Med Check
Regulatory and Legal Briefs
• Pharmacogenomics “holds great promise to shed scientific light on the often risky and costly process of drug development and provide[s] greater confidence about the risks and benefits of drugs in specific populations,” said Mark McClellan, M.D., Ph.D., commissioner of the Food and Drug Administration (FDA). On November 3 the agency issued a Draft Guidance for Industry encouraging drug developers to conduct tests on the interactions of medications with specific genes and clarifying how the agency will use data submitted in the approval process. An FDA Talk Paper on the topic is posted on the Web at www.fda.gov/bbs/topics/NEWS/2003/NEW00969.html.
• Paxil CR won approval from the FDA for the treatment of social anxiety disorder (SAD). Also indicated for the treatment of depression, panic disorder, and PMDD, Paxil is the first long-acting SSRI to gain approval for SAD. The approval was based on two 12-week, multisite clinical trials in which Paxil CR was found efficacious. The most common adverse events reported for Paxil CR were infection, trauma, nausea, diarrhea, dry mouth, constipation, somnolence, dizziness, sexual dysfunction, and sweating.
• Risperdal Consta won approval from the FDA as the first long-acting, second-generation (or atypical) antipsychotic medication for the treatment of schizophrenia. Two 12-week studies showed that the long-acting injectible form of the medication is effective in reducing symptoms of schizophrenia with an injectible 25 mg dose given once every two weeks. Adverse effects include headache, agitation, psychosis, insomnia, dizziness, rhinitis, and pain. The United States becomes the 41st country to grant approval of the depot antipsychotic.
• The long-expected approvals of both Cymbalta and Zyprexa IntraMuscular are one step closer as the FDA cleared Eli Lilly and Co.’s manufacturing plant outside Indianapolis. Final approvals for the two medications had been held up while the company worked to remedy manufacturing deficiencies that the FDA cited in March 2001. The company’s best estimate now targets a summer 2004 launch for Cymbalta, its new combined serotonin-norepinephrine reuptake inhibitor and the injectible form of its market-leading antipsychotic.
• Adderall XR was deemed approvable by the FDA for the treatment of adults with attention-deficit/hyperactivity disorder. It is believed that nearly two-thirds of children continue to have symptoms of ADHD well into adulthood, and the adult market is predicted to be twice that of the current pediatric market for ADHD medications. Adderall XR, a sustained-release mixture of amphetamine salts, becomes the second medication approved for adults with ADHD, following Strattera.
• Seroquel was deemed approvable by the FDA as a monotherapy and adjunctive therapy for mania in patients with bipolar disorder. Efficacy was shown in a series of clinical trials with a target dose range of 300 mg to 400 mg in two divided daily doses. The most frequent adverse effects seen with Seroquel were dizziness, postural hypotension, dry mouth, and dyspepsia. Seroquel also carries labeled warnings for tardive dyskinesia and lowered seizure threshold.
Research Briefs
• Topiramate may be an effective treatment for bulimia nervosa. A randomized, double-blind, placebo-controlled trial evaluated topiramate, starting at 25 mg a day and increasing to as much as 400 mg a day for 10 weeks. In the 35 patients taking topiramate, the mean weekly number of days on which patients engaged in binge eating, purging, or both was reduced by 44 percent compared with a reduction of 10.7 percent in the 33 patients who received placebo. The average daily dose of topiramate was 100 mg. The study continues with a 40-week, open-label, extension phase.
J Clin Psych2003; 64:1335-1341
• Escitalopram, the single-isomer form of citalopram, is significantly more effective than its parent compound. In a meta-analysis of 1,262 patients in four clinical trials comparing the two SSRIs, escitalopram showed consistently significant greater reductions in depression symptoms than citalopram. Escitalopram also was noted to be especially superior in patients who were more severely depressed. In addition, fewer adverse events were reported with the single-isomer than the parent medication.
Int J Psychiatr Clin Pract2003; 7:259-268
• Escitalopram is effective in panic disorder as well as depression. In a randomized double-blind, placebo and comparator–controlled trial involving 366 patients, the frequency of panic attacks was significantly reduced, and the number of patients experiencing no panic attacks while taking the medicine increased as well. Patients taking escitalopram improved the most; patients taking citalopram as an active comparator improved as well, but not as significantly. Both drugs were statistically significantly better than placebo.
J Clin Psych2003; 64:1322-1327
• Lithium levels must be monitored closely in patients concomitantly taking any nonsteroidal anti-inflammatory drug, even those that selectively inhibit only the cox-2 enzyme. A systematic review of the FDA’s adverse-event reporting system found 18 cases of increased serum lithium concentrations associated with one or the other of the two cox-2 inhibitors approved for sale in the United States. Serum lithium levels were elevated on average 99 percent with celecoxib and 448 percent with rofecoxib.
