Med Check
Regulatory Briefs
• The Food and Drug Administration (FDA) approved combination olanzapine/fluoxetine capsules (Symbyax) for the acute treatment of treatment-resistant depression, defined as “major depressive disorder in adults who do not respond to two separate trials of different antidepressants of adequate dose and duration in the current episode,” according to an Eli Lilly announcement on March 23.
This is the first drug therapy approved for this indication. The combination was also approved for depressive episodes associated with bipolar I disorder in adults. In addition, the individual labels of fluoxetine, which is currently available in generic form, and olanzapine now contain approved indications for treatment-resistant depression and bipolar I depression if each drug is taken in combination with the other. The labels of the combination drug and olanzapine alone were also revised to contain clinical trial findings regarding weight gain, hyperglycemia, and increased cholesterol associated with the antipsychotic.
• The labels of all selective serotonin-reuptake inhibitor (SSRI) and serotonin- and norepinephrine-reuptake inhibitor (SNRI) antidepressants were updated in January, as mandated by the FDA, with warnings about the risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions. The warning cautions that concomitant use of SSRIs or SNRIs with monoamine oxidase inhibitors, serotonergic drugs such as triptans (5-hydroxytryptamine receptor agonists), antipsychotics, or dopamine antagonists may exacerbate the risk of these potentially life-threatening adverse events and require careful monitoring.
• The FDA posted changes to the “Warnings and Precautions” and “Adverse Reactions” sections of the label for duloxetine delayed-release capsules (Cymbalta) in March. The updated wording warns of adverse reactions reported in clinical trials and postmarketing reports. These reactions include tinnitus, poor sleep quality, polyuria, aggression and anger (particularly early in treatment or after discontinuation), restless legs syndrome, and other adverse events.
• The FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC) sent letters to 14 companies requesting that inappropriate and unlawful drug-promotional Internet links be removed because they omitted risk information or contained misleading claims. The DDMAC appears to be stepping up its monitoring and regulation of online drug and medical-device advertising in recent months. This batch of warning letters focused on company-sponsored links on Internet search engines that are intended to draw Internet users to Web sites focused on these drugs, including duloxetine.
Legal Briefs
• A proposed settlement of a lawsuit involving paroxetine extended-release tablets may entitle patients and third-party payers to reimbursement for buying Paxil CR tablets that were manufactured by GlaxoSmithKline from April 1, 2002, to March 4, 2005. The lawsuit claimed that these tablets were defective and tended to split apart. If the proposed settlement is approved in the final hearing, scheduled for July, the company will pay up to $28 million to settle claims. The manufacturer has denied any liability in the suit.
Details of the settlement are posted at<www.simonetpaxilcrsettlement.com>.
• IMS Health and SDI filed a petition with the U.S. Supreme Court on March 27, seeking to overturn a New Hampshire law that restricts prescription data mining. Both are large data-gathering companies that collect, analyze, and sell health care market data, including prescription data that allow pharmaceutical companies to monitor prescribing patterns of physicians and other prescribers and identify and target specific prescribers in marketing efforts. New Hampshire, Maine, and Vermont have passed laws to ban this type of data mining, but they were struck down or tied up in lower courts based on First Amendment arguments. However, in November 2008 a federal appellate court overturned a lower court ruling and upheld the New Hampshire Prescription Confidentiality Act and in April Vermont's law was upheld in U.S. District Court.
Industry and R&D Briefs
• Eli Lilly announced inconclusive results from a phase 2 study of LY2140023, a glutamate mGlu2/3 receptor agonist and a candidate drug to treat schizophrenia. The finding was somewhat unexpected, as the compound appeared to be a promising first-in-kind antipsychotic with positive efficacy data in a previous phase 2a study in 2007.
In this randomized, placebo-controlled trial, 393 patients with schizophrenia completed four weeks of treatment with LY2140023, olanzapine, or placebo. The placebo group had an unexpectedly high response rate, according to the company announcement, and neither olanzapine 15 mg daily nor LY2140023 led to a statistically significant reduction in patients' symptoms compared with placebo. Lilly said it would continue the clinical development of LY2140023 and would conduct another phase 2 trial to determine the molecule's efficacy.
