Med Check

Regulatory Briefs

• The Food and Drug Administration (FDA) has approved the labeling claim that dexmethylphenidate extended release (Focalin XR) capsules have a 30-minute onset of action in treatment of attention-deficit/hyperactivity disorder (ADHD), according to a November 12 announcement by Norvartis, which markets the drug.

The approval was based on data from a randomized, multicenter, double-blind, crossover study in 86 pediatric patients aged 6 to 12 with ADHD. Patients randomized to the group of 20 mg dexmethylphenidate extended release had a significantly greater improvement in ADHD symptoms from baseline than did patients taking placebo at 30 minutes after drug administration. The study was conducted by Matthew Brams, M.D., and colleagues and published in the August CNS Drugs.

An abstract of “A Randomized, Double-Blind, Crossover Study of Once-Daily Dexmethylphenidate in Children With Attention-Deficit Hyperactivity Disorder: Rapid Onset of Effect” is posted at<cnsdrugs.adisonline.com/pt/re/cns/abstract.00023210-200822080-00006.htm>.

• The safety sections on the labels of citalopram, escitalopram, and paliperidone extended release have been changed, the FDA noted on its MedWatch Web site. For citalopram and esciptalopram, several adverse reactions including abnormal bleeding, potential interaction with other drugs that also increase risk of bleeding, and hyponatremia especially in geriatric patients have been added to the“ Precautions” section. For paliperidone, the “Drug Interactions” section now identifies the drug as a weak inhibitor of P-glycoprotein at high concentrations. In addition, paliperidone concentration in blood may be decreased by coadministration of carbamazepine because of reduction in renal clearance of paliperidone. Dose adjustment may be necessary if both drugs are prescribed.

Revised labeling safety information can be accessed at<www.fda.gov/medwatch/safety/2008/sep08_quickview.htm>.

• At its October meeting, the Committee for Medicinal Products for Human Use (CHMP), which advises the European Medicines Agency on new drug approvals, adopted a positive opinion for eszopiclone (brand name Lunesta in the United States and Lunivia in Europe) for treating insomnia in adults. The indications approved by the CHMP were short-term use to treat difficulty falling asleep, nocturnal awakening, or early awakening. Eszopiclone is manufactured by Sepracor Pharmaceuticals.

• AstraZeneca announced on November 13 that quetiapine, in both immediate- and extended-release formulations, was approved by the European authority for the treatment of major depressive episodes in bipolar disorder. Quetiapine extended-release tablets were approved for treating moderate to severe manic episodes in bipolar disorder. The drugs already carry similar indications in the United States.

• A record number of serious injuries (20,745) and deaths (4,824) suspected to be associated with drug therapy were reported to the FDA in the first quarter of 2008, according to a report released on October 23 by the Institute for Safe Medication Practices (ISMP), a nonprofit organization that conducts research on and advocates for medication safety for hospitals, pharmacists, and consumers. The number of suspected medication-related deaths was “a 2.6-fold increase from the previous quarter,” the ISMP stated.

Varenicline accounted for the largest number of serious injuries and deaths reported to the FDA during this period. Heparin-related serious injuries were ranked second, with 779 reports to the agency. During this time, the agency had issued a massive heparin recall because of possible contamination from suppliers in China. Medication errors accounted for 7.1 percent of drug-related serious injuries.

The ISMP regularly monitors drug-related adverse events stored in the FDA's database known as the Adverse Event Reporting System. These adverse events are reported voluntarily by physicians, nurses, pharmacists, and drug companies.

The ISMP report is posted at<www.ismp.org/QuarterWatch/2008Q1.pdf>.

Industry Briefs

• Asenapine was more effective than placebo in the long-term prevention of relapse in patients with schizophrenia, according to a randomized, placebo-controlled, double-blind, multicenter trial. The results were announced by Schering-Plough on October 23. In the study, 700 patients first took asenapine for up to 26 weeks. At the end of the open-label study, 386 patients who remain stabilized on the drug were randomized to either placebo or asenapine in a double-blind, controlled phase for another 26 weeks. No additional details were published.

• Auspex Pharmaceuticals announced in October positive safety data from a phase 1 clinical trial of SD-254, a selective serotonin norepinephrine reuptake inhibitor. SD-254 is essentially the same as venlafaxine except that some hydrogen atoms in the molecule are substituted with deuterium, an isotope of hydrogen.

