International Approvals: Tamiflu, Macugen, Naglazyme

Yael Waknine

February 13, 2006

Feb. 13, 2006 — The European Commission has approved an expanded indication for oseltamivir phosphate capsules and suspension, allowing their use for the prophylaxis of influenza in children aged 1 through 12 years; pegaptanib sodium injection for the treatment of neovascular (wet) age-related macular degeneration; and galsulfase injection for long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis VI.

Oseltamivir (Tamiflu) for Influenza Prophylaxis in Children in EU

On January 31, the European Commission approved an expanded indication for oseltamivir phosphate ( Tamiflu
capsules and suspension, made by Hoffman LaRoche, Inc), allowing its use for the prophylaxis of influenza in children aged 1 through 12 years.

The antiviral drug was previously approved for this indication in patients aged 13 years and older, and for the treatment of influenza in patients aged 1 year and older.

Dosing for the new pediatric indication is based on weight and ranges from 30 to 60 mg daily for a period of 10 days. Treatment should be initiated within 2 days of close contact with an infected individual.

According to a company news release, clinical studies have demonstrated that oseltamivir administered within 48 hours of exposure significantly decreases the incidence of influenza, compared with placebo (3% vs 17%).

The approval was based in part on data from a subset of pediatric patients in a study of household influenza transmission. In the study, oseltamivir treatment of influenza patients combined with postexposure prophylaxis of other household members was more effective in preventing secondary spread of influenza infection than treating the patient alone. In addition, the drug's protective efficacy in children aged 1 to 12 years was similar to that for the whole population (up to 89%).

Gastrointestinal events, particularly vomiting, were the most frequently reported adverse events in children receiving oseltamivir. Abdominal pain, epistaxis, ear disorder, and conjunctivitis were also observed and generally occurred once and resolved despite continued dosing.

The expanded indication was previously approved by the US Food and Drug Administration in December 2005.

Pegaptanib (Macugen) for Wet Age-Related Macular Degeneration in EU

On February 2, the European Commission approved pegaptanib sodium injection ( Macugen
, made by OSI Pharmaceuticals, Inc, and marketed by Pfizer, Inc) for the treatment of all types of neovascular (wet) age-related macular degeneration (AMD). The 0.3-mg dose is administered by intravitreal injection once every 6 weeks.

The approval was based on a data from two phase 2/3 randomized, multicenter, double-blind clinical trials involving 1186 patients with all subtypes of neovascular AMD. Results at 1 year showed that patients receiving pegaptanib showed significantly greater maintenance of visual acuity (loss of fewer than 3 lines of vision on eye chart) compared with placebo (70% vs 55%; P
< .001).

Data from a 2-year extension study showed continued benefit in patients randomized to prolonged pegaptanib therapy, and that treatment should be initiated as early as possible.

Pegaptanib was well tolerated overall; most adverse events were mild, transient, and attributed by investigators to the injection procedure rather than the study drug. According to a company news release, rare postmarketing cases of allergic reaction have been reported within several hours of injection with pegaptanib, but a causal role for the drug or other factors has not been established.

Pegaptanib was previously approved for use in the United States, Canada, Brazil, Argentina, Peru, Pakistan, and the Philippines.

Galsulfase (Naglazyme) for Mucopolysaccharidosis VI in EU

On January 30, the European Commission approved galsulfase 1-mg/mL injection ( Naglazyme
, made by Biomarin Pharmaceutical, Inc) for long-term enzyme-replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis VI (MPS VI, also known as Maroteaux-Lamy syndrome).

The approval was based in part on data from a 24-week, double-blind, phase 2 clinical trial in 39 patients showing that galsulfase therapy significantly improved endurance compared with placebo, as evaluated via increases from baseline in 12-minute walk test (12-MWT) distance (109 ± 154 min vs 26 ± 122 min; P
= .025) and rate of 3-minute stair climb (7.4 ± 9.9 stairs/min vs 2.7 ± 6.9 stairs/min; P
= .053).

Although normal ranges were not achieved in the active treatment group, galsulfase bioactivitiy was confirmed by decreased levels of urinary glycosaminoglycans that were maintained for up to 144 weeks in 2 long-term extension trials involving 17 patients.

Also, an open-label, 24-week extension trial in 38 patients from the original study showed that continued treatment with galsulfase led to further improvements in 12-MWT distance and rate of stair climbing (36 ± 97 min; 3 ± 7 stairs/min). Among patients originally randomized to placebo, corresponding improvements during this period were 66 ± 133 min and 6 ± 8 stairs/min, respectively.

The most commonly reported galsulfase-related adverse events included headache, fever, arthralgia, vomiting, upper respiratory tract infections, abdominal pain, ear pain, cough, and otitis media. Infusion-related reactions commonly included fever, chills/rigor, headache, rash, and mild to moderate urticaria.

Because antihistamine use may increase the risk for apneic episodes, consideration should be given to evaluating airway patency prior to initiation of galsulfase therapy, and to delaying treatment in patients presenting with acute febrile or respiratory illness.

Galsulfase injection was previously approved by the US Food and Drug Administration in May 2005 for use in patients with MPS VI to improve stair-climbing capacity. Both agencies have required postmarketing surveillance programs as a condition of licensure.

Reviewed by Gary D. Vogin, MD


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