Med Check

• The FDA approved Abilify for “the maintenance of stability in patients with schizophrenia.” The approval is based on results of placebo-controlled clinical trials involving 310 patients who were discontinued from existing medication regimens and started on Abilify 15 mg daily or placebo for 26 weeks. Patients who received Abilify experienced a longer time to relapse and had about half the relapse risk of those taking placebo. The dopamine/serotonin system stabilizer is considered weight neutral and has no significant effect on prolactin, fasting glucose, lipids, or cholesterol. The most common adverse effects associated with Abilify are headache, sleep disturbance, nausea, and vomiting. Prescribing information is posted on the Web at www.abilify.com.

• Wellbutrin XL won FDA approval and was to be on pharmacy shelves as this column went to press, according to GlaxoSmithKline. The once-daily version of the norepinephrine/dopamine reuptake inhibitor is said to have little to no effect on the serotonin system and markedly lower incidence of sexual side effects and weight gain than other antidepressants. The new product will be available in 150 mg and 300 mg extended-release tablets. Prescribing information is posted on the Web at http://www.wellbutrin-xl.com.

• The FDA also approved Paxil CR last month for the treatment of premenstrual dysphoric disorder (PMDD). In clinical trials, the long-acting SSRI was significantly better at reducing the physical and emotional symptoms of PMDD at both the 12.5 mg and 25 mg daily doses. The most common adverse events noted in the trials were infection, nausea, diarrhea, dry mouth, constipation, decreased appetite, somnolence, dizziness, sleep disturbances, sexual dysfunction, and sweating. Paxil CR should not be taken with MAOIs and should not be discontinued abruptly. Prescribing information is posted on the Web at www.paxilcr.com.

• Sales and distribution of ORLAAM by Roxanne Laboratories will end after the depletion of the current inventory, the company and the FDA announced. The treatment for the management of opiate dependence has been tied to increasing reports of severe cardiac side effects, including fatal arrhythmias. ORLAAM was withdrawn from the European market in March 2001. With the addition of buprenorphine to the accepted regimens for methadone treatment, the company said, the benefits no longer outweigh the risks associated with the drug. The FDA Product Discontinuation Notice is available on the Web at www.fda.gov/cder/drug/shortages/orlaam.html.

• Serzone may be withdrawn from the Canadian market in the near future. Spokespersons for GlaxoSmithKline acknowledged that the company was in discussions with Canadian regulators over the safety of the SSRI antidepressant. Canada, the United States, and Australia are the only markets where the medication is still available. The drug had been tied to increasing reports of severe liver damage. Meanwhile, in the U.S. the FDA approved two companies’ generic versions of nefazadone.

• Shire Pharmaceuticals filed suit against Barr Laboratories to defend its patent protection for Adderall XR. The filing is in accordance with the FDA’s newly enacted rule allowing one 30-month stay on approval of a generic form of a medication. The 30-month period is intended to allow the court sufficient time to determine whether the branded drug’s patents are valid and enforceable.

• Generic paroxetine hydrochloride becomes the poster child for generic manufacturers challenging the legitimacy of patents on brand-name medications. As generic paroxetine hit the shelves in mid-September, the chair of the Federal Trade Commission (FTC) hailed its arrival in the marketplace as proof that competition works. It was the FTC’s concerns over several practices of Paxil maker GlaxoSmithKline that led to the FDA issuing its final rule in August limiting the number of stays a brand-name-product maker could be granted while its patents were challenged. Under pressure from both agencies, GlaxoSmithKline withdrew a series of patents that the FTC had questioned. Generic maker Apotex was then able to put its generic paroxetine on the shelf. “These developments,” the FTC chair said, “are an example of how the FDA’s new rule has accelerated generic drug competition.” The FTC chair’s statement is posted on the Web at www.ftc.gov/opa/2003/09/paxillaunch.htm.

