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New schizophrenia drug has good side-effect profile

Patients with schizophrenia now have a therapeutic option with a novel mechanism of action and favorable adverse-effect profile. Last month, the Food & Drug Administration approved aripiprazole (Abilify, Bristol-Myers Squibb/Otsuka America Pharmaceuticals) for the treatment of schizophrenia. Aripiprazole is currently available in pharmacies.

Aripiprazole stabilizes the dopamine-serotonin system by acting as a potent partial agonist of D₂ and D₃ dopamine receptors and 5-HT_1A receptors, and an antagonist of 5-HT_2A receptors, according to the package insert (PI). Other antipsychotics used in the treatment of mental illnesses, including schizophrenia, are dopamine antagonists. Aripiprazole also has moderate affinity for alpha-1 adrenergic and histamine H₁ receptors.

In clinical trials, aripiprazole was associated with minimal weight gain, minimal extrapyramidal symptoms, and minimal sedation, said Daniel Casey, M.D., chief of psychiatric research/psychopharmacology, Veterans Affairs Medical Center, Portland, Ore. The drug was not associated with prolactin elevation or QTc interval prolongation. Aripiprazole may cause orthostatic hypotension, possibly due to its alpha-1 adrenergic receptor antagonism. It should, therefore, be used with caution in patients with known cardiovascular disease (history of MI, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive agents).

Aripiprazole did not appear to affect glucose metabolism, so it would not increase the risk of diabetes, continued Casey, who is also associate director of the Mental Illness, Education, and Clinical Center at the Portland Veterans Affairs Medical Center. It also did not appear to affect lipid profiles, he added. It did not increase total cholesterol or low-density lipid cholesterol, and it did not have a deleterious effect on triglyceride levels.

The recommended starting and target dose for aripiprazole is 10 mg or 15 mg administered once daily without regard to meals or the time of day. The effective dose range for aripiprazole is 10 mg to 30 mg per day. Adjustments in dosage should not be made before two weeks of treatment have been completed, so that a steady state may be achieved. Dosage adjustments are not necessary on the basis of age, race, gender, or renal or hepatic impairment status. As Casey said, "Aripiprazole is pretty user-friendly."

Inhibitors of the cytochrome P-450 (CYP) 3A4 system, such as ketoconazole, can inhibit the elimination of aripiprazole and raise blood levels of the drug, according to Bristol-Myers Squibb. Inhibitors of the CYP2D6 system, such as quinidine, fluoxetine (Prozac, Eli Lilly), and paroxetine (Paxil, GlaxoSmithKline), have the same effect. The dose of aripiprazole should be reduced by half when the drug is administered concomitantly with these medications. The dose should then be increased when treatment with CYP3A4 and CYP2D6 inhibitors is discontinued.

The label further states that inducers of the CYP3A4 system, such as carbamazepine, can cause an increase in aripiprazole clearance and reduce blood levels of the drug. The dose of aripiprazole should be doubled to 20 mg or 30 mg per day when administered concomitantly with carbamazepine. When carbamazepine therapy is discontinued, the dose of aripiprazole can be decreased.

Aripiprazole is classified as a pregnancy category C. Its use is contraindicated in women who are pregnant or breast-feeding. Use of aripiprazole in children is also contraindicated, because its safety and efficacy in children have not been established.

"A large majority of patients [75%-80%] are taking atypical antipsychotics, compared with older, conventional drugs," Casey said. "We still have unmet needs, however, because many patients do not respond to the older drugs, which have a significant side-effect burden. Aripiprazole will change clinical practice, because its novel mechanism of action can benefit more patients and offer clinicians more choices in the selection of a drug that is highly effective without a significant side-effect profile."

Adverse effects reported by >= 2% of treated patients include headache, asthenia, fever, nausea, vomiting, constipation, anxiety, insomnia, lightheadedness, somnolence, akathisia, tremor, rhini-tis, coughing, rash, and blurred vision. Potential cardiovascular adverse effects include hypertension, tachycardia, hypotension, and bradycardia.

"Aripiprazole gives clinicians another option, certainly," concurred Matthew Fuller, Pharm.D., clinical pharmacy specialist in psychiatry, Louis Stokes Veterans Affairs Medical Center, Cleveland. "We are always searching for the best ways to help our patients with schizophrenia and mental illness in general, so it is nice to have a new treatment option. We hope that aripiprazole will offer clinical benefits at least similar to those of currently available drugs. Ideally, patients will reap additional benefits from treatment with aripiprazole compared with older antipsychotics, but with a cleaner adverse-effect profile than the older drugs."

Charlotte LoBuono

TIPS TO REMEMBER: Abilify

• Dosage adjustment is not necessary on the basis of tobacco-use status.

• Use of Abilify may be associated with orthostatic hypotension. Abilify should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions that would predispose them to hypotension.

• A blood glucose measurement and a chem-7 could be done at baseline and repeated at least yearly; they may be repeated as often as quarterly. A lipid panel and weight assessment could also be done at baseline and repeated at least yearly and could be repeated as often as quarterly.

• All patients on the drug should be advised to avoid alcohol, overheating, and dehydration.

• Because Abilify can impair judgment, thinking, or motor skills, caution patients against operating hazardous machinery, including automobiles, until they are reasonably certain that the therapy does not affect them adversely.

 

Charlotte LoBuono. New schizophrenia drug has good side-effect profile. Drug Topics 2002;23:30.