PART 343—INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. Source: 63 FR 56814, Oct. 23, 1998, unless otherwise noted. Subpart A—General Provisions § 343.1 Scope. (a) An over-the-counter analgesic-antipyretic drug product in a form suitable for oral administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part in addition to each of the general conditions established in § 330.1 of this chapter. (b) References in this part to regulatory sections of the Code of Federal Regulations are to chapter I of title 21 unless otherwise noted. § 343.3 Definitions. As used in this part: Analgesic antipyretic drug. Cardiovascular drug. Rheumatologic drug. Subpart B—Active Ingredients § 343.10 [Reserved] § 343.12 Cardiovascular active ingredients. (a) Aspirin. (b) Buffered aspirin. Aspirin identified in paragraph (a) of this section may be buffered with any antacid ingredient(s) identified in § 331.11 of this chapter provided that the finished product contains at least 1.9 milliequivalents of acid-neutralizing capacity per 325 milligrams of aspirin as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18. § 343.13 Rheumatologic active ingredients. (a) Aspirin. (b) Buffered aspirin. Aspirin identified in paragraph (a) of this section may be buffered with any antacid ingredient(s) identified in § 331.11 of this chapter provided that the finished product contains at least 1.9 milliequivalents of acid-neutralizing capacity per 325 milligrams of aspirin as measured by the procedure provided in the United States Pharmacopeia 23/National Formulary 18. § 343.20 [Reserved] § 343.22 Permitted combinations of active ingredients for cardiovascular-rheumatologic use. Combinations containing aspirin must meet the standards of an acceptable dissolution test, as set forth in § 343.90. The following combinations are permitted: Aspirin identified in §§ 343.12 and 343.13 may be combined with any antacid ingredient identified in § 331.11 of this chapter or any combination of antacids permitted in accordance with § 331.10(a) of this chapter provided that the finished product meets the requirements of § 331.10 of this chapter and is marketed in a form intended for ingestion as a solution. Subpart C—Labeling §§ 343.50-343.60 [Reserved] § 343.80 Professional labeling. The labeling of an over-the-counter drug product written for health professionals (but not for the general public) shall consist of the following: (a) For products containing aspirin identified in §§ 343.12 and 343.13 or permitted combinations identified in § 343.22. (1) The labeling contains the following prescribing information under the heading “Comprehensive Prescribing Information” and the subheadings “Description,” “Clinical Pharmacology,” “Clinical Studies,” “Animal Toxicology,” “Indications and Usage,” “Contraindications,” “Warnings,” “Precautions,” “Adverse Reactions,” “Drug Abuse and Dependence,” “Overdosage,” “Dosage and Administration,” and “How Supplied” in the exact language and the exact order provided as follows: COMPREHENSIVE PRESCRIBING INFORMATION DESCRIPTION ( Insert the proprietary name and the established name (if any) of the drug, type of dosage form (followed by the phrase “for oral administration”), the established name(s) and quantity of the active ingredient(s) per dosage unit, the total sodium content in milligrams per dosage unit if the sodium content of a single recommended dose is 5 milligrams or more, the established name(s) (in alphabetical order) of any inactive ingredient(s) which may cause an allergic hypersensitivity reaction, the pharmacological or therapeutic class of the drug, and the chemical name(s) and structural formula(s) of the drug. CLINICAL PHARMACOLOGY Mechanism of Action: Pharmacokinetics Absorption: Pharmacokinetics Metabolism Distribution: i.e. Adverse Reactions Overdosage. Metabolism: Elimination: i.e. Overdosage. Pharmacodynamics 2 At higher doses aspirin is an effective anti-inflammatory agent, partially due to inhibition of inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies suggest that other mediators of inflammation may also be suppressed by aspirin administration, although the precise mechanism of action has not been elucidated. It is this nonspecific suppression of cyclo-oxygenase activity in peripheral tissues following large doses that leads to its primary side effect of gastric irritation. (See Adverse Reactions. CLINICAL STUDIES Ischemic Stroke and Transient Ischemic Attack (TIA): Suspected Acute Myocardial Infarction (MI): Prevention of Recurrent MI and Unstable Angina Pectoris: Chronic Stable Angina Pectoris: Revascularization Procedures: Rheumatologic Diseases: ANIMAL TOXICOLOGY The acute oral 50 percent lethal dose in rats is about 1.5 g/kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and decreased urinary