According to the company's Web site, this molecular drug design, known as deuteration, could allow many drugs to preserve their efficacy but alter the pharmacokinetics and possibly reduce side effects. In this trial, the pharmacokinetic profile of SD-254 in 16 healthy volunteers appeared to be“ superior to that of venlafaxine,” the announcement stated.

• GlaxoSmithKline will publicly disclose its payments to physicians and limit the annual payment for any one person to $150,000, according to an October 24 press release. The decision follows several other major pharmaceutical companies, including Eli Lilly and Merck, that recently announced plans to post payments and gifts to physicians on their Web sites. Congress has been discussing but has not passed the Physician Payments Sunshine Act, which will mandate such disclosure for all drug and device manufacturers.

• Azur Pharma and Elan Corp. will collaborate in the development of once-daily formulations of clozapine, Azur announced on November 10. Drug-delivery technologies owned by Elan, intended to manipulate the pharmaceutical properties of various formulations, had been explored as a possible vehicle for extended-release clozapine since 2007. Azur currently manufactures and markets the orally disintegrating clozapine tablets and will carry out the clinical development of the once-daily formulations.

Clinical Trial Briefs

• The National Institute of Mental Health will fund a clinical trial on effective approaches to mitigate the metabolic side effects, such as weight gain, blood glucose increase, and blood lipid increase, of second-generation antipsychotics in children and adolescents. The study will recruit overweight youths aged 8 to 17 who have a diagnosis of either schizophrenia or bipolar disorder and who have gained 10 percent or more body weight on risperidone, quetiapine, or olanzapine. The patients will be randomly assigned to three interventions for 24 weeks: adding metformin, switching to aripiprazole, or continuing on the current treatment. The weight, metabolic profile, and psychiatric outcomes of the three groups will be compared.

• An investigational drug known as nepicastat, a dopamine beta hydroxlase inhibitor, will be studied in a randomized, double-blind, placebo-controlled, phase 2a clinical trial for treatment of posttraumatic stress disorder (PTSD). The drug is owned and developed by Synosia Therapeutics. The trial, funded by the U.S. Department of Defense, will be conducted with veterans of the Iraq war and assess the efficacy and tolerability of nepicastat in treating PTSD, including symptom improvement, remission, and quality of life. The trial will be conducted at Veterans Affairs medical centers in Tuscaloosa, Ala.; Houston; and Charleston, S.C.

Dopamine beta hydroxylase is an enzyme that converts dopamine into norepinephrine. Nepicastat has been shown to increase dopamine and decrease norepinephrine concentrations in blood and brain in animal studies, according to the November 3 announcement by Synosia.

• The National Institute on Aging has given Ceregene Inc., a $5.4 million grant to conduct a phase 2 clinical trial of the company's CERE-110, a gene therapy “designed to deliver nerve growth factor (NGF) for the treatment of Alzheimer's disease,” Ceregene announced on November 4. Cere-110 is expected to deliver the gene for NGF using an adeno-associated virus as a vector and is surgically injected into the nucleus basalis of Meynert in the brain, where cholinergic cell degeneration occurs in Alzheimer's disease, the announcement stated. The hope is to restore the function of these neurons with increased NGF gene expression.

In a previous phase 1 trial, CERE-110 was given to 10 patients with mild to moderate Alzheimer's disease and appeared to be safe and well tolerated. The phase 2 trial is expected to begin in early 2009.

• The National Institute on Drug Abuse will fund a clinical trial of Avigen Inc.'s investigational drug AV411, also known as ibudilast, for the treatment of opioid withdrawal symptoms, the company announced on October 15. AV411 is a nonopioid molecule that suppresses proinflammatory cytokines, such as interlukin (IL)-1 beta, tumor necrosis beta, and IL-6, according to the announcement. Preclinical studies indicated that the drug may reduce the behavioral and neurochemical symptoms of opioid withdrawal. The trial will evaluate safety and efficacy of AV411 for the treatment of opioid withdrawal symptoms and will be conducted by the New York State Psychiatric Institute and Columbia University. The drug is also being investigated for treating neuropathic pain. ▪