OTC INTERNAL ANALGESIC-ANTIPYRETICS TFM EXPANDS INDICATIONS TO CITE SPECIFIC TYPES OF PAIN; "EXTRA STRENGTH" CLAIMS ARE OUTSIDE TFM SCOPE, FDA SAYS

Monograph-approved indications for OTC analgesic and antipyretic drug products may identify specific types of pain and causes of fever that are amenable to OTC treatment, according to FDA's tentative final monograph (TFM) for OTC internal analgesic, antipyretic, and antirheumatic drug products. Under the TFM, published in the Nov. 16 Federal Register, products containing analgesic-antipyretic ingredients may state in the approved indications section: "`For the temporary relief of minor aches and pains (which may be followed by one or more of the following: (`associated with' (select one or more of the following: `a cold,' `the common cold' `sore throat,' `headache,' `toothache,' `muscular aches,' `backache,' `the premenstrual and menstrual periods' (which may be followed by: `(dysmenorrhea),') or `premenstrual and menstrual cramps' (which may be followed by: `(dysmenorrhea)', (`and for the minor pain from arthritis'), and (`and to reduce fever.'))" Analgesic-antipyretic products containing acetaminophen may also carry an indication for flu. The ability to cite specific causes of pain and fever represents a victory for the OTC industry, which had opposed the limited general claim proposed by the agency in its 1977 advanced notice of proposed rulemaking (ANPR). In addition to expanding the approved indications for analgesics and antipyretics, the TFM allows the same indications for the two ingredient types. Under the ANPR, the indications section for analgesics would have been limited to: "For the temporary relief of occasional minor aches, pains and headache," while the indications section for antipyretics would have been limited to: "For the reduction of fever." Explaining the change in indications, FDA noted that the analgesic-antipyretic panel "found that the various claims on the labels it reviewed were often vague and lacked clarity [and] was concerned that a plethora of claims would be confusing and misleading to the consumer." However, the TFM states, "the agency does not believe that a statement describing one or more specific types of pain on an analgesic-antipyretic drug product properly labeled with the active ingredient and with the statement of identity (e.g., `pain reliever-fever reducer') would mislead consumers. Such labeling would be helpful to consumers to provide them with examples of the general types of pain for which OTC internal analgesic drug products are useful." Under the flexibility rule, manufacturers may include additional truthful and nonmisleading claims on other portions of labeling. FDA noted that while it is not proposing low back pain and sinusitis for the FDA-approved boxed indications section, those claims would be appropriate for other sections of labeling. "The agency would not object to the use of the claim `low back pain' [or `pain of sinusitis'] elsewhere on the label provided it is not intermixed with labeling established by the monograph," FDA said. The TFM notes that terms to identify higher dosage products, such as "extra strength," are "outside the scope" of the monograph. However, the TFM indicates that FDA will not object to use of the terms if not intermixed with monograph labeling. "The agency tentatively concludes that `extra strength,' `maximum strength,' `extra pain relief,' and similar terms that are only peripherally related to product safety and effectiveness are outside the scope of the OTC review," the TFM states. "Therefore, these terms will not be included in labeling required by the monograph, but may be used elsewhere in labeling, but not intermixed with monograph labeling." If terms like "extra strength" are used, "the agency encourages drug manufacturers voluntarily to provide consumers with an explanation of [the] terms," FDA said. The TFM moves claims for reaching the bloodstream faster than aspirin from Category II to Category III for several ingredients including buffered aspirin, powdered aspirin, carbaspirin calcium and choline salicylate. The agency noted that a rationale exists for the claim, but that data must be submitted "to demonstrate that differences in absorption will result in clinically important differences in the onset intensity or incidence of the relief of pain or fever." A claim for better gastrointestinal tolerance than plain aspirin, requested in comments for buffered aspirin, choline salicylate and magnesium salicylate, is also Category III under the TFM. The agency noted, however, that it has three new clinical studies under review for a gastric irritation claim for buffered aspirin. To address different strength analgesic-antipyretics, the ANPR had proposed using the terms "standard" and "non-standard" on products. FDA rejected that proposal in the TFM, stating the current labeling practices (i.e., statements such as "extra strength") have not resulted in misuse of products. Comments on the ANPR had opposed the "standard" and "non-standard" language, "arguing that such labeling implies differences in quality or therapeutic effect, would confuse consumers, and crowd information on the label," FDA noted. "The agency agrees with the comments in opposition to the panel's recommendation...