concentrating ability occur in rodents chronically administered high doses. Dose-dependent gastric mucosal injury occurs in rats and humans. Mammals may develop aspirin toxicosis associated with GI symptoms, circulatory effects, and central nervous system depression. (See Overdosage. INDICATIONS AND USAGE Vascular Indications (Ischemic Stroke, TIA, Acute MI, Prevention of Recurrent MI, Unstable Angina Pectoris, and Chronic Stable Angina Pectoris): Revascularization Procedures (Coronary Artery Bypass Graft (CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA), and Carotid Endarterectomy): i.e. Rheumatologic Disease Indications (Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Spondyloarthropathies, Osteoarthritis, and the Arthritis and Pleurisy of Systemic Lupus Erythematosus (SLE)): CONTRAINDICATIONS Allergy: Reye's Syndrome: WARNINGS Alcohol Warning: Coagulation Abnormalities: GI Side Effects: Peptic Ulcer Disease: PRECAUTIONS General Renal Failure: Hepatic Insufficiency: Sodium Restricted Diets: Laboratory Tests Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Drug Interactions Angiotensin Converting Enzyme (ACE) Inhibitors: Acetazolamide: Anticoagulant Therapy (Heparin and Warfarin): Anticonvulsants: Beta Blockers: Diuretics: Methotrexate: Nonsteroidal Anti-inflammatory Drugs (NSAID's): Oral Hypoglycemics: Uricosuric Agents (Probenecid and Sulfinpyrazone): Carcinogenesis, Mutagenesis, Impairment of Fertility: Pregnancy. Pregnancy: Labor and Delivery: Nursing Mothers: Pediatric Use: i.e. ADVERSE REACTIONS Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature. (See Warnings. Body as a Whole Cardiovascular: Central Nervous System: Fluid and Electrolyte: Gastrointestinal: Hematologic: Hypersensitivity: Musculoskeletal: Metabolism: Reproductive: Respiratory: Special Senses: Urogenital: DRUG ABUSE AND DEPENDENCE Aspirin is nonnarcotic. There is no known potential for addiction associated with the use of aspirin. OVERDOSAGE Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 µg/mL. Plasma concentrations of aspirin above 300 µg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 µg/mL. (See Clinical Pharmacology. Signs and Symptoms: Treatment: Severity of aspirin intoxication is determined by measuring the blood salicylate level. Acid-base status should be closely followed with serial blood gas and serum pH measurements. Fluid and electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Children should be sponged with tepid water. Replacement fluid should be administered intravenously and augmented with correction of acidosis. Plasma electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function is normal. Infusion of glucose may be required to control hypoglycemia. Hemodialysis and peritoneal dialysis can be performed to reduce the body drug content. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required. Exchange transfusion may be indicated in infants and young children. DOSAGE AND ADMINISTRATION Each dose of aspirin should be taken with a full glass of water unless patient is fluid restricted. Anti-inflammatory and analgesic dosages should be individualized. When aspirin is used in high doses, the development of tinnitus may be used as a clinical sign of elevated plasma salicylate levels except in patients with high frequency hearing loss. Ischemic Stroke and TIA: Suspected Acute MI: Prevention of Recurrent MI: Unstable Angina Pectoris: Chronic Stable Angina Pectoris: CABG: PTCA: Carotid Endarterectomy: Rheumatoid Arthritis: i.e. Juvenile Rheumatoid Arthritis: i.e. Spondyloarthropathies: Osteoarthritis: Arthritis and Pleurisy of SLE: i.e. HOW SUPPLIED ( Insert specific information regarding, strength of dosage form, units in which the dosage form is generally available, and information to facilitate identification of the dosage form as required under § 201.57(k)(1), (k)(2), and (k)(3).) Store in a tight container at 25 REV: October 23, 1998. (2) In addition to, and immediately preceding, the labeling required under paragraph (a)(1) of this section, the professional labeling may contain the following highlights of prescribing information in the exact language and exact format provided, but only when accompanied by the comprehensive prescribing information required in paragraph (a)(1) of this section. (b) [Reserved] [63 FR 56814, Oct. 23, 1998; 63 FR 66015, 66016, Dec. 1, 1998, as amended at 64 FR 49653, Sept. 14, 1999] Subpart D—Testing Procedures § 343.90 Dissolution and drug release testing. (a) [Reserved] (b) Aspirin capsules. (c) Aspirin delayed-release capsules and aspirin delayed-release tablets. (d) Aspirin tablets. (e) Aspirin, alumina, and magnesia tablets. (f) Aspirin, alumina, and magnesium oxide tablets. (g) Aspirin effervescent tablets for oral solution. (h) Buffered aspirin tablets.