International Approvals: Levemir, Plavix, Celsentri

Yael Waknine

October 29, 2007

October 29, 2007 — The Japanese Ministry of Health, Labor, and Welfare has approved insulin detemir injection for the treatment of types 1 and 2 diabetes, including use with oral antidiabetic agents, and clopidogrel bisulfate tablets for the treatment of acute coronary syndrome in patients scheduled to undergo percutaneous coronary intervention. Health Canada has approved maraviroc tablets for the combination antiretroviral treatment of treatment-experienced adults infected with chemokine (C-C motif) receptor 5 tropic HIV-1

Long-Acting Insulin Detemir Injection ( Levemir) for Diabetes in Japan

On October 22, the Japanese Ministry of Health, Labor, and Welfare approved insulin detemir injection ( Levemir, NovoNordisk, Inc) once- or twice-daily use in the treatment of adult and pediatric patients with type 1 diabetes and adults with type 2 diabetes who require basal insulin for the control of hyperglycemia.

The approval also allows use of detemir in combination with oral antidiabetic drugs (OADs) for the treatment of type 2 diabetes in patients who are unable to achieve adequate glycemic control with OADs alone. According to a company news release, diabetes is thought to affect more than 16 million people in Japan.

Detemir is active for up to 24 hours and serves to cover the body's basal insulin need. Because it is released gradually, the insulin analog causes less fluctuation in glucose levels; in pharmacodynamic studies, the mean duration of action of insulin detemir ranged from 5.7 hours at the lowest dose to 23.2 hours at the highest dose (sampling period, 24 hours). For doses ranging from 0.2 to 0.4 U per kilogram, detemir exerts more than 50% of its maximum effect from 3 to 4 hours up to approximately 14 hours after dose administration.

The product is expected to available in prefilled FlexPen and Penfill devices before the end of 2007. It previously was approved by the US Food and Drug Administration for use in type 1 diabetics and adult type 2 diabetics who require basal insulin.

Clopidogrel Tablets ( Plavix) for the Treatment of ACS in Japan

On October 22, the Japanese Ministry of Health, Labor, and Welfare (MHLW) approved a new indication for clopidogrel bisulfate tablets ( Plavix, Sanofi-Aventis), allowing their use for the treatment of acute coronary syndrome (ACS; unstable angina pectoris and non-ST-segment elevation myocardial infarction) for which percutaneous coronary intervention (PCI) is being planned.

According to a company news release, clopidogrel is the first drug to be approved for this indication in Japan. With the exception of the United States, Japan has the highest annual number of ACS patients worldwide who elect to undergo PCI (about 100,000 cases).

The approval was based on safety and efficacy data from multiple large-scale Japanese and international landmark trials of more than 100,000 patients and from clinical experience derived from more than 70 million clopidogrel-treated patients around the world.

Clopidogrel previously was approved by the MHLW to reduce the risk for recurrence of ischemic cerebrovascular disorder (excluding cardiogenic cerebral embolism), 1 of the 3 major causes of death in Japan.

It is approved by the US Food and Drug Administration to reduce atherothrombotic events in patients with non-ST-segment elevation ACS who are to be managed medically or with coronary artery bypass graft surgery and in those with recent myocardial infarction, stroke, or established peripheral arterial disease.

Maraviroc Tablets ( Celsentri) for HIV in Treatment-Experienced Patients in Canada

On October 15, Health Canada approved maraviroc tablets ( Celsentri, Pfizer, Inc) for combination antiretroviral treatment of treatment-experienced adults infected with chemokine (C-C motif) receptor 5 (CCR5)-tropic HIV-1 (also known as R5 virus). The recommended dose is 300 mg taken twice daily.

"There is an important need for new medicines to help the many Canadians living with HIV/AIDS who are running out of effective medications to control the virus," said Dr. Sharon Walmsley, MSc, FRCPC, Department of Medicine, University of Toronto in a company news release. "The approval of maraviroc is a significant breakthrough in that it provides a new class that blocks an early step in the viral life cycle that can be used for people with HIV who have developed resistance to our currently available drugs."

Maraviroc is the first in a class of drugs called CCR5 coreceptor antagonists that are designed to interfere with its interaction with HIV, which uses CCR5 or another protein (CXCR4) to enter white blood cells. Although several chemokine receptors can function as viral coreceptors, CCR5 is likely the most physiologically important coreceptor during natural infection, and at least 50% to 60% of treatment-experienced infected patients harbor CCR5-using viruses.

The approval was based on priority review of 6-month data from 2 ongoing studies (Maraviroc Plus Optimized Therapy In Viremic Antiretroviral Treatment-Experienced Patients; MOTIVATE-1 and -2) showing that the addition of maraviroc to optimized background therapy yielded significantly greater viral load reductions vs optimized background therapy alone, with more than twice as many patients achieving undetectable levels. Patients receiving maraviroc also achieved significantly greater increases in CD4+ cell counts.

The most frequently reported adverse events occurred with similar frequency in both groups and included diarrhea, nausea, and headache.

Maraviroc previously was approved by the US Food and Drug Administration (marketed as Selzentry) and European Commission in August and September 2007, respectively.

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