# 70 FR 741: Orally Administered Drug Products for Relief of Symptoms Associated With Overindulgence in Food and Drink for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph > Federal · Regulations · In force URL: https://www.frixlaw.com/law-library/statutes/FR_PRORULE_05-154 ## Section - **Citation:** 70 FR 741 - **Heading:** Orally Administered Drug Products for Relief of Symptoms Associated With Overindulgence in Food and Drink for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph - **Jurisdiction:** Federal - **Kind:** Regulations - **Status:** In force - **Text as of:** August 14, 2026 - **Source:** Compiled text - **Location:** Federal Register / Vol. 70 / 70 FR 741 ## Text DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 357 [Docket No. 1982N-0166] RIN 0910-AF51 Orally Administered Drug Products for Relief of Symptoms Associated With Overindulgence in Food and Drink for Over-the-Counter Human Use; Proposed Amendment of the Tentative Final Monograph AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. SUMMARY: The Food and Drug Administration (FDA) is proposing to amend the tentative final monograph (TFM) for over-the-counter (OTC) orally administered drug products for relief of symptoms associated with overindulgence in food and drink to include an additional use for products that contain bismuth subsalicylate as an active ingredient labeled for the relief of symptoms of upset stomach due to overindulgence resulting from food and drink. This proposal is part of FDA's ongoing review of OTC drug products. DATES: Submit written or electronic comments by April 5, 2005. Please see section X of this document for the proposed effective date of any final rule that may publish based on this proposal. ADDRESSES: You may submit comments, identified by Docket No. 1982N-0166 or RIN 0910-AF51, by any of the following methods: • Federal eRulemaking Portal: http://www.regulations.gov . Follow the instructions for submitting comments. • Agency Web site: http://www.fda.gov/dockets/ecomments . Follow the instructions for submitting comments on the agency Web site. • E-mail: fdadockets@oc.fda.gov . Include Docket No. 1982N-0166 or RIN 0910-AF51 in the subject line of your e-mail message. • FAX: 301-827-6870. • Mail/Hand delivery/Courier [For paper, disk, or CD-ROM submissions]: Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Instructions: All submissions received must include the agency name and Docket No. or Regulatory Information Number (RIN) for this rulemaking et No. 1982N-0166 or RIN 0910-AF51 in the subject line of your e-mail message. • FAX: 301-827-6870. • Mail/Hand delivery/Courier [For paper, disk, or CD-ROM submissions]: Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Instructions: All submissions received must include the agency name and Docket No. or Regulatory Information Number (RIN) for this rulemaking. All comments received will be posted without change to http://www.fda.gov/dockets/ecomments , including any personal information provided. For detailed instructions on submitting comments and additional information on the rulemaking process, see the “Request for Comments” heading of the SUPPLEMENTARY INFORMATION section of this document. Docket: For access to the docket to read background documents or comments received, go to http://www.fda.gov/dockets/ecomments and/or the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-2307. SUPPLEMENTARY INFORMATION: I. Background In the Federal Register of October 1, 1982 (47 FR 43540), FDA published an advance notice of proposed rulemaking to establish a monograph for OTC orally administered drug products for relief of symptoms associated with overindulgence in alcohol and food, together with the recommendations of the Advisory Review Panel on OTC Miscellaneous Internal Drug Products (the Panel), which was the advisory review panel responsible for evaluating data on the active ingredients in these drug products (§ 330.10(a)(6) (21 CFR 330.10(a)(6))). In the Federal Register of December 24, 1991 (56 FR 66742), FDA published the proposed rule (in the form of a TFM) for OTC orally administered drug products for relief of symptoms associated with overindulgence in food and drink (the Panel), which was the advisory review panel responsible for evaluating data on the active ingredients in these drug products (§ 330.10(a)(6) (21 CFR 330.10(a)(6))). In the Federal Register of December 24, 1991 (56 FR 66742), FDA published the proposed rule (in the form of a TFM) for OTC orally administered drug products for relief of symptoms associated with overindulgence in food and drink. In the Federal Register of May 5, 1993 (58 FR 26886), FDA proposed to amend the overindulgence TFM to include a Reye's syndrome warning for OTC drug products containing bismuth subsalicylate. In the Federal Register of April 17, 2003 (68 FR 18861), FDA published a final rule to revise the Reye's syndrome warning (§ 201.314(h) (21 CFR 201.314(h))) to include OTC drug products containing nonaspirin salicylates (e.g., bismuth subsalicylate) as active ingredients. FDA stated that there was no need to address this warning in a separate rule for overindulgence drug products containing bismuth subsalicylate (68 FR 18861 at 18862). Thus, the April 17, 2003, final rule completed the May 5, 1993, proposed rule. Products containing bismuth subsalicylate as an active ingredient must contain the required Reye's syndrome warning statement as of April 19, 2004, except that products with annual sales less than $25,000 have until April 18, 2005, to be in compliance. In the Federal Register of March 17, 1999 (64 FR 13254), FDA established a standardized format and content for the labeling of all OTC drug products (see § 201.66). The labeling in the TFM and the labeling in this amendment are not in that format. However, the labeling in the final monograph (FM) will incorporate the standardized labeling format and content. In response to the TFM, FDA received a number of comments and is addressing part of one comment in this document. The remaining comments will be addressed in the final rule. All “OTC Volumes” cited throughout this document refer to information on public display in the Division of Dockets Management (see ADDRESSES ) final monograph (FM) will incorporate the standardized labeling format and content. In response to the TFM, FDA received a number of comments and is addressing part of one comment in this document. The remaining comments will be addressed in the final rule. All “OTC Volumes” cited throughout this document refer to information on public display in the Division of Dockets Management (see ADDRESSES ). II. The Comment's Recommendation, Arguments, and Data One comment recommended that FDA include combination upset stomach/antiflatulent (antigas) drug products containing bismuth subsalicylate and simethicone in the overindulgence monograph for the relief of upset stomach and gas due to overindulgence in food and drink. The comment provided the following arguments and data to support its recommendation. • FDA's “General Guidelines for OTC Drug Combination Products, September 1978” (Ref. 1) provide that Category I active ingredients from different therapeutic categories may be combined to treat different symptoms concurrently if each ingredient is present within its established safe and effective dosage range, and the combination meets the OTC drug combination policy in all other respects. FDA's OTC drug combination regulations (§ 330.10(a)(4)(iv)) provide that an OTC drug may combine two or more safe and effective active ingredients and may be generally recognized as safe and effective when each active ingredient makes a contribution to the claimed effect(s); when combining of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients; and when the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population. A combination drug product containing bismuth subsalicylate and simethicone would combine two Category I active ingredients as specified in these Guidelines and meet the requirements of this regulation ts; and when the combination, when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population. A combination drug product containing bismuth subsalicylate and simethicone would combine two Category I active ingredients as specified in these Guidelines and meet the requirements of this regulation. • FDA proposed bismuth subsalicylate as safe and effective for the relief of symptoms of upset stomach associated with overindulgence in food and drink in the TFM, and simethicone is included in the antiflatulent monograph (21 CFR part 332). Bismuth subsalicylate acts in the stomach to relieve upset stomach/indigestion symptoms such as nausea, heartburn, and fullness, while simethicone acts in the stomach to break up gas bubbles resulting from overindulgence in food and drink. Together, these active ingredients will provide relief from upset stomach symptoms occurring in the presence of gas. • Combining the active ingredients does not decrease the safety and effectiveness of either ingredient. The comment cited data to support that (1) Bismuth subsalicylate does not decrease the foam-reducing capacity of simethicone (Ref. 2), (2) serum salicylate bioavailability of a combination of bismuth subsalicylate-simethicone was equivalent to bismuth subsalicylate alone in dogs (Ref. 3), and (3) the combination and bismuth subsalicylate alone in rats provided equivalent stomach protection against alcohol (Ref. 4). • The combination provides rational concurrent therapy for a significant proportion of the target population. The comment noted a consumer study of 285 subjects suffering from upset stomach due to overindulgence in which 56 percent of the subjects reported gas as one of their symptoms (Ref. 5). The comment mentioned another consumer study of 159 adults who reported having gas concurrently with symptoms for which bismuth subsalicylate has been shown to be effective (Ref. 6) ortion of the target population. The comment noted a consumer study of 285 subjects