# Presentation: 708067

## Overview of Aspirin and  NSAID’s Label Warnings

**William E. Gilbertson, PharmD.**
**Division OTC Drug Products**

**1**

## 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**

## 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**

**Notes:**
and minor occult bleeding.
erosion, ulceration, or .

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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).**
** **

## 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**

## 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**