The U.S. Food and Drug Administration (FDA) approved the antipsychotic ziprasidone for the maintenance treatment of bipolar I disorder as an adjunct to lithium or valproate, according to a Pfizer announcement on November 20, 2009. This approval was based on a six-month, double-blind clinical trial, in which 240 patients were randomized to receive either ziprasidone or placebo after being stabilized on open-label ziprasidone. All patients also received lithium or valproate throughout the trial. During the six months, 19.7 percent of patients in the ziprasidone group relapsed or required intervention for a mood episode, compared with 32.4 percent in the placebo group. This difference was statistically significant. The medication had previously been approved for schizophrenia and acute treatment of mania and mixed episodes in bipolar I disorder.
The antipsychotic aripiprazole was approved by the FDA for treating symptoms of autism-related irritability, such as aggression toward others, self-injurious behavior, and tantrums, in patients aged 6 to 17, Bristol-Myers Squibb announced on November 20, 2009. The drug is jointly developed and marketed by that firm and Otsuka Pharmaceuticals.
In two randomized, double-blind, placebo-controlled, phase 3 clinical trials, more than 300 pediatric patients with a DSM-IV diagnosis of autistic disorder and moderate to severe symptoms of irritability were treated with either aripiprazole or placebo. The dosage was adjusted from a starting dose of 2 mg/day up to no more than 15 mg/day; the average dose at the study end was 8.6 mg/day.
After eight weeks, the reduction in irritability symptoms, measured by the Irritability Subscale of the Aberrant Behavior Checklist (ABC-I) and the Clinical Global Impression-Improvement (CGI-I) scale, was statistically significantly higher in the aripiprazole group than the placebo group. The aripiprazole group had a mean weight gain of 1.6 kg over eight weeks, compared with a 0.4 kg weight gain among placebo-treated patients. Clinically significant weight gain (a gain of at least 7 percent from baseline) occurred in 26 percent of the aripiprazole group and 7 percent of the placebo group.
The FDA approved duloxetine hydrochloride for the maintenance treatment of generalized anxiety disorder (GAD) in adults, Eli Lilly announced on November 30, 2009. In the clinical trial supporting this indication, 429 patients with a GAD diagnosis who had responded to duloxetine in a 26-week, open-label phase were randomized to an additional 26 weeks of a double-blind phase, in which approximately half of the patients remained on duloxetine and the other half received placebo. The relapse rate in the double-blind phase was 46.4 percent in the placebo group and 15 percent in the duloxetine group, and the difference was statistically significant. Duloxetine was previously approved for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia, and acute treatment for GAD.
On November 19, 2009, Otsuka Pharmaceuticals Europe withdrew its application to the European Medicines Agency (EMEA) for expanding the indication of aripiprazole to include adjunctive treatment for major depressive disorder. The drug is currently approved in Europe for the treatment of schizophrenia and the prevention of manic episodes in bipolar I disorder. The company filed the application in late 2008. The agency's review committee said that the long-term data supporting this application were insufficient.
The FDA announced on November 20, 2009, that it was conducting a safety review on sibutramine, an appetite suppressant indicated for treatment of obesity, because a recent study suggested that patients taking the drug may have a higher number of cardiovascular events than those on placebo. The study is part of a postmarketing commitment between the EMEA and the manufacturer, Abbott Laboratories, and has been ongoing since 2002 with approximately 10,000 participants.
Preliminary analysis from the study showed that 11.4 percent of patients on sibutramine experienced cardiovascular events, compared with 10 percent of patients on placebo. All study participants were at least 55 years old, overweight or obese, had a history of heart disease or type 2 diabetes, and had another cardiovascular risk factor. However, patients with a history of heart attack, stroke, or poorly controlled congestive heart failure were excluded from enrollment. The FDA said it would continue to review sibutramine data and adverse-event reports. The agency recommended that the drug be "avoided in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke, as recommended in the current sibutramine labeling."
The FDA's notice of ongoing review on sibutramine is posted at <www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm191650.htm>.
Safety-related labeling changes in October 2009 were applied to two antipsychotic drugs. The label for desipramine was revised to add warnings about cardiac risks and manifestations and management of overdose. In addition, the manufacturer Sanofi-Aventis sent out a "Dear Healthcare Professionals" letter to inform prescribers about these safety warnings added to the product label. Further, paliperidone's label was modified to include priapism in the Warnings and Precautions section and Adverse Reactions section.
Information about safety labeling changes is posted at <www.fda.gov/Safety/MedWatch/SafetyInformation/ucm187420.htm>. The desipramine warning letter is posted at <www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM192657.pdf>.
A federal lawsuit filed by the manufacturer Allergan against the FDA could result in lifting of the current FDA ban on drug companies promoting off-label indications of their products. The lawsuit, filed in October 2009, argues that the prohibition violates the constitutional right to free speech. In recent years, a number of manufacturers have paid millions of dollars to settle federal lawsuits that charged them with illegally promoting unapproved indications for prescription drugs. Last September the FDA asked Allergan to develop a Risk Evaluation and Mitigation Strategy plan for its product botulinum toxin A (Botox) that is to discuss the risks of the product's off-label uses.
A six-month, randomized, double-blind, phase 3 clinical trial of naltrexone extended-release injection suspension showed efficacy in treating opioid dependence, manufacturer Alkermes Inc. announced on November 16, 2009. In the study, 250 patients with opioid dependence and recent detoxification were randomized to monthly injections of either naltrexone or placebo for 24 weeks. Efficacy was measured by the cumulative rate of opioid-free urine-screening results in the later 20 weeks. Patients who received naltrexone injections had significantly more opioid-free urine tests than those who received placebo. The study also met two secondary efficacy endpoints: At least half of the patients on naltrexone had 90 percent opioid-free urine samples, and patients on naltrexone reported significantly lower opioid craving on a visual analog scale than did those on placebo. Natrexone extended-release intramuscular injection is currently approved for the treatment of alcohol dependence.
Direct-to-consumer (DTC) advertising was associated with increased drug costs but not an increase in actual use, a study in the December 2009 Archives of Internal Medicine found. Researchers compared usage rates and costs of clopidogrel in 27 state Medicaid programs before (1999 and 2000) and after (2001 to 2005) DTC advertisements for the drug began. The number of units dispensed for clopidogrel, an antiplatelet drug used to prevent blood clots, did not change significantly after the start of DTC advertisements for the drug, but the unit cost to Medicaid programs increased by an average of $0.40.
The authors assumed that the increased Medicaid reimbursement reflected an increase in the manufacturer's price for the drug, as there was no other plausible reason for this increase across 27 state programs. However, pricing data were confidential and could not be obtained to verify the suspicion.
As a result, Medicaid paid an additional $40.58 in pharmacy cost per 1,000 enrollees per quarter, or $207 million in total. The manufacturer spent over $350 million on DTC advertising for clopidogrel between 2001 and 2005. In 2005, sales of clopidogrel reached $5.9 billion worldwide.
An abstract of "Costs and Consequences of Direct-to-Consumer Advertising for Clopidogrel in Medicaid" is posted at <archinte.ama-assn.org/cgi/content/short/169/21/1969>.