International Approvals: Atripla, Cubicin, Galvus

Yael Waknine

October 22, 2007

October 22, 2007 — Health Canada has approved efavirenz plus emtricitabine/tenofovir disoproxil fumarate tablets for use alone or with other antiretroviral agents in the treatment of HIV-1 infection; and daptomycin intravenous infusion for the treatment of gram-positive complicated skin and skin structure infections and bloodstream infections caused by Staphylococcus aureus. The European Commission has approved vildagliptin tablets in combination with metformin, sulfonylureas, or thiazolidinediones for the once-daily treatment of type 2 diabetes.

Once-Daily Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate Tablets ( Atripla) for HIV in Canada

On October 17, Health Canada approved efavirenz/emtricitabine/tenofovir disoproxil fumarate 600-, 200-, and 300-mg tablets ( Atripla, Bristol-Myers Squibb Company) alone or with other antiretroviral agents for the treatment of HIV-1 infection in adults.

The product is a combination of efavirenz ( Sustiva, Bristol-Myers Squibb), emtricitabine ( Emtriva, Gilead Sciences), and tenofovir disoproxil fumarate ( Viread, Gilead); all 3 components are reverse transcriptase inhibitors.

The approval was based on data from a 48-week, open-label, randomized, active-controlled, multicenter study (N = 487), showing that once-daily use of the efavirenz/emtricitabine/tenofovir product was noninferior to efavirenz plus twice-daily lamivudine/zidovudine ( Combivir, GlaxoSmithKline) for achieving a viral load of less than 400 copies/mL (84% vs 73%).

In addition, 80% and 70% of efavirenz-treated patients in the emtricitabine plus tenofovir and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA levels of less than 50 copies/mL. Corresponding mean increases from baseline in CD4+ cell counts were 190 cells/mm3 and 158 cells/mm3.

According to a company news release, the disparity between groups was largely attributed to an increased number of adverse event-related discontinuations in the efavirenz plus lamivudine/zidovudine group (9% vs 4%), as well as other reasons such as loss to follow-up, patient withdrawal, noncompliance, and protocol violation (14% vs 10%).

Treatment-emergent adverse events (grades 2 - 4) reported at a frequency of 5% or more in patients receiving efavirenz/emtricitabine/tenofovir tablets included dizziness, nausea, diarrhea, fatigue, headache, and rash.

Use of the fixed-dose combination tablet is not recommended for patients requiring dosage adjustment such as those with moderate or severe renal impairment (creatinine clearance < 50 mL/min).

Efavirenz/emtricitabine/tenofovir tablets previously were approved by the US Food and Drug Administration in July 2006.

Daptomycin Injection ( Cubicin) for Skin/Skin Structure Infection and Bacteremia in Canada

On September 24, Health Canada approved daptomycin intravenous infusion ( Cubicin, Cubist Pharmaceuticals, Inc, and marketed by Oryx Pharmaceuticals, Inc) for the treatment of complicated skin and skin structure infections caused by certain gram-positive infections and for bloodstream infections, including right-sided infective endocarditis, caused by Staphylococcus aureus.

"There is a great need in Canada for new approved therapies to treat serious, sometimes life-threatening infections, particularly those caused by methicillin-resistant Staphylococcus aureus," said Oryx President Doug Reynolds in a news release.

During the regulatory review process, daptomycin was available upon request via Health Canada's Special Access Program, which provides access to nonmarketed drugs for patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or are unavailable.

The recommended dose for complicated skin/skin structure infections and bacteremia is 4 mg/kg in normal saline infused over a 30-minute period every 24 hours for 7 to 14 days. Patients with bacteremia should receive 6 mg/kg daptomycin administered in the same manner for a minimum of 2 to 6 weeks.

Because renal excretion is the primary route of elimination, the dosing interval should be expanded to 48 hours for patients with a creatinine clearance of less than 30 mL/min.

Daptomycin injection previously was approved for these indications by the US Food and Drug Administration, the European Commission, and regulatory bodies in Switzerland, Taiwan, South Korea, and Israel. Its launch in the Canadian market is expected by late November 2007.

Vildagliptin Tablets ( Galvus) With Other Agents to Treat Type 2 Diabetes in EU

On September 28, the European Commission (EC) approved vildagliptin tablets ( Galvus, Novartis Pharmaceuticals Corp) in combination with metformin, sulfonylureas (SUs), or thiazolidinediones (TZDs) for the once-daily treatment of type 2 diabetes. The approval applies in all 27 countries of the European Union (EU), as well as in Norway and Iceland.

Vildagliptin belongs to a class of drugs called dipeptidyl peptidase 4 (DPP-4) inhibitors that includes sitagliptin ( Januvia, Merck & Company, Inc). DPP-4 inhibitors serve to increase incretin levels, which trigger the pancreas to increase insulin and signal the liver to stop glucose production. Adding vildagliptin to insulin sensitizers, such as pioglitazone or metformin, therefore addresses the 3 key defects of diabetes: insulin resistance, beta-cell dysfunction, and alpha-cell dysfunction.

An analysis of phase 3 study data (N = 592) revealed that the addition of vildagliptin to pioglitazone yielded a significantly greater decrease in HbA1c compared with pioglitazone alone (1.9% vs 1.4%; P < .001): 66% of patients receiving combination treatment achieved the American Diabetes Association-defined goal of 7% or less, compared with 42.5% and 42.9% receiving vildagliptin or pioglitazone alone, respectively.

Moreover, efficacy was observed in those with poor glycemic control, elderly patients (age > 65 years), and the obese (HbA1c decreases of 2.8% [baseline, ≥9%], 2.3% [baseline, 8.4%], and 2.2% [baseline, 8.6%; BMI ≥ 35]).

Results from a separate study (N = 700) showed that vildagliptin was similarly efficacious to rosiglitazone for achieving glycemic control; however, severely obese patients experienced a mean decrease in body weight of more than 1 kg, with an overall mean difference of 2.8 kg between the study groups. Viltagliptin-treated patients likewise experienced a decreased incidence of edema (2.5% vs 4.9%).

"Galvus lowers high blood sugar levels with no weight gain and a low incidence of hypoglycemia, two side effects commonly associated with currently available drugs such as SUs and TZDs. With Galvus, we now have another treatment option to help get patients to goal," says Burkhard Göke, MD, of the department of gastroenterology at Ludwig-Maximilians-University in Munich, Germany, in a company news release. The most common adverse events reported in clinical trials were stuffy nose, headaches, dizziness, and upper respiratory tract infection.

The product previously was approved in Mexico and Brazil and has been designated as "approvable" by the US Food and Drug Administration. A tablet containing vildagliptin and metformin ( Eucreas, Novartis) is currently under consideration for approval by the EC.


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