EMEA goes a step further than FDA’s decision to restrict the drug to inadequately controlled patients.

The European Medicines Agency (EMEA) has recommended suspending the marketing authorization for GlaxoSmithKline’s (GSK) type 2 diabetes drug Avandia (rosiglitazone) and the rosiglitazone combination treatments Avandamet and Avaglim. The agency has effectively gone one step further than FDA, which yesterday decided to restrict the use of Avandia in the U.S. through a risk evaluation and mitigation strategy to patients with type 2 diabetes who cannot control their disease on other medications.

In response to the EU recommendation to withdraw the drug, GSK says it will now stop promoting Avandia in all the territories in which it is active. Physicians in the EU are already being advised to switch patients on the three affected drugs to alternative treatments. EMEA’s recommendation will be passed to the European Commission for a legally binding final decision.

Cardiovascular safety concerns have led to incremental restrictions on the use of Avandia since its first European marketing authorization back in 2000, EMEA points out. At the time it was originally sanctioned, the drug was restricted to second-line therapy for type 2 diabetes and was contraindicated in patients with heart failure or a history of heart failure. Further restrictions in those with ischemic heart disease were subsequently introduced on the back of accumulating data from clinical trials, observational studies, and meta-analyses of existing data.

The latest review of available Avandia data was initiated by EMEA’s Committee for Medicinal Products for Human Use (CHMP) in July. The agency says the results of its review support the longstanding tenet that Avandia increases cardiovascular risks. Given the restrictions already in place for use of the drug, it could “not identify additional measures” capable of reducing health risks further. The only option is therefore to pull the drug from the market completely, it states. The suspension will remain in place unless GSK can “provide convincing data to identify a group of patients in whom the benefits of the medicine outweigh their risks,” EMEA notes.

Avandia’s downfall could reasonably be expected to spell good news for its main direct competitor, Takeda’s Actos® (pioglitazone). The Japanese drug giant reported ¥99.5 billion ($1,170 million) in global sales of Actos during the first fiscal quarter of 2010 (April 1–June 30), up 3.6% on the same period in 2009. Sales of Actos during fiscal year 2009 were up 6.5%, at $3,193 million.

Marketing authorizations for fixed combination drugs including pioglitazone have also been granted in 2010. In April Japanese regulatory authorities cleared Takeda’s Metact, a fixed-dose combination of Actos and metformin. In June the firm started U.S. marketing of Actoplus metXR, a fixed-dose combination of Actos with extended-release metformin. In July it started Japanese promotion of orally disintegrating Actos tablets in Japan.

Despite the fact that the first of Takeda’s pioglitazone patents is not due to expire until January 2011, and others providing protection against potential market infiltration by generics will not expire until much later, the firm has already been embroiled in patent litigation battles. In April Takeda confirmed it had completed settlement agreements with six out of eight defendants in patent-infringement suits brought against them in response to abbreviated New Drug Applications (aNDAs) filed for generic Actos and Actoplus met. Patent infringement lawsuits against Teva Pharmaceutical Industries and Aurobindo Pharma are still ongoing.

Under terms of the settled lawsuits, Takeda has granted Mylan, Watson, and Ranbaxy licenses to enter the U.S. market with generic pioglitazone on August 17, 2012, although there is a possibility that the date will be brought forward. Mylan, Watson, and Ranbaxy are first-filers of aNDAs with paragraph IV certifications for generic Actos, and Taked says it is anticipated that FDA will grant them 180-day marketing exclusivity. The firm has consequently granted Alphapharm, Sandoz, and Torrent licenses to get their generic Actos drugs into the U.S. market 180 days after Mylan, Watson, and Ranbaxy.

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