Ortho Folic Acid/OC Combo Will Require Further Discussion Of Dosing

Ortho will seek additional input from FDA on the appropriate dose of folic acid to use in combination with oral contraceptives before beginning clinical trials of the new formulation.

The Reproductive Health Drugs Advisory Committee agreed Dec. 15 that development of a folic acid/OC combination product would be appropriate. FDA convened the committee to discuss the idea of adding a supplement to prevent birth defects to standard OC products.

[Editor's note: To view a ¹ webcast of this meeting, visit FDAAdvisoryCommittee.com.]

However, committee members suggested that the recommended dose of folic acid as a dietary supplement (400 µg) may not be the right dose for the combination product.

"I think it is important that we have more information," Valerie Montgomery Rice, MD, Meharry Medical College, said. "I think 400 µg is a reasonable place to start....If we're going to do this we might as well make sure that we're given the best dose to get the maximum benefit."

The committee agreed with Ortho that the "counter-intuitive" OC/folic acid combination makes sense from a public health perspective (see ² (Also see "Ortho Oral Contraceptives May Add Folic Acid, New Patent Life" - Pink Sheet, 22 Dec, 2003.)).

Folic acid has been shown to prevent neural tube birth defects if the mother receives at least 400 µg a day either through diet or supplements prior to pregnancy. The majority of women, especially those not planning to become pregnant, have deficient levels of folate.

The committee expressed concern that the folic acid dose could mask vitamin B12 deficiency in patients suffering from pernicious anemia. Folic acid itself is "really not toxic," Barry Shane, PhD, University of California-Berkeley, said. So "it is not a traditional safety issue. It is a masking issue."

Pernicious anemia is a disorder that predominantly affects seniors, but about 10% of sufferers are not elderly, Shane noted. The estimated incidence of the disorder in younger patients is about 60,000 cases.

"The lowest dose of folic acid that has been associated with masking is 400 µg," National Institute of Child Health & Human Development Pediatric Epidemiology Section Chief James Mills, MD, said.

The Institute of Medicine "and other groups have picked 1,000 µg as the safe upper limit in part because they thought that that was the dose where it looked - from very incomplete data - [like] masking became a real serious problem," Mills added.

Another possible issue with using too high a dose of folic acid, committee members noted, is the potential that it will impede the efficacy of other drugs.

"If you gave people larger and larger doses of folic acid, eventually you would reach a point where drugs that work by antagonizing folate would be compromised," Mills noted. "Methotrexate is a good example of that."

Committee members also asked about any potential interactions between folic acid and oral contraceptives themselves.

Ortho-McNeil Women's Health Care Research Director Andrew Friedman, MD, acknowledged that there are at least two older studies in the literature that suggest higher doses of oral contraceptives may lead to a decrease in serum folate levels.

"However, more recent case-controlled studies containing 70 women and 48 adolescents that were published in the last three to four years suggest no such interaction with current low-dose formulations," Friedman said.

Committee members voted 14-4 against the need to identify a subpopulation who would be targeted to receive the additional folic acid.

Katherine Wenstrom, MD, University of Alabama at Birmingham, suggested an analogy to multivitamins, where no attempt is made to limit use to the relatively small patient population that is deficient in each ingredient. "Since folic acid has such low risk and is so inexpensive, do we need to identify a subpopulation?" Wenstrom asked.

The committee was divided on the broad question of whether there are "any" safety issues associated with folic acid, with 11 members saying there are none and seven saying there are some.

Irwin Rosenberg, MD, Tufts University, felt there were safety issues if a subpopulation was not defined.

"Clearly, we're going to have a considerable number of people who are getting more than a milligram a day of crystalline folic acid from a combination of their oral contraceptive and other supplements and the two or three hundred [µg] crystalline folic acid that they're also getting from other sources," he said.

Mills suggested that identifying the patient population is "a very simple clinical management issue. I think that when the woman walks into the clinician's office the question is, 'Are you taking a supplement containing 400 µg of folic acid?' If the answer is 'Yes'...you do not give them the oral contraceptive with folic acid. If the answer is 'No,' you say, 'You should take an oral contraceptive with folic acid.'"

The committee noted that the public health benefits of marketing a folic acid/OC combination will depend in part on Ortho's commercial strategy.

Committee Chair Linda Giudice, MD/PhD, Stanford University, asked if the discussion was limited to a particular oral contraceptive or if other companies would be able to add folic acid to their products.

FDA Reproductive & Urologic Drug Products Division Deputy Director Donna Griebel responded by noting that Ortho has a patent on folic acid/OC combos. "We're not sure of the implications of the patent that was mentioned earlier would have on this," she said. "So from a regulatory standpoint, we don't know the answer to that."

"I think the public health implications, based on what we have heard, are that folic acid certainly can benefit," David Hager, MD, University of Kentucky, said. "I would hate to see us limit it to a single product."

"We're here today to discuss the concept to see if the concept itself makes sense to this committee," Ortho-McNeil's Friedman said. "We feel it does and have presented arguments to that effect. With regard to issues of other companies, it's a little premature now to speculate on their interest in such a product."

Pressed on the issue of whether other companies would be interested, Friedman replied, "We would hope that would be the case."

Ortho noted that it represents about 40% of the OC market. The company estimates that 85% of all OCs could become combination products.