• Cephalon announced positive results from a phase 3 trial of armodafinil for the treatment of excessive sleepiness in jet-lag disorder on April 6. An R-enantiomer of modafinil, armodafinil is currently approved for promoting wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome, narcolepsy, and shift-work sleep disorder.
The randomized, double-blind, placebo-controlled trial was conducted in 427 healthy adults with a history of jet-lag symptoms during the previous five years. Study participants traveled eastbound from the United States to France and received either armodafinil or placebo for three days. The drug was generally well tolerated and was shown to be more effective than placebo in reducing excessive sleepiness. The company said it would file a supplemental new drug application with the FDA later this year for this indication.
• A modified-release formulation of eszopiclone, a nonbenzodiazepine drug currently approved to treat insomnia, failed a phase 2 clinical trial to evaluate its efficacy in patients with generalized anxiety disorder (GAD), according to a March 5 announcement by its maker Sepracor. In this 440-patient trial, the drug did not meet the primary endpoint in reducing the symptoms of GAD.
• Repligen Corp. announced on March 31 that it licensed the patent rights to the use of uridine to treat bipolar disorder from McLean Hospital in Belmont, Mass. An oral formulation of uridine is currently in phase 2 clinical development by the company for treatment of bipolar depression.
• Switzerland-based Roche and Germany-based Evotec announced a plan to co-develop a group of compounds that belong to the category of N-methyl D-aspartate receptor NR2B subtype selective antagonists. These molecules act on a type of glutamate receptor and may become candidates for treating a number of central nervous system disorders, including Alzheimer's disease and Parkinson's disease. One of these drug candidates, EVT 101, is currently in phase 2 clinical development for treatment-resistant depression.
• A once-daily formulation of bupropion hydrobromide extended-release tablets, marketed under the brand name Aplenzin, has entered the U.S. market, said the manufacturer Sanofi-Aventis on April 7. The highest dosage form, 522 mg, delivers the equivalent of a 450 mg bupropion hydrochloride tablet. Approved by the FDA for marketing in April 2008, the tablet was developed by Biovail and has shown bioequivalence to other formulations of bupropion tablets.
• Shire announced on March 16 that it has decided to withdraw a previous application to European regulators to market methylphenidate transdermal system (Day-trana), a medicated patch approved in the United States to treat attention-deficit/hyperactivity disorder. The European authority had asked the company to conduct additional clinical trials.
• A phase 3 study of vilazodone, an investigational antidepressant developed by Clinical Data Inc., showed positive outcomes in the treatment of major depressive disorder, according to a study published in the March Journal of Clinical Psychiatry. In the randomized, double-blind, placebo-controlled study, 198 patients with depression received vilazodone and 199 received placebo for eight weeks. The mean Montgomery-Asberg Depression Rating Scale scores were reduced from baseline by 12.9 points in the vilazodone group and 9.6 points in the placebo group after eight weeks, and the difference was statistically significant. The reductions in 17-item Hamilton Rating Scale for Depression scores from baseline were 10.4 points and 8.6 points in the vilazodone and placebo groups, respectively, also a statistically significant difference. The most frequent adverse events associated with vilazodone included diarrhea, nausea, and somnolence. Vilazodone is an SSRI and a partial agonist of the 5HT1A receptor.
An abstract of “Evidence for Efficacy and Tolerability of Vilazodone in the Treatment of Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial” is posted at<www.psychiatrist.com/abstracts/abstracts.asp?abstract=200903/030903.htm>.
• Janssen, a division of Johnson and Johnson, announced on April 1 that results from a clinical trial of paliperidone extended-release tablets for the treatment of schizoaffective disorder were presented by the company at the 12th International Congress on Schizophrenia Research in San Diego. In the randomized, double-blind, placebo-controlled study, 311 patients with acute symptoms were treated with either paliperidone or placebo for six weeks. The reduction in Positive and Negative Syndrome Scale total score in the paliperidone group was significantly more than that in the placebo group. The most common adverse events were headache, dizziness, insomnia, akathisia, and dyspepsia, according to the company.
Paliperidone is approved to treat schizophrenia. In February Janssen submitted an application to the FDA seeking approval to use paliperidone to treat schizoaffective disorder. ▪
