Over-the-Counter Drug Products Containing Analgesic/Antipyretic Active Ingredients for Internal Use; Required Alcohol Warning

I. Background

In the Federal Register of November 16, 1988 (53 FR 46204), FDA published a notice of proposed rulemaking, in the form of a tentative final monograph (TFM), that would establish conditions in part 343 (21 CFR part 343) under which OTC internal analgesic, antipyretic, and antirheumatic drug products are generally recognized as safe and effective and not misbranded. In the preamble to the proposed rule of this current rulemaking, the agency addressed concerns raised in the 1988 proceeding about the need for a warning on the increased risk of liver toxicity when acetaminophen is taken with substances or drugs that induce microsomal enzyme activity, i.e., alcohol, barbiturates, or prescription drugs for epilepsy (53 FR 46204 at 46217). The agency found that the available data did not provide a sufficient basis to require such a warning at that time. Interested persons were invited to submit new data or file written comments, objections, or requests for oral hearing before the Commissioner of Food and Drugs regarding the proposal. In response to the proposed rule, the agency received a number of comments containing new data addressing the need for an alcohol warning for acetaminophen. Copies of the comments received are on display in the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. On June 29, 1993, NDAC met to consider the need for an alcohol warning for acetaminophen. NDAC concluded that heavy drinkers are at increased risk for developing liver toxicity when using acetaminophen and recommended that the labeling of OTC analgesic/antipyretic drug products containing this ingredient bear an alcohol warning. However, NDAC recommended that the agency not implement an alcohol warning for OTC analgesic/antipyretic drug products containing acetaminophen until it had a chance to consider data on the risk of alcohol use with other internal analgesic/antipyretic ingredients. On September 8, 1993, NDAC and ADAC (the Committees) met jointly to evaluate the available data on the use of aspirin and other OTC analgesics by heavy alcohol users or abusers. The Committees concluded that the use of aspirin, ibuprofen, and naproxen sodium increases the risk of upper gastrointestinal (UGI) bleeding in heavy alcohol users or abusers. Concerning whether the data support an alcohol warning for OTC drug products containing these ingredients, the Committees voted 12 yes, 2 no for aspirin; 12 yes, 2 no for ibuprofen; and 12 yes, 1 no, and 1 abstention for naproxen sodium. The Committees further concluded that a recommendation on the need for an alcohol warning for OTC drug products containing other monograph salicylates (carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium salicylate) was outside their advisory scope. In the Federal Register of November 14, 1997 (62 FR 61041), the agency published a proposed amendment of part 201 (21 CFR part 201) that would establish alcohol warnings for all OTC drug products labeled for adult use containing internal analgesic/antipyretic active ingredients. This warning would be required for all OTC internal analgesic/antipyretic drug products whether marketed under an OTC drug monograph or an approved new drug application (NDA). In the proposal to amend part 201, the agency advised that any final rule based on the proposal will be effective 6 months after the date of publication in the Federal Register. Therefore, on or after April 23, 1999, any OTC drug product that is subject to this final rule, that contains nonmonograph labeling may not be initially introduced or initially delivered for introduction into interstate commerce unless it is the subject of an approved application or abbreviated application. Further, any OTC drug product subject to this final rule that is repackaged or relabeled after the effective date of the rule must be in compliance with the rule regardless of the date that the product was initially introduced or initially delivered for introduction into interstate commerce.

II. The Agency's Response to Comments

A. Comments on Specific Ingredients

1. Two comments argued that the agency's proposed requirement for an alcohol warning for OTC analgesic/antipyretic drug products containing aspirin is not based on sound scientific evidence. One comment asserted that it is necessary for FDA to demonstrate that a significant risk of gastrointestinal (GI) bleeding would result if heavy alcohol users were not specifically warned against the use of aspirin. Both comments suggested that the proposed requirement is contrary to agency statements in the TFM for OTC internal analgesic/ antipyretic drug products that warning statements should be ``limited to those that are scientifically documented, clinically significant, and important for the safe and effective use of products by consumers'' (53 FR 46204 at 46213). In support of this position, one comment included data that purport to show that heavy alcohol use: (1) Does not increase the risk of stomach bleeding (Refs. 1 through 4), (2) alcohol protects against GI problems (Refs. 5 and 6), and (3) GI bleeding in patients who reported prior aspirin and alcohol use is not more severe (Ref. 7). The comment also asserted that its evaluation of the adverse drug reaction data contained in FDA's Spontaneous Reporting System (SRS) failed to demonstrate a correlation between GI bleeding and heavy alcohol use, although the results of this evaluation were not included. Another comment supporting the need for an alcohol warning for OTC analgesic/antipyretic drug products containing aspirin reviewed the data evaluated by the agency during the development of its proposal. To substantiate the need for an alcohol warning for aspirin, the comment also included data from a recently published study of the relationship between aspirin and nonsteroidal anti-inflammatory drug (NSAID) use and GI perforation (Ref. 8). The agency continues to believe that warning statements should be limited to those that are scientifically based, clinically relevant, and important for the safe and effective use of these products by consumers. The agency disagrees with the comments asserting that the alcohol warning is not based on solid scientific evidence. An alcohol warning is needed for OTC analgesic/antipyretic drug products containing nonsteroidal anti-inflammatory ingredients, including aspirin. This warning is based on the data and information on the adverse GI effects of aspirin and other NSAID ingredients, the adverse GI effects of alcohol use, and the documented risk of combining them. Although the previous comments pertain specifically to aspirin- containing OTC analgesic/antipyretic products, the agency's response will provide the scientific reasoning for applying the alcohol warning

