Generic versions of metformin will carry labeling that refers prescribers to Bristol-Myers Squibb's Glucophage label for information on pediatric patients.

"Pediatric usage information for metformin, as monotherapy, is approved for Bristol-Myers Squibb Company's metformin hydrochloride tablets," the indications section of generic metformin labeling states. "However," generic labeling notes, "due to marketing exclusivity rights, this drug product is not labeled for pediatric use."

A similar statement appears in the "clinical studies," "precautions," "adverse reactions" and "dosage & administration" sections of labeling.

The patient information insert for generic metformin urges patients to consult a physician for information on use of metformin in children. "If you have any questions about the use of metformin hydrochloride tablets in children, talk to your doctor or other health care provider," the insert says.

FDA approved the first generic versions of metformin on Jan. 24. As of Jan. 25, at least 10 ANDAs had been cleared by the agency. Generics for metformin have been "approvable" since October, after Bristol argued that generics could not carry pediatric use labeling protected by Waxman/Hatch exclusivity (¹ Also see "Metformin Generics Are "Approvable"; Barr Says Delay Helps Other Generics" - Pink Sheet, 15 October, 2001., p. 9).

Congressional action via "The Best Pharmaceuticals for Children Act" signed Jan. 4 gives FDA the authority to carve out the pediatric language in Glucophage labeling for generic versions of metformin (² Also see "Barr Expects Metformin Launch By Early February; Pediatric Bill Signed" - Pink Sheet, 14 January, 2002., p. 5).

The statute directs that generics can be approved with "a statement that, because of marketing exclusivity for a manufacturer, the drug is not labeled for pediatric use." The law also authorizes FDA to include "a statement of any appropriate pediatric contraindications, warnings, or precautions."

Bristol submitted a citizen petition asking FDA to conduct formal rulemaking before implementing the new law ("The Pink Sheet" Jan. 7, p. 3).

FDA rejected the petition and approved the generics. Bristol said it does not plan to challenge the agency's decision in court.

Bristol's decision to end the Glucophage fight without a final court challenge, coupled with its de-listing of a controversial Taxol patent that could have led to the removal of generic versions of paclitaxel, are clear indications that the company is ready to move beyond its recent emphasis on no-holds barred patent defenses (see ³ Also see "Bristol De-Lists ABI Taxol Patent Under Settlement With Ivax" - Pink Sheet, 28 January, 2002.).

Ivax, Watson, Mylan, Andrx, Alpharma, Barr, and Eon all received approval for the three marketed doses of Glucophage (500 mg, 850 mg and 1,000 mg). Ivax also received approval for 625 mg and 750 mg strengths. Genpharm and Teva received approval for the 500 mg and 850 mg doses.

U.S. Glucophage sales in 2001 totaled $2.02 bil., an increase of 18%. Bristol will continue to try to convert patients to the Glucovance and Glucophage XR formulations (with combined sales of $631 mil. in 2001).

Par, which will market Genpharm's generic metformin, estimates that generics will erode Glucophage sales by up to 70% in two months. The projection assumes a slightly less steep erosion rate than was the case for Lilly's Prozac (fluoxetine). Bristol is predicting a $1.7 bil. sales drop in 2002 (⁴ Also see "Bristol Readies For Glucophage Generics: Adds 600 Reps, Refiles Vanlev" - Pink Sheet, 17 December, 2001., p. 8).

Prozac faced competition from three manufacturers selling different strengths and dosage forms with 180 days of exclusivity; Glucophage will face many more generic competitors, which will presumably trigger rapid price erosion.

Par hopes to capture 10% of the generic market for metformin. Before the protracted delay touched off by the pediatric labeling issue, Barr expected to have a market share advantage based on supply issues, but the company believes that opportunity has been reduced.

The delay has allowed many generic companies to lock in agreements with wholesalers and retail chains for the metformin generic, Watson said.

Mylan told investors during a Jan. 24 conference call that it was not including significant metformin sales in its forecast for the year. Mylan is unsure "how the market will react to the product because there are a number of competitors that may be coming in at the same time".

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