suffering from upset stomach due to overindulgence in which 56 percent of the subjects reported gas as one of their symptoms (Ref. 5). The comment mentioned another consumer study of 159 adults who reported having gas concurrently with symptoms for which bismuth subsalicylate has been shown to be effective (Ref. 6). The percent of adults reporting gas with each symptom included: Fullness/bloating (57), upset stomach (55), indigestion (44), and heartburn (24). • Antacid-simethicone combination products were included in the antacid monograph (21 CFR part 331) and the antiflatulent monograph without any supporting clinical data. FDA's determination to allow this combination was based on a reasonable expectation that simethicone will be effective if used in combination with an antacid drug product (38 FR 31260 at 31266, November 12, 1973). Further, FDA has proposed that any antacid covered by the antacid monograph may be labeled “for the relief of * * * upset stomach associated with * * * overindulgence in food and drink” (56 FR 66754 at 66756, December 24, 1991). FDA did not review any clinical data to support the indication of upset stomach and gas due to overindulgence in food and drink. III. FDA's Evaluation of the Comment's Recommendation FDA has evaluated the comment's recommendation and reconsidered the Panel's review of bismuth subsalicylate for the relief of symptoms of upset stomach associated with overindulgence in food and drink. The Panel stated that upset stomach that occurs as a result of overindulgence in food and drink consists of a group of symptoms that includes heartburn, fullness, and nausea (47 FR 43540 at 43543 and 43545) evaluated the comment's recommendation and reconsidered the Panel's review of bismuth subsalicylate for the relief of symptoms of upset stomach associated with overindulgence in food and drink. The Panel stated that upset stomach that occurs as a result of overindulgence in food and drink consists of a group of symptoms that includes heartburn, fullness, and nausea (47 FR 43540 at 43543 and 43545). One of the indications statements that the Panel recommended for products containing bismuth subsalicylate included these symptoms: “For the relief of upset stomach associated with” (select one or more of the following: “nausea,” “heartburn,” and “fullness”) “due to overindulgence in the combination of food and drink.” (See 47 FR 43540 at 43550 and 43558.) FDA proposed this indication statement without the words “the combination of” in § 357.950(b)(2) of the TFM (see 56 FR 66742 at 66751). The Panel discussed the consumer study of 285 subjects (Ref. 5) (47 FR 43540 at 43545), cited by the comment, and noted that 96 percent of the subjects had at least one of the symptoms of “gas (fullness), heartburn (or acid indigestion), or nausea” and that 56 percent [the highest percentage] reported gas as one of their symptoms. The Panel cited studies by Newsom (Ref. 7) and by Berkowitz (Ref. 8) (47 FR 43540 at 43548 to 43549) to support the effectiveness of bismuth subsalicylate for treating upset stomach due to overindulgence. The Newsom study was subsequently published in the Archives of Internal Medicine (Ref. 9). Newsom conducted a randomized, placebo-controlled, double-blind, multiple-crossover study (Refs. 7 and 9) to evaluate the effectiveness of bismuth Newsom defined indigestion or acute gastrointestinal discomfort as a symptom complex consisting of two or more of the following symptoms occurring during or after ingestion of food: Nausea, heartburn, upper-abdominal pain, flatulence (gas) and eructation (belching), sense of fullness, or a feeling of abdominal distention. Stedman's Medical Dictionary (Ref to evaluate the effectiveness of bismuth Newsom defined indigestion or acute gastrointestinal discomfort as a symptom complex consisting of two or more of the following symptoms occurring during or after ingestion of food: Nausea, heartburn, upper-abdominal pain, flatulence (gas) and eructation (belching), sense of fullness, or a feeling of abdominal distention. Stedman's Medical Dictionary (Ref. 10) defines indigestion as a nonspecific term for a variety of symptoms resulting from a failure of proper digestion and absorption of food in the alimentary tract [relating to the organs of digestion]. FDA notes that the investigator's definition of indigestion or acute gastrointestinal discomfort is consistent with the Stedman's definition in that the dictionary's term is nonspecific and the investigator's symptoms relate to the digestive system. The 48 test subjects had no significant differences in reported symptoms or identified causes in the six individual episodes of symptoms. Eating specific foods was the most commonly identified cause of symptoms, followed by overeating. The overall relief of symptoms showed more episodes treated with bismuth subsalicylate were relieved (132/144) than were episodes treated with placebo (121/144). However, the difference between the two groups was not statistically significant (0.05