DOCUSATE SALTS PROPOSED FOR CATEGORY I STATUS AS OTC STOOL SOFTENERS

DOCUSATE SALTS PROPOSED FOR CATEGORY I STATUS AS OTC STOOL SOFTENERS by FDA in a notice of proposed rulemaking published in the Federal Register on September 2. The proposal would amend the tentative final monograph for OTC laxative drug products published in January 1985. FDA requests that comments on the proposed rule be submitted to the agency by Dec. 31. FDA is proposing to include three docusate salts -- docusate sodium, docusate calcium and docusate potassium -- in the OTC laxative monograph after reviewing evidence from rat studies that docusate is an animal teratogen. FDA said that the ingredients will be included in the monograph as stool softener laxatives and will be "required to bear the labeling proposed for all laxative drug products," which limits use of OTC laxatives to "relief of occasional constipation." Based on the recommendations of the OTC Laxative, Antidiarrheal, Emetic and Antiemetic Products panel, FDA is proposing oral dosage forms for docusate sodium and docusate calcium, and oral and rectal dosage forms for docusate potassium. "Manufacturers of docusate salt products in other forms . . . need to submit data on these products to support the use of the various docusate salts interchangeably in both oral and rectal dosage forms," the notice states. Although FDA's Sept. 2 proposed rule follows the panel recommendations, the agency delayed ruling on the docusate salts when it published the tentative final monograph on OTC laxative drug products in 1985 after learning of the animal studies. FDA noted that the rat study results raised "questions about the Panel's conclusions and recommendations for these laxative ingredients." To resolve the issue, FDA called together an intergovernmental scientific review panel to review the existing data, information and views pertaining to the teratogenicity and reproductive toxicity of docusate salts. In a March 1984 report, the review panel recommended that docusate salts should not be considered potential human teretogens but that additional studies should be conducted including further animal tests, pharmacokinetic studies, and epidemiological surveillance of pregnancy outcomes in women taking docusate salts. The panel concluded that the human risk from docusate salts "appears" to be "very low" and that for therapeutic uses of docusate sodium "a safety margin of nearly 120-fold is adequate," FDA noted. FDA concluded that the teratogenicity seen in studies of docusate calcium and docusate sodium was "due specifically to a surfactant induced deficiency of the B vitamin calcium pantothenate." To address the risk of docusate salts and pantothenic acid deficiency, FDA examined the existing literature to determine whether there was any indication of this association but was unable to uncover any "clinical evidence in the literature that showed pantothenic acid deficiency or possible toxicity problems even to a moderate degree." Furthermore, FDA believes that "the distribution of pantothenic acid in foods is so widespread that an occurrence of a deficiency of the vitamin is probably extremely rare." However, FDA has proposed some revisions with respect to the OTC panel report. Because of the "enhanced" absorption of mineral oil when taken with docusate salts the panel has recommended a drug interaction precaution -- "Do not take this product if you are presently taking mineral oil." However, FDA is proposing to add the wording -- "unless directed by you doctor" -- to that warning. FDA noted that this alteration was based on a comment that the drug interaction precaution should be expanded to "allow concomitant use of stool softeners with mineral oil if deemed necessary by a doctor." The panel also recommended dosages for children under two. However, FDA proposed that dosing instructions for children under two not appear on the packaging because "of the concern that constipation in infants may be a sign of a more serious condition that should be properly diagnosed by a doctor." The FDA proposed rule also does not include combinations of docusate sodium or docusate calcium with danthron due to that ingredient's potential as a human carcinogen. All danthron- containing products were recalled in 1987 due to concerns about the ingredient's carcinogenicity.