Med Check

Regulatory Briefs

• On July 26, the Food and Drug Administration (FDA) released two drug-safety communications regarding serious CNS reactions that are possible when a patient is taking serotonergic psychiatric medications. Both the antibacterial drug Zyvox (linezolid) and the drug methylene blue are reversible monoamine oxidase inhibitors (MAOIs), which inhibit the action of monoamine oxidase A, an enzyme responsible for breaking down serotonin in the brain. This may to lead to serotonin buildup in the brain, causing the toxicity known as serotonin syndrome. Symptoms include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering, diarrhea, trouble with coordination, and/or fever.

Linezolid is used to treat pneumonia, infections of the skin, and infections caused by a resistant bacterium (Enterococcus faecium). Methylene blue is used to treat methemoglobinemia, vasoplegic syndrome, ifosfamide-induced encephalopathy, and cyanide poisoning. It is also used as a dye in diagnostic applications. The FDA recommended that these drugs not be given to patients taking serotonergic drugs, but recognizes there are some conditions that may be life-threatening or require urgent treatment with those drugs.

The FDA's 2011 safety alerts for human medical products are posted at <www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm238512.htm>.

• On August 5, Alexza Pharmaceuticals announced that it has resubmitted its AZ-004 (Staccato loxapine) New Drug Application (NDA) to the FDA in response to a Complete Response Letter received in October 2010.

AZ-004 is being developed for the rapid treatment of agitation in schizophrenia or bipolar disorder patients. In addition to the data from the original NDA and additional analyses of some of those data, the AZ-004 resubmission contains new data from the completed human-factors study, stability data from new production batches manufactured late last year, updated manufacturing and controls sections, updated draft labeling, and a comprehensive Risk Evaluation and Mitigation Strategy (REMS) proposal.

Alexza's technology, the Staccato system, vaporizes unformulated drug to form a condensation aerosol that when inhaled allows for rapid systemic drug delivery through deep lung inhalation. The drug is quickly absorbed into the bloodstream, providing speed of therapeutic onset that is comparable to intravenous administration, but with greater ease and patient comfort, according to the company. Alexza has announced positive results from both of its AZ-004 phase 3 clinical trials. The company completed an end-of-review meeting with the FDA in December 2010 and a REMS guidance meeting in April.

International Brief

• Valeant Pharmaceuticals announced on July 25 that its wholly owned subsidiary, Valeant Canada Ltd., has received notice that the New Drug Submission for Sublinox has been approved by the Canadian regulatory authority Health Canada. Sublinox, a sublingual orally dissolving tablet of zolpidem tartrate, is indicated for the short-term treatment and symptomatic relief of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Sublinox will be the first commercially available zolpidem tartrate formulation in Canada. Sublinox has been clinically demonstrated to initiate a statistically significant latency to persistent sleep, sleep onset latency, and latency to stage one sleep compared with oral zolpidem tartrate. Analysis of sleep-continuity endpoints, total sleep time, and wake after sleep onset showed no major treatment differences compared with oral zolpidem tartrate tablets.

Legal Briefs

• Google has agreed to pay to the U.S. government as a "civil forfeiture" $500 million for allowing online Canadian pharmacies to place advertisements through its AdWords program targeting U.S. consumers, resulting in the unlawful importation of controlled and noncontrolled prescription drugs into the United States, announced Deputy Attorney General James Cole; Peter Neronha, U.S. Attorney for the District of Rhode Island; and Kathleen Martin-Weis, acting director of the FDA's Office of Criminal Investigations on August 24. The asset forfeiture, one of the largest ever in the United States, represents the gross revenue received by Google as a result of Canadian pharmacies advertising through Google's AdWords program, plus gross revenue made by Canadian pharmacies from their sales to U.S. consumers.

The shipment of prescription drugs from pharmacies outside the United States to U.S. customers typically violates the Federal Food, Drug, and Cosmetic Act and, in the case of controlled prescription drugs, the Controlled Substances Act. Google was aware as early as 2003 that generally it is illegal for pharmacies to ship controlled and noncontrolled prescription drugs into the United States from Canada.

"The Department of Justice will continue to hold accountable companies who in their bid for profits violate federal law and put at risk the health and safety of American consumers," said Cole. "This settlement ensures that Google will reform its improper advertising practices with regard to these pharmacies while paying one of the largest financial forfeiture penalties in history."

Under the terms of an agreement signed by Google and the government, Google acknowledged that it improperly assisted Canadian online pharmacy advertisers to run advertisements that targeted the United States through AdWords, and the company accepted responsibility for this conduct. In addition to requiring Google to forfeit $500 million, the agreement also sets forth a number of compliance and reporting measures that Google must take to ensure that the conduct described in the agreement does not occur in the future.