requirement to the pharmacologic class of OTC analgesic/antipyretic drug products containing nonsteroidal anti-inflammatory ingredients, which include aspirin, nonaspirin salicylates, ibuprofen, ketoprofen, and naproxen sodium. These OTC analgesic/antipyretic drug products contain NSAID ingredients, which belong to the carboxylic acid class. Aspirin and other salicylates are salicyclic acids; ibuprofen, ketoprofen, and naproxen sodium are derivatives of propionic acid. All of these ingredients share certain pharmacologic properties, including inhibitory effects on prostaglandin synthesis and platelet function. As with aspirin, propionic acid derivatives produce adverse GI side effects, alter platelet function, and can affect bleeding time (Refs. 9 through 14). Adverse GI effects are caused by aspirin and nonaspirin NSAID ingredients, which can irritate the mucosal epithelium (stomach lining) directly and/or can suppress prostaglandin synthesis. Prostaglandins normally help protect the stomach lining by promoting secretion of mucus and bicarbonate, repair of epithelial (lining) cells, immune cell function, and blood flow. Adverse bleeding effects can occur because NSAID's inhibit platelet aggregation. Although there are data and information available concerning all of these ingredients, the largest body of data relied upon by the agency pertains to aspirin. Because these NSAID ingredients all share similar pharmacologic properties and can all cause adverse GI effects, including bleeding, it is reasonable for the agency to rely on the data pertaining to individual ingredients and to reason and apply these data to all of these NSAID ingredients. More specific comments concerning other ingredients will be addressed elsewhere in section II of this document. Drug-related adverse effects can be evaluated through clinical data collected various ways, including randomized controlled trials, cohort studies, case-control studies, surveys, and spontaneous case reports. Prospective, randomized, blinded clinical trials require large patient enrollments to demonstrate a difference between groups when adverse events are infrequent, even if serious. Thus, most studies which examine the adverse GI effects of NSAID's are observational rather than experimental. Observational studies provide important information when investigating an association between a risk and a predisposing event. However, these studies may be subject to specific biases which should be considered. For example, case-control studies examine the prevalence of NSAID (and alcohol) exposure in patients who already have the outcome (GI events or bleeding) with a control population, which is matched for other factors. These studies may suffer from recall bias; that is, individuals in cases may be more likely than controls to remember that they took an NSAID (or alcohol). When reviewing these data from various studies, the agency has taken into account the limitations of each study method. Despite the limitations of individual studies, the data generated by each of these methods collectively provide a sound body of evidence from which it is scientifically reasonable to assess risk. Therefore, the agency believes that the collected body of scientific evidence supports the labeled warning. As previously discussed in the notice of proposed rulemaking (62 FR 61041 at 61049), the adverse GI effects of aspirin are well known. Medical texts document adverse effects associated with the use of aspirin. These effects include, but are not limited to, gastritis, ulcerations, and colitis (Refs. 15 through 18). In addition, aspirin irreversibly interferes with normal platelet function for the life of the platelet, prolongs the bleeding time, and interferes with clotting whenever bleeding occurs (Ref. 13). Nonsalicylate NSAID ingredients reversibly inhibit platelet aggregation for as long as the drug is in the blood (Refs. 13 and 14). GI mucosal damage caused by aspirin has been widely acknowledged in the medical literature (Ref. 15 through 18), confirmed by endoscopic observational studies (Ref. 19), and taught through medical texts to students of medicine (Ref. 20). In 1977, the Advisory Review Panel for OTC Analgesic and Antipyretic Drug Products (the Panel) first reviewed relevant data and concluded that aspirin causes adverse GI effects. The Panel concluded that the adverse effects of aspirin on the GI system range from relatively mild effects such as gastric distress (minor stomach pain, heartburn, or nausea), mucosal irritation and occult (not easily seen) bleeding, to less frequent but more serious effects such as mucosal erosion, ulceration, and life-threatening massive bleeding. The Panel further concluded that the acute use of aspirin may activate symptoms of both gastric and duodenal ulcer (42 FR 35346 at 35386 through 35397, July 8, 1977). In addition to the Panel's conclusions, FDA also evaluated published literature, including studies which demonstrate adverse GI effects even with low-dose aspirin use (Refs. 21 and 22). The agency also reviewed data from controlled, prospective clinical trials on aspirin for cardiovascular and cerebrovascular uses and established that bleeding can occur with long-term aspirin use, even at low doses (62 FR 61041 at 61050). Just as aspirin is well known to produce adverse GI effects, including bleeding, it is also well known that alcohol is a gastric toxin and that heavy alcohol use may cause a number of adverse GI effects, including bleeding. Routinely heavy alcohol use is associated with a number of medical conditions. These conditions include, but are not limited to, esophagitis, varices, acute gastritis, hemorrhagic lesions of the duodenal villi, and peptic ulcer disease (Refs. 23 through 28). Also, chronic heavy alcohol use can cause bleeding because of increased prothrombin time, decreased circulating platelets, and altered function of platelets (Ref. 13). Early (Ref. 23) and continuing (Refs. 24 through 26) study of the effects of alcohol on the stomach have been widely published in the scientific literature and alcoholic gastritis is a well-recognized cause of acute hemorrhagic gastritis (Ref. 29). These effects of heavy, chronic alcohol use on the GI system and bleeding parameters are explained in many standard medical textbooks (Refs. 25, 27 and 28). The Panel recognized alcohol as a major factor that may produce acute gastric mucosal lesions, and thus increase the risk of bleeding from the use of aspirin (42 FR 35346 at 35479). Given these observations and the well established and recognized medical acceptance of GI and bleeding problems associated with the use of either aspirin or alcohol, the agency was concerned about the risks present for consumers who routinely and heavily drink alcohol and also use aspirin. This concern led to a review of relevant medical literature and studies (Refs. 8, 30, and 31), which confirmed the increased risk of adverse GI events, including bleeding, when alcohol use and aspirin use are combined. Published studies which include randomized controlled clinical trials (Refs. 32 through 35), case-control studies (Refs. 8, 36 through 39a), cohort studies (Ref. 40), meta-analyses (Refs. 41 and 42), physician surveys (Ref. 31), and case reports (Ref. 43) have established an association between NSAID's, including aspirin, and adverse GI events, including bleeding. Because chronic alcohol use causes GI disease and bleeding, some studies simply exclude these patients from entry or analysis when assessing the risk of NSAID use on adverse GI outcomes (Ref.

