Cascara Sagrada, Aloe Laxatives, O-9 Contraceptive Are Category II – FDA

Reformulation of all cascara sagrada- and aloe-containing laxatives with approved active ingredients could cost industry up to $17.8 mil., including an estimated relabeling cost of $612,000, FDA states.

However, the agency predicts the figure likely is an overestimate, as some firms will opt to discontinue their products rather than replace the active ingredient.

FDA addresses the cost of aloe and cascara sagrada product reformulation and reclassifies the ingredients as Category II (nonmonograph) in a final rule published in the May 9 Federal Register.

"Stimulant laxative ingredients aloe (including aloe extract and aloe flower extract) and cascara sagrada (including casanthranol...cascara sagrada bark, [as well as extracts and fluid extracts of the herb]) in over-the-counter drug products are not generally recognized as safe and effective," the rulemaking states.

The rule, however, does not preclude testing of these ingredients, nor does it preclude the submission of "new, relevant data...at a later date as the subject of a new drug application that may provide for prescription or OTC marketing status."

Alternatively, manufacturers could submit such data in a citizen petition to amend the OTC laxatives monograph, the agency says.

Fifteen OTC laxatives containing aloe and 160 with cascara sagrada currently are available in the U.S., according to FDA. "Approximately 35 manufacturers and 70 distributors/repackers/relabelers market these 170 products," the agency adds.

However, none of these stakeholders provided data to support classifying either ingredient as safe and effective for use in laxatives, as requested by FDA in June 1998 (¹ (Also see "Bisacodyl, senna OTC laxative safety data requested by June 1999 in FDA proposal." - Pink Sheet, 22 Jun, 1998.), p. 6).

The notice proposed reclassifying aloe and cascara sagrada, along with senna and bisacodyl, as Category III (more data needed). The agency said the stimulant laxative ingredients would be designated Category II (not safe and effective) should interested parties fail to submit safety and efficacy data supporting their use.

Bisacodyl has since been reclassified as a Category I monograph ingredient; FDA notes the status of senna will be addressed in the future.

However, "any drug product containing...aloe or cascara sagrada and labeled for OTC laxative use will be considered nonmonograph and misbranded," as well as an unapproved new drug, the final rule says.

Laxative products with these ingredients must be removed from the market within 180 days of the final rule's publication, even if "further testing is undertaken to justify future use," the agency notes.

In a separate, same-day final rule, FDA also is reclassifying vaginal contraceptive octoxynol-9 as Category II, a move that will have a minor impact on industry relative to the laxatives regulation.

"There are a limited number of products currently marketed that will be affected by this rule," FDA says, noting it has identified five products produced by two manufacturers.

If all products were reformulated and relabeled, the firms would incur costs of $100,000 to $500,000 per product, yielding a total cost to industry of roughly $1.5 mil., FDA estimates.

Manufacturers have known since February 1995 that such a move would be imminent if "adequate data from clinical trials were not submitted to support safety and effectiveness," FDA points out.

Like producers of aloe- and cascara sagrada-containing laxatives, octoxynol-9 manufacturers failed to submit data or comments on the ingredient. Moreover, there are no ongoing clinical trials on O-9, FDA says.

Accordingly, the ingredient "should be deemed not generally recognized as safe and effective for OTC use [and] any drug product containing octoxynol-9 and labeled for OTC use as a vaginal contraceptive or vaginal spermicide will be considered nonmonograph and misbranded," the rule states.

Octoxynol-9 should be removed from OTC drug products 180 days following the rule's publication, but data may be submitted at a later day in support of an NDA for the ingredient.

Manufacturers also may reformulate O-9 items with nonoxynol-9 "pending completion of the final rule for these products," FDA says. The agency is awaiting completion of ongoing clinical trials before addressing the monograph or new drug status of N-9.