[and] does not believe that use of the terms `standard' and `non-standard' would simplify the comparison of various products containing different quantities of active ingredients or would aid consumers in selecting an OTC analgesic-antipyretic drug product," FDA said. In addition, the TFM continues, "The agency is not aware that the existing manner of labeling these products has caused consumer confusion or resulted in misuse of these products. Therefore, the panel's recommendation on standard and non-standard labeling is not being included in this tentative final monograph." The TFM revises the panel's recommended dosage schedule of acetaminophen to conform with that of aspirin. Under the proposed rule, the adult dosage ranges for aspirin, acetaminophen and sodium salicylate are: 325 to 650 mg every four hours, 325 to 500 mg every three hours, or 650 to 1,000 mg every six hours. The TFM also amends the dosage ranges for children's aspirin, acetaminophen and sodium salicylate to account for both 80 and 81 mg strength tablets. The panel had proposed doses only in 80 mg increments. FDA revised the schedule because many products use the 81 mg strength since the standard 325 mg tablet is a more accurate multiple of 81 mg. The TFM also revises the doses of magnesium salicylate tetrahydrate to reflect the ingredient's salicylic acid content compared to aspirin. The minimum effective dose of the ingredient is increased from 325 mg to 377 mg, while the maximum dose is increased from 650 mg to 754 mg. Category I ingredients in the TFM are identical to those proposed in the ANPR: aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate, and sodium salicylate. The TFM does, however, add potassium salicylate - an ingredient which had not been considered by the panel - to the list of Category III ingredients. The ingredient is contained in Alval Amco's Diurex OTC menstrual drug product line and Robin's prescription pain reliever Pabalate-SF. Noting that the ingredient has been marketed in the U.S. in OTC and prescription analgesics, FDA said that because of its marketing history the ingredient is being given Category III status but that "until data...are submitted for review, the agency has an insufficient basis to consider further the request to include this ingredient in an OTC drug monograph." FDA also considered requests to add two other ingredients that had not been considered by the panel - lysine aspirin and calcium salicylate - to the monograph. FDA determined that both ingredients are "new drugs" because they have not, to the agency's knowledge, been marketed in the U.S. and sufficient information on their safety and efficacy was not submitted. The TFM does not classify any analgesic-antipyretic adjuvants in Category I. However, the agency noted that it currently has "additional data ... under review" for caffeine, a Category III analgesic adjuvant in both the TFM and ANPR. Caffeine is a Category I diuretic for use in menstrual drug products under the menstrual TFM (see story p. 11). Caffeine is contained in a number of OTC analgesics, including American Home Products' Anacin and Bristol-Myers' Excedrin. Bristol-Myers has been among the most active sponsors in seeking an upgrade to Category I. In previous pushes for a standing OTC advisory committee, the Proprietary Association has also identified the status of caffeine as an issue for the industry. The TFM does not change the status of any of the analgesic adjuvants, with the exception of methapyrilene fumarate. The ingredient was moved from Category III to Category II in connection with an earlier DESI ruling. In addition to caffeine, Category III adjuvants under the TFM are: pheniramine maleate, phenyltoloxamine dihydrogen citrate, pyrilamine maleate, and salicylamide. The TFM proposes to require dissolution testing of all analgesic-antipyretic ingredients for which the United States Pharmacopeia has determined a testing methodology, including aspirin, buffered aspirin, acetaminophen, and combination products containing aspirin, alumina and magnesium. Enteric coated aspirin, previously a Category III product because of the lack of dissolution testing standards, moves up to Category I with the recently adopted USP standards for "aspirin delayed-release" tablets and capsules. FDA noted that once USP develops dissolution tests for additional ingredients, the tests will be required for those products. The TFM revises a number of the warnings proposed in the ANPR, including a strengthened statement against use of aspirin in pregnant women. Under a 1982 ruling for all systemically absorbed OTCs, manufacturers are required to state: "As with any drug, if you are pregnant or nursing a baby seek the advice of a health professional before using this product." Under the TFM, aspirin and carbaspirin products must carry the additional warning: "IMPORTANT: Do not take this product during the last three months of pregnancy unless directed by a doctor. Aspirin taken near time of delivery may cause bleeding problems in both mother and child." The TFM also revises the warning about length of use for all analgesic-antipyretic products. The proposed use warning for products labeled for adults states: "Do not take this product for pain for more than ten days or for fever for more than three days unless directed by a doctor. If pain or fever persists or gets worse, if new symptoms occur, or if redness or swelling is present, consult a doctor because these could be signs of a serious condition." The warning for products labeled for children has a five day limitation for pain-related use. The currently used acetaminophen overdose warning - "In case of accidental overdose, contact a physician immediately" - has been expanded to warn consumers that overdose is dangerous even if there are not symptoms, such as ringing in the ears. The proposed rule adds the statement: "Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms." FDA is accepting comments on the proposed rule until May 16.