44). However, some studies have examined both NSAID and alcohol use (Refs. 8, 30, 31, and 45) and assessed the risk of developing adverse GI events, including bleeding. P. J. DeSchepper et al. (Ref. 45) measured fecal blood loss in 10 healthy males in a double-blind, parallel study and in 12 healthy subjects in a double-blind crossover study. Fecal blood loss was demonstrated with aspirin ingestion and concomitant ingestion of alcohol significantly increased (by three times) this blood loss. D. Aarons et al. (Ref. 30) conducted a double blind prospective study of 27 healthy volunteers with initial normal baseline endoscopies who were given alcohol and either placebo, aspirin, or acetaminophen. Repeat endoscopy showed that alcohol and aspirin together caused significantly greater erythema (redness) due to irritation and hemorrhage in the stomach than alcohol alone. The agency has reviewed adverse events reported to its SRS data base (Ref. 43). From 1993 to 1995, 37 case reports were submitted for serious UGI bleeding, 36 involving hospitalizations and 1 death. Most bleeds were documented by endoscopy. In these reports, ibuprofen was listed as the suspect drug in patients who reported chronic alcohol use (nearly 80 percent reported alcoholism or more than two drinks/day). Of important note, concomitant use of salicylates, primarily aspirin, was reported in almost 50 percent of these cases, thus associating both ibuprofen and/or salicylates with these reports of bleeding. From 1994 to 1996, five case reports were submitted for serious UGI bleeding with naproxen sodium listed as the suspect drug in patients who reported daily (or binge) alcohol ingestion. Two of these reports also listed salicylate use and two reports listed concomitant ibuprofen use. From 1993 to 1996, 10 case reports were submitted for serious UGI bleeding with aspirin listed as the suspect drug in patients who also reported alcohol ingestion (more than 2 drinks/day or unspecified). All 10 cases were hospitalized. Cases of concomitant NSAID ingredient use were excluded. Thus, the agency's SRS data base provides additional serious adverse events documenting the association between NSAID ingredient use and UGI bleeding in persons with a history of chronic alcohol use. In a prospective community clinical case study, Lee et al. (Ref. 46) endoscoped 400 consecutive patients hospitalized for UGI hemorrhage to identify factors which predispose patients who bleed from hemorrhagic erosive gastritis. Of the 74 patients with stomach bleeding, salicylate use (31 percent), alcohol use, usually chronic (27 percent), or both (16 percent) were reported. There was no case-matched control and relative risk was not assessed. However, this study demonstrates that patients who have experienced hemorrhagic erosive gastritis (stomach bleeding) commonly report having used alcohol and/or salicylates. Peura et al. (Ref. 31) surveyed American College of Gastroenterology physicians to assess demographics, management strategies, and outcomes for 1,235 patients who were diagnosed with GI bleeding. OTC doses of NSAID's were associated with a three-fold increased risk for developing GI bleeding and alcohol use increased this risk to four-fold. Lanas et al. (Ref. 8) conducted a single-center, prospective, case- controlled study, which examined the relationship between NSAID use, including aspirin, and GI perforation. Detailed clinical histories and laboratory tests were obtained in 76 hospital admitted patients with surgically documented GI perforations and in 152 matched case controls. Histories of NSAID use were confirmed by measuring platelet cyclo- oxygenase activity. In the study cohort, 67 percent of the patients used aspirin (90 percent of these were over-the-counter formulations). The calculated odds ratio (OR) for GI perforation in patients who had used an NSAID within a week prior to hospitalization was 6.64 (95 percent confidence interval: 3.6-12.2; p www.health.org/pubs/ nhsda/96hhs/httoc.htm> 81. National Institute on Alcohol Abuse and Alcoholism, ``Surveillance Report #40: Trends in Alcohol-Related Morbidity Among Short-Stay Community Hospital Discharges, United States, 1979-94'', published December 1996, ``silk/niaaa1/publication/ SR40.pdf''.