• In separate action on Paxil, a federal judge in California refused for the second time to certify a class-action suit against GlaxoSmithKline regarding claims that patients taking the drug were harmed by withdrawal symptoms or aggressive and violent behavior. The judge noted that not all parties were actually harmed by taking the drug, and that “some plaintiffs’ complaints may be due to reasons unrelated to their taking Paxil.” The judge also confirmed that constitutional separation-of-powers problems would result if he allowed plaintiffs to “use the court as a forum to challenge and second-guess the FDA’s prior approval of Paxil’s safety and efficacy.”

• Galantamine appears to be more effective than donepezil at retarding the rate of deterioration in patients with Alzheimer’s disease. In an industry-funded, double-blind, parallel group trial conducted at 18 outpatient centers in Europe, 182 patients (94 on galantamine, 88 on donepezil) were followed for 52 weeks. At the end of the study, patients taking galantamine had no significant deterioration in scores on the Mini-Mental State Examination (MMSE), while patients taking donepezil had significant deterioration. In addition, scores on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS–Cog) were also significantly different, with patients taking galantamine dropping 1.61 points compared with 4.08 points for those taking donepezil.

• Methylphenidate may be safe and effective in children with attention-deficit/hyperactivity disorder, even though manic symptoms are present. In the Multimodal Treatment Study of Children With ADHD (MTA), a group of 270 patients participated in a one-month, double-blind, placebo-controlled titration trial of methylphenidate. All children were screened using the Diagnostic Interview Schedule for Children (DISC) and the Child Behavior Checklist (CBCL). Of the total group, 32 (11 percent) screened positive for symptoms of mania using the DISC, while 29 screened positive using the CBCL. Comparing children who had manic symptoms with those who had no such symptoms, researchers found no differential response to methylphenidate and no difference in reported adverse events.

• Oxcarbazepine appears to be effective in about half of patients with bipolar disorder, according to a chart review of naturalistic treatment involving 42 patients. Based on scores from the Clinical Global Impressions–Improvement Scale, oxcarbazepine was moderately to markedly effective in 57 percent of patients. Sedation was the most commonly reported side effect, and 22 patients (52 percent) stopped medication due to side effects. Sixteen patients (38 percent) reported no side effects. Men were more likely to respond than women. Dose, bipolar subtype, prior response to mood stabilizers, and concurrent use of mood stabilizers versus oxcarbazepine monotherapy did not, however, predict oxcarbazepine response.

• Lamotrigine is safe and effective in the long-term treatment of bipolar I disorder. Over 1,300 recently manic or depressed patients were followed in two 18-month, randomized, double-blind trials comparing lamotrigine with both placebo and lithium. Lamotrigine was significantly better than placebo at prolonging the time to relapse and was most effective at preventing depressive relapse, while lithium was more effective than placebo and lamotrigine against mania.

• Lithium should remain the gold standard for long-term maintenance treatment of bipolar disorder, according to a new meta-analysis of data including results from the lamotrigine bipolar trials, which used lithium as an active comparator. Lithium was significantly more effective than placebo at preventing overall relapse (relative risk of 0.65) and was more effective at preventing manic relapse (relative risk of 0.61) than depressive relapse (relative risk of 0.71, not statistically significant).

• Long-term use of statins appears to be associated with a reduced risk of anxiety, depression, and perhaps hostility, two new studies suggest. In the first study, 140 patients with cardiovascular disease who were taking statins to reduce cholesterol were compared with 231 patients who received no cholesterol-lowering medications. With follow-up ranging from four to seven years, patients who took statins were significantly less likely to develop anxiety, depression, or hostility. In the second study, researchers in the United Kingdom identified all cases within the United Kingdom General Practice Research Database with newly treated depression and all cases with first-recorded diagnoses of suicidal behavior. Patients who were taking statins were as much as 60 percent less likely to develop depression than those who were not. There was no statistically significant difference in rates of suicidal behavior or completed suicide between the groups.

J Am Coll Cardiol2003; 42(4):690-697 and Arch Intern Med2003; 163:1926-1932 ▪