik, are published monthly by MICROMEDEX. Additional MICROMEDEX databases include DRUGDEX (drug information), MARTINDALE (international drug reference), and PDR (Physicians' Desk Reference). Visit MICROMEDEX atwww.micromedex.com for a complete product listing.

P&T Portfolio - Abilify.

Drug Topics

2003;2:HSE8.