List of Subjects in 21 CFR Part 201

Drugs, Labeling, Reporting and recordkeeping requirements. Therefore, under the Federal Food, Drug, and Cosmetic Act and under authority delegated to the Commissioner of Food and Drugs, 21 CFR part 201 is amended as follows:

PART 201--LABELING

1. The authority citation for 21 CFR part 201 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

2. Section 201.322 is added to subpart G to read as follows:

Sec. 201.322 Over-the-counter drug products containing internal analgesic/antipyretic active ingredients; required alcohol warning.

(a) People who regularly consume large quantities of alcohol (three or more drinks every day) have an increased risk of adverse effects (possible liver damage or gastrointestinal bleeding). OTC drug products containing internal analgesic/antipyretic active ingredients may cause similar adverse effects. FDA concludes that the labeling of OTC drug products containing internal analgesic/antipyretic active ingredients should advise consumers with a history of heavy alcohol use to consult a physician. Accordingly, any OTC drug product, labeled for adult use, containing any internal analgesic/antipyretic active ingredients (including, but not limited to, acetaminophen, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate) alone or in combination shall bear an alcohol warning statement in its labeling as follows: (1) Acetaminophen. ``Alcohol Warning'' [heading in boldface type]: ``If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen may cause liver damage.'' (2) Nonsteroidal anti-inflammatory analgesic/antipyretic active ingredients--including but not limited to aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate. ``Alcohol Warning'' [heading in boldface type]: ``If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take [insert one nonsteroidal anti- inflammatory analgesic/antipyretic active ingredient] or other pain relievers/fever reducers. [Insert one nonsteroidal anti-inflammatory analgesic/antipyretic active ingredient] may cause stomach bleeding.'' (3) Combinations of acetaminophen with nonsteroidal anti- inflammatory analgesic/antipyretic active ingredients--including but not limited to aspirin, carbaspirin calcium, choline

salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate. ``Alcohol Warning'' [heading in boldface type]: ``If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take [insert acetaminophen and one nonsteroidal anti-inflammatory analgesic/antipyretic active ingredient--including, but not limited to aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium salicylate] or other pain relievers/fever reducers. [Acetaminophen and (insert one nonsteroidal anti-inflammatory analgesic/antipyretic ingredient-- including, but not limited to aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, or sodium salicylate] may cause liver damage and stomach bleeding.'' (b) Requirements to supplement approved application. Holders of approved applications for OTC drug products that contain internal analgesic/antipyretic active ingredients that are subject to the requirements of paragraph (a) of this section must submit supplements under Sec. 314.70(c) of this chapter to include the required warning in the product's labeling. Such labeling may be put into use without advance approval of FDA provided it includes the exact information included in paragraph (a) of this section. (c) Any drug product subject to this section that is not labeled as required and that is initially introduced or initially delivered for introduction into interstate commerce after April 23, 1999, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352) and is subject to regulatory action.

Dated: July 22, 1998. Michael A. Friedman, Acting Commissioner of Food and Drugs. Donna E. Shalala, Secretary of Health and Human Services. [FR Doc. 98-28520 Filed 10-21-98; 10:58 am] BILLING CODE 4160-01-F