J Clin Psych2003; 64:1328-1334
• Risperidone and olanzapine are as effective as, but more tolerable than, conventional antipsychotics in the treatment of elderly patients with schizophrenia. In an international double-blind trial, 175 patients were randomized to either of the two atypical antipsychotics. Scores on the Positive and Negative Syndrome Scale and rates of extrapyramidal symptoms (EPS) significantly improved at all time points, including at the endpoint, in both medication groups. EPS-related events were reported by 9.2 percent of patients taking risperidone and 15.9 percent of those taking olanzapine.
Am J Geriatr Psychiatry2003; 11:638-647
• Combined treatment with olanzapine and divalproex is associated with significantly higher elevations of hepatic enzymes than treatment with either agent alone. In a retrospective study of hepatic enzyme levels of 52 children, a greater percentage of patients taking the combination had significantly higher elevations than patients taking either drug, and peak serum hepatic enzyme levels were significantly higher in the combination group. While the specific long-term significance of this finding is not known, increased liver enzyme levels over time are indicative of liver damage; thus, the authors stressed monitoring and further study.
J Am Acad Child Adolesc Psychiatry2003; 42:1227-1233
• Risperidone appears to reduce symptoms of tardive dyskinesia when patients are switched from conventional antipsychotic medications to atypicals. In a double-blind, placebo-controlled, 12-week trial, patients were randomly assigned to either risperidone or placebo after a four-week washout of prior antipsychotic therapy. The 22 patients who were switched to risperidone had a 5.5-point improvement in scores on the Abnormal Involuntary Movement Scale, compared with an improvement of 1.1 points for those taking placebo. The average dose of risperidone was 6 mg a day.
J Clin Psych2003; 64:1342-1348
Industry Briefs
• Olanzapine may promote better adherence to medication compared with other antipsychotics. Findings from Lilly’s Schizophrenia Care and Assessment Program (SCAP)—a three-year, “real world” study of the disease—were presented at APA’s 2003 Institute on Psychiatric Services in Boston in October. The study found that patients taking olanzapine were significantly more likely to adhere to their medication and continue taking medication for a longer period compared with patients taking risperidone, quetiapine, or haloperidol. The company-funded longitudinal observational study followed 2,400 patients across the country.
In another session at the institute, researchers presented data showing that olanzapine also reduces hospitalization and costs associated with inpatient stays compared with risperidone. Over the study period, patients taking olanzapine were hospitalized for an average of 9.9 days, compared with 14.5 days for those taking risperidone. The mean annual group difference of 4.6 days translated into a cost savings of $2,502 per patient.
• Atomoxetine enjoyed the strongest launch ever for a new ADHD medication, according to data from IMS Health. In its first nine months on the market, physicians wrote more than 2 million prescriptions for the nonstimulant medication. Sales growth for the drug, launched in December 2002, was attributed to strong acceptance by pediatricians and primary care physicians, two markets heavily detailed by the drug’s maker, Lilly. As of September 30, Strattera held a 16.3 percent market share, compared with market leaders Concerta at 24 percent and Adderall XR at 22.4 percent.
• Asenapine, a 5HT-2/D2 receptor antagonist, is being jointly developed by Pfizer and Organon, the companies said last month. The two signed a global agreement for the exclusive rights to develop and market the third-generation antipsychotic for treatment of schizophrenia and bipolar disorder. Phase II clinical trials have shown promising results, the companies said, and phase III trials are in development.
• Ziprasidone is safe and effective in the treatment of acute bipolar mania, according to a Supplemental Drug Application filed by Pfizer asking for approval to market the medication for mania. Two clinical trials demonstrated efficacy in more than 400 patients with bipolar disorder, with improvement seen as early as on day 2 of medication. The most common adverse effects noted were somnolence, headache, and dizziness.
• Pfizer submitted its long-awaited New Drug Application for pregabalin for the management of neuropathic pain, partial seizures, and generalized anxiety disorder. Pfizer had acknowledged in September 2002 that it would delay the filing while it conducted additional clinical studies on the drug’s safety. A spokesperson for Pfizer would not comment on what issues had been addressed in the new trials.
• Merck and Co. acknowledged November 12 that it would halt work on its substance-P antagonist, aprepitant, or MK-0869, for the treatment of depression. Phase III clinical trials were halted when the compound failed to demonstrate efficacy. ▪
