Med Check
Regulatory Briefs
• The U.S. Food and Drug Administration (FDA) approved risperidone long-acting injection for maintenance treatment of bipolar I disorder as a monotherapy or an adjunct to lithium or valproate. Risperidone injection is manufactured by Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, and was approved for treatment of schizophrenia in 2003. The May 18 approval was based on two randomized, double-blind, placebo-controlled trials.
In one of the trials, about 300 patients with bipolar I disorder who had been stabilized on risperidone long-acting injection were randomized to either the same dose of the active injection or placebo as monotherapy. The primary endpoint, time to relapse to a mood episode, was delayed significantly in the group receiving risperidone injection compared with the placebo group. In the other trial, 240 patients who were already on lithium or valproate and still symptomatic for bipolar symptoms were first given risperidone long-acting injections for 16 weeks of open-label treatment, then randomized to double-blind treatment of either active or placebo injections while remaining on oral mood stabilizers for 52 weeks. Again, the time to relapse was later in the active-injection group than the placebo group. The updated product label is posted at<www.janssen.com/janssen/shared/pi/risperdalconsta.pdf>.
• The FDA has approved lamotrigene orally disintegrating tablets (ODT) for marketing in the United States, according to a May 11 GlaxoSmithKline announcement. The ODT formulation was deemed to be bioequivalent to lamotrigene tablets and was expected to be available in 25 mg, 50 mg, 100 mg, and 200 mg strengths starting in July.
A June 1 announcement by Glaxo said that lamotrigene extended-release tablet has been approved by the FDA for once-daily adjunct therapy for epilepsy in patients aged 13 or older. Patients with partial seizures currently taking immediate-release lamotrigene tablets twice daily can be converted directly to once-a-day extended-release tablets using the same total daily dosage, according to the company.
• Schering-Plough announced on June 2 that it had filed a marketing authorization application with the European Medicines Agency for asenapine sublingual tablets for the treatment of schizophrenia and manic episodes of bipolar I disorder. In the United States a new drug application for asenapine is under FDA review for acute treatment of schizophrenia and manic or mixed episodes in bipolar I disorder.
• The FDA announced on June 12 that it had requested manufacturers of montelukast, zafirlukast, and zileuton to add a precaution about neuropsychiatric adverse reactions in the drugs' prescribing information. These drugs belong to the class of leuokotriene modifiers used primarily to treat asthma and allergies. The agency received multiple case reports of mood and behavioral changes, including agitation, aggression, anxiety, depression, insomnia, irritability, and suicidal thinking and behavior associated with these medications. Additional information and FDA's safety review are posted at<www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165489.htm>
Research and Development Briefs
• At the 2009 annual meeting of the American Society of Clinical Oncology on May 30, Medco Health Solutions, a large pharmacy benefit manager, and Indiana University School of Medicine presented the results of a joint study that indicated a significant interaction between tamoxifen and certain antidepressants. This interaction was associated with a two-fold increase in the risk of breast cancer recurrence in women who were taking tamoxifen. Because tamoxifen is a prodrug activated by the cytochrome P450 CPY2D6 isoenzyme, potent inhibitors of this isoenzyme can reduce the availability of the active metabolite of tamoxifen in the body. Many selective serotonin-reuptake inhibitors (SSRIs) are known to inhibit CYP2D6 to various degrees.
This study was a retrospective analysis of almost 1,300 women with breast cancer in the Medco database who were treated with tamoxifen, with an average of 2.7 years of follow-up. The women who were taking an SSRI that was a moderate to potent CYP2D6 inhibitor (fluoxetine, paroxetine, or sertraline) concurrently with tamoxifen had a 16 percent rate of cancer recurrence in two years, which was significantly higher than the 7.5 percent recurrence rate in women who took no CYP2D6 inhibitor (reference cohort). The risk ratio was 2.2. Women who took a weak CYP2D6 inhibitor SSRI (citalopram, escitalopram, or fluvoxamine), had a recurrence rate of 8.8 percent, which was not statistically significantly different from the reference cohort.
• In May, Eli Lilly and Company started two phase-3 pivotal trials to test the efficacy and safety of solanezumab (also known as LY2062430) in treating mild to moderate Alzheimer's disease (AD). Solanezumab is a monoclonal antibody aimed at neutralizing amyloid beta, the protein believed to be largely responsible for the pathogenesis of AD. In earlier investigations, this monoclonal antibody was shown to bind to amyloid beta and prevent the protein from aggregating in the brain. The company said 2,000 patients worldwide were expected to be enrolled in the randomized, double-blind, placebo-controlled, 18-month trials. The antibody is administered by intravenous infusion once every four weeks. The primary endpoints are whether the drug will slow the cognitive and functional decline of AD compared with placebo.
• Positive results from a phase-3 clinical trial of vilazodone were announced by Clinical Data Inc., the company developing this drug for treatment of major depressive disorder. Vilazodone is both an SSRI and a partial serotonin 5-HT1A receptor agonist. This randomized, double-blind, placebo-controlled trial assigned 481 patients with major depressive disorder to either vilazodone or placebo treatment for eight weeks. The vilazodone group achieved a greater reduction in the Montgomery-Asberg Depression Rating Scale score than the placebo group, and the difference was statistically significant. The changes from baseline on 17-item Hamilton Depression Rating Scale scores in both groups also differed significantly. The vilazodone group had a 4.3 percent discontinuation rate due to adverse events, versus 1.7 percent in the placebo group. The most common adverse events associated with vilazodone were diarrhea, nausea, and headache. The company said it intended to file a new-drug application with the FDA seeking the approval of vilazodone for treatment of major depression.
• Three phase-3 clinical trials of Lu AA21004 have produced disappointing results for the drug as a potential treatment for major depressive disorder, according to a June 8 announcement by H. Lundbeck A/S, a Danish pharmaceutical company, and its U.S. partner, Takeda Pharmaceuticals. In two of the trials, the drug at 2.5 mg and 5 mg doses did not show a statistically significant difference from placebo in depression symptom reduction. In the third trial, the 5 mg and 10 mg doses showed mixed results, with significant differences in some but not other endpoints when compared with placebo. The companies said they plan to reevaluate the therapeutic dose for regulatory submission. The molecule is in phase-3 development for treatment of generalized anxiety disorder.
Legal Brief
• AstraZeneca, the defendant in a civil lawsuit involving its antipsychotic drug quetiapine, received a judgment in its favor in Delaware. The plaintiff was a Kansas woman who claimed that quetiapine caused her to develop diabetes. In the June 2 ruling, the superior court judge granted the company's request to exclude the testimony of a plaintiff's medical expert and issued a summary judgment in favor of the company. Thousands of other injury suits involving quetiapine are still pending. ▪
