Wyeth ReFacto To Be Launched First In Germany And Austria

Wyeth-Ayerst is planning to launch its Factor VIII product ReFacto in Germany and Austria following approval by the European Commission April 13.

Wyeth intends to make ReFacto available in all 15 EU markets shortly after the Austrian and German launches, the firm said. ReFacto is indicated "for the control and prevention of hemorrhagic episodes and for routine and surgical prophylaxis in patients with hemophilia A (congenital Factor VIII deficiency or classic hemophilia)." The product is not indicated for von Willebrand's disease.

Under a 1997 agreement between Pharmacia & Upjohn and Wyeth's Genetics Institute subsidiary, P&U will manufacture the product and co-promote it in Nordic countries and the Middle East.

In the U.S., approval of ReFacto continues to await resolution of orphan drug issues. Wyeth's BLA had a user fee deadline in February.

FDA indicated at a December meeting of the Blood Products Advisory Committee that a decision on whether to nullify orphan exclusivity for Bayer's competitor product Kogenate would depend on whether the supply of Kogenate was deemed sufficient to meet demand ("The Pink Sheet" Dec. 21, 1998, p. 32).

The advisory committee discussion focused on the complex dosing required for ReFacto. The committee determined that information contained in the proposed dosage and administration labeling for the product would be acceptable.

European labeling notes that dosage and length of treatment depend on the "severity of the Factor VIII deficiency, the location and extent of bleeding and the patient's clinical condition."

The labeling provides a formula to determine the required dose of ReFacto, as well as a table to guide dosing in bleeding episodes and surgery.

"The calculation of the required dosage of Factor VIII is based upon the empirical finding that 1 International Unit (IU) of Factor VIII per kg body weight raises the plasma Factor VIII activity by 2 IU/dL per IU/kg administered," labeling states. The required dose of ReFacto is determined by multiplying body weight by the desired Factor VIII rise and then by 0.5 IU/kg.

Duration of dosing ranges from a single infusion for patients undergoing minor procedures like tooth extraction to multiple infusions repeated every 8-24 hours for up to seven days in cases where a 60%-100% increase in Factor VIII levels are desired in cases of major hemorrhage or surgical procedures.

"For routine prophylaxis to prevent spontaneous musculoskeletal hemorrhage in patients with hemophilia A, doses of 10 to 50 IU of Factor VIII per kg body weight should be given at least twice a week," labeling states. Infants and children may require higher doses or shorter dosage intervals.

European labeling addresses another issue raised during the FDA committee review: "If clinically indicated, Factor VIII blood levels should be determined using the chromogenic assay," labeling states.

If the chromogenic assay is not available, the one-stage clotting assay may be used, labeling continues. "However, it must be noted that the one-stage clotting assay yields results which are lower than the values obtained with the chromogenic assay."

During the FDA advisory committee review, Bayer, Baxter and Centeon objected to Genetics Institute's use of Chromogenix AB's chromogenic assay to determine doses in ReFacto clinical trials. The assay is not widely available in the U.S. because of its cost.

The European label contains warnings and precautions typical of other intravenous protein and coagulation Factor VIII products, and ReFacto is contraindicated in patients with known severe hypersensitivity to mouse, hamster or bovine proteins. Drug interaction studies have not been conducted, labeling states.

Wyeth has touted ReFacto as "the first recombinant Factor VIII product produced without the addition of human serum albumin to the final formulation, providing physicians and patients with unsurpassed safety from contamination by blood-borne pathogens."

Adverse event data in European labeling reports that "72 adverse events probably or possibly related to therapy were reported for 32,013 infusions (0.2%)" in ReFacto trials. Undesirable effects included nausea, dyspnea, venous access catheter complications, headache and paresthesia.