International Approvals: Kepivance, Generic Flixonase, Revatio

Yael Waknine

November 07, 2005

Nov. 7, 2005 — The European Commission has approved palifermin injection to reduce the incidence, duration, and severity of oral mucositis secondary to myeloablative therapy in patients with hematologic malignancies, and generic fluticasone propionate nasal spray for use in 11 European countries. The European Medicines Evaluation Agency has approved orphan drug status for sildenafil citrate 20-mg tablets in the treatment of severe pulmonary arterial hypertension.

Palifermin (Kepivance) to Decrease Incidence, Duration, and Severity of Mucositis in EU

On Oct. 28, the European Commission (EC) approved palifermin injection (Kepivance, made by Amgen Inc.) to decrease the incidence, duration, and severity of oral mucositis in patients with hematologic malignancies undergoing myeloablative therapy associated with a high incidence of oral mucositis, and requiring autologous blood and bone marrow transplantation.

Palifermin is a recombinant human keratinocyte growth factor that stimulates epithelial cell growth in areas damaged by chemotherapy and/or radiation, such the lining of the mouth and digestive tract.

The approval was based on the results of a phase 3, double-blind trial comparing placebo with use of palifermin 60 µg/kg/day administered intravenously for three days prior to conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and repeated after bone marrow transplantation.

Palifermin therapy was found to significantly reduce the incidence of World Health Organization (WHO) grade 4 and grade 3-4 mucositis compared with placebo (20% vs 62% and 63% vs 98%, respectively; P < .001 for both). Duration of WHO grade 2-4 painful oral mucositis was also significantly reduced in patients receiving palifermin (8 vs 14 days with placebo).

Palifermin was found to significantly decrease mouth and throat soreness (P < .001) and improve patients' ability to eat, drink, swallow, and talk. Fewer days of morphine were required for pain relief in patients administered palifermin compared with placebo (7 vs 11 days).

Adverse events were transient and mild to moderate in severity, including rash, pruritus, erythema, paresthesias, mouth/tongue disorders, and taste alteration.

The EC notes that the safety and efficacy of palifermin has not been established in patients with nonhematologic malignancies.

Palifermin injection was previously approved by the U.S. Food and Drug Administration in December 2004 to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies undergoing chemotherapy with or without radiation in preparation for bone marrow transplantation.

Generic Fluticasone Nasal Spray (Flixonase) Approved in 11 European Countries

On Oct. 28, the European Commission approved a mutual recognition procedure (MRP) for generic fluticasone propionate nasal spray (made by Ivax Corp; brand name Flixonase, made by GlaxoSmithKline), allowing its use in 11 European countries for the treatment of allergic rhinitis.

Fluticasone nasal spray was originally approved in May 2005 by the U.K.'s Medicine and Healthcare Products Regulatory Agency, allowing that country to serve as the MRP reference member state.

Fluticasone propionate nasal spray is marketed by GlaxoSmithKline as Flonase in the U.S., where the generic formulation is currently under consideration for approval by the Food and Drug Administration.

Sildenafil Citrate (Revatio) Granted Orphan Drug Status for Severe PAH in EU

On Nov. 4, the European Medicines Evaluation Agency approved orphan drug status for sildenafil citrate 20-mg tablets (Revatio, made by Pfizer, Inc.) to improve exercise capacity in patients with severe pulmonary arterial hypertension (PAH; World Health Organization [WHO] functional class 3).

The 20-mg Revatio pill is white and round, allowing it to be easily distinguished from the blue diamond-shaped Viagra tablet, which is not available in a 20-mg dose.

The approval was based on data from a three-month, double-blind, placebo-controlled trial in 278 patients with PAH who were randomized to receive 20, 40, or 80 mg of sildenafil three times daily or placebo.

Results showed that patients in all three active-treatment groups achieved significant improvements in exercise capacity, as evaluated by increases in six-minute walk distance (placebo-corrected increase, 45-50 minutes). Patients receiving sildenafil also showed significant improvements in mean pulmonary arterial pressure and other measures of cardiac function.

Because improvements in the primary end point (six-minute walk distance) were similar among the three treatment groups, the approved dose was limited to 20 mg three times daily.

Long-term data from an open-label extension trial showed that improvements in walk distance and cardiac function were preserved at one year, with sildenafil-treated patients showing a 96% survival rate (vs an expected rate of 71%). It should be noted that without a control group, these data must be interpreted cautiously.

Sildenafil was well tolerated; the most commonly reported adverse events were similar to those associated with Viagra and included headache, dyspepsia, flushing, epistaxis, and insomnia.

Sildenafil 20-mg tablets were approved by the U.S. Food and Drug Administration (FDA) in June 2005 to improve exercise ability in patients with early-stage PAH (WHO class 1).

Sildenafil 25-, 50-, and 100-mg tablets (Viagra, made by Pfizer, Inc.) were previously approved by the European Commission and the FDA for the treatment of erectile dysfunction.

Reviewed by Gary D. Vogin, MD


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