1. Overview of Aspirin and NSAID’s Label Warnings William E. Gilbertson, PharmD. Division OTC Drug Products 1

2. Advisory Panel Conclusions (1977) Safety well-established for the majority of the population and risk benefit ratio is low. Risks can be identified and labeling provided for safe OTC use. Adult Dose 325 to 650 every 4 hours not to exceed 4,000 mg in 24 hours for < 10 days. Children’s Dose Age-based dosing for children > 2 years based on a standard 81-mg dosage unit 2

3. Advisory Panel Conclusions (1977) Aspirin has several adverse effects on the GI tract ranging from relatively mild to severe. –Mild gastric distress (minor stomach pain, heartburn, or nausea). –Superficial mucosal irritation and minor occult bleeding. –Serious mucosal erosion, ulceration, or life- threatening massive GI bleeding. –Massive bleeding is relatively rare and unpredictable. 3

4. Advisory Panel Conclusions (1977) Irritation or exacerbation of stomach ulcers, stomach irritation, and intestinal inflammation occurs in a significant number of individuals that take aspirin. Particularly at risk are individuals with a history or symptoms of GI problems. 4

5. Advisory Panel Conclusions (1977) Acute ingestion of aspirin has a significant effect on duodenal bleeding and a synergistic effect with alcohol in bleeding from duodenal ulcers. Aspirin may potentiate bleeding from GI lesions even though aspirin alone may not initiate the lesion. Insufficient evidence to include an alcohol warning. 5

6. Advisory Panel Conclusions (1977) Recommended warning: Caution: Do not take this product if you have stomach distress, ulcers or bleeding problems except under the advice and supervision of a physician. Carbaspirin and other nonaspirin salicylates (choline, magnesium, sodium) have similar safety profiles and should also bear warning. 6

7. Advisory Panel Conclusions (1977) Use of aspirin in the general population: Although prolonged use of high doses of aspirin may produce kidney disease in some individuals, the risk is insignificant in the recommended target population. A warning regarding aspirin causing kidney disease is unwarranted for OTC use. 7

8. Advisory Panel Conclusions (1977) Use of aspirin in subjects with renal disease: Evidence suggests aspirin may contribute to or exacerbate chronic or acute renal disease (other than analgesic kidney disease). Not clear whether aspirin contributes to renal deterioration in individuals with analgesic kidney disease. Warning is premature as definitive studies are lacking. 8

9. Tentative Final Monograph (TFM) (1988) Adult Dose –325 to 650 mg every 4 hours; –325 to 500 mg every 3 hours; –650 to 1,000 mg every 6 hours not to exceed 4,000 mg in 24 hours for < 10 days. Children’s Dose Age-based dosing for children > 2 years based on an 80- or 81-mg or a 325-mg dosage unit 9

10. FDA Conclusions in TFM (1988) Recommended warning: Do not take this product if you have stomach problems (heartburn, upset stomach, stomach pain) that persist or recur, or if you have ulcers or bleeding problems except under the advice and supervision of a physician. 10

11. Timeline 1977 OTC Advisory Panel Report 1984 Ibuprofen approved for OTC use 1988 Tentative Final Monograph 1993 Naproxen sodium approved for OTC use 1993 NDAC (June) considers alcohol warning for acetaminophen 1993 NDAC (September) considers alcohol warning for aspirin and NSAID’S 1995 Ketoprofen approved for OTC use 11

12. NDAC Meeting (September 1993) Data Reviewed Risk of upper GI bleeding associated with alcohol and aspirin, ibuprofen, and naproxen sodium. Additive effects of these ingredients with alcohol. Alcohol's ability to potentiate aspirin-prolonged bleeding times. Effects of aspirin on ethanol pharmacokinetics. Panel's conclusions on monograph ingredients. 12

13. Questions to NDAC (1993) Are data sufficient to support an alcohol warning for aspirin, ibuprofen, and naproxen sodium? Are data sufficient to support an alcohol warning for the other monograph salicylates? Type of information an alcohol warning should include, i.e., organ specific information or statement of risk? What information should appear in labeling of combination products containing aspirin and acetaminophen? 13

14. NDAC Conclusions (1993) Aspirin, ibuprofen, and naproxen sodium increases the risk of upper GI bleeding in heavy alcohol users or abusers and a warning is warranted. No consensus on an organ-specific warning. No data to support a warning for nonaspirin salicylates. No specified level of alcohol consumption need be mentioned. 14

15. FDA Conclusions (1997) History of heavy alcohol use or abuse may increase the risk of adverse GI effects, including serious GI bleeding and a warning is needed. Specific warnings are more effective and should include organ-specific information. Products with no warning may lead consumers to conclude that they are safer to use with alcohol. Nonaspirin salicylates should also bear an alcohol warning. 15

16. Alcohol Warning Final Rule (1998) Alcohol warning: If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take aspirin or other pain relievers/fever reducers. Aspirin may cause stomach bleeding. Combinations of acetaminophen and aspirin should be labeled: May cause liver damage and stomach bleeding. 16

17. Aspirin Professional Labeling FR(1998) WARNINGS GI Side Effects: stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. 17 PRECAUTIONS Renal Failure: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

18. Aspirin Professional Labeling FR(1998) ADVERSE REACTIONS GI Side Effects: dyspepsia, GI bleeding, ulceration, perforation, nausea, vomiting. 18 Urogenital: interstitial nephritis, pappilary necrosis, proteinuria, renal insufficiency, and failure

19. Ibuprofen Proposed Rule (2002) Ask a doctor before use if you have: Stomach problems that last or come back, such as heartburn, upset stomach, or pain Ulcers Bleeding problems High blood pressure Heart or kidney disease Are taking a diuretic Over 65 years of age 19