# Presentation: 708066

## Overview of Acetaminophen  Label Warnings

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

**1**

## Advisory Panel Conclusions (1977) 

**Safe and effective for OTC use.**
**Relatively free of adverse effects in most age groups, even in the presence of a variety of disease states.**
**Adult Dose**
**325 to 650 mg 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)

**Liver disease may prolong half-life of unchanged drug. **
**Could not conclude that the observed increased half-life will increase the potential or severity of hepatotoxicity. **
**Definitive studies are not available on whether or not acetaminophen should be used in patients with certain preexisting liver diseases.**
**High priority should be given to well-designed studies to resolve this issue.**

**3**

## Advisory Panel Conclusions (1977)

**Harmful effects on the liver are well-documented in acute overdose.**
**Single doses < 15 gm are not usually associated with serious liver damage.**
**Overdose may result in severe liver damage and a warning regarding this effect is obligatory. **

**4**

## Advisory Panel Conclusions (1977)

**Recommended warning: **
**“****Do not exceed recommended dosage because severe liver damage may occur”.**

**5**

## Comments Opposed to Warnings

**Places the responsibility of recognizing organ damage on the consumer.**
**May be misunderstood or may alarm or cause anxiety in consumers who use drugs rationally. **
**May encourage suicidal persons to abuse acetaminophen.**
**Inappropriate for children's products because there is a lack of documented fatalities in children from acute overdose.**** **

**6**

## Comments For A Liver Warning

**There are no unique signs of toxicity, such as ringing in the ears (tinnitus), and symptoms of toxicity do not appear until a few days after the overdose. **
**Consumers are increasing use of acetaminophen.**
**Fatalities and liver damage have occurred in children.**
**Warning may discourage consumers from exceeding the recommended daily dosage.**** **

**7**

## 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***

**8**

## FDA Conclusions (1988)

**Data inadequate to support the warning within the recommended labeled dose.**
**Warnings need not specify toxic effects of particular organs of the body caused by acute overdose.**
**Liver damage can occur from overdosage and a warning statement is warranted.**
**Lack of symptoms could delay the use of antidote.**
**Prompt medical attention is essential to the proper management of acetaminophen overdose.**

**9**

## FDA Conclusions (1988)

**Recommended Warning**
**Keep this and all drugs out of the reach of children.  In case of accidental overdose, seek professional assistance or contact a poison control center immediately. *****Prompt medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms*****.**

**10**

## Comments for an alcohol warning

**75 reports cited of liver damage in alcohol abusers who used acetaminophen for labeled claims.**
**Animal data confirms increased liver toxicity.**
**Chronic alcohol ingestion induces microsomal enzymes, increasing formation of the toxic metabolite (NAPQI) and interferes with it’s detoxification by depleting hepatic glutathione (GSH). **
**Recommended a reduced (2 gm) maximum daily dose for alcohol abusers.**

**11**

## Comments Opposed To Warning

**Existing data provide no rational basis for a warning.  **
**Majority of reports involved subjects with a history of alcohol abuse and use far in excess of the maximum daily dose.  **
**Other studies were cited that disagreed that animal and human data have demonstrated increased liver toxicity.**

**12**

##  NDAC Meeting (June 1993) 

_**Data Reviewed:**_
**Issues raised in TFM comments. **
**Published reports of acetaminophen-induced liver toxicity in alcohol users at various doses.**
**Acetaminophen metabolism in alcohol abusers.**
**Microsomal enzyme induction in subjects with liver disease.**
**Effect of alcohol abuse on acetaminophen overdose.**
**Animal data (effects of ethanol and diet on metabolism and on glutathione levels).**

**13**

## Questions to  NDAC (June 1993) 

**Does the data support a warning for alcohol abusers?**
**What population is at risk (drinks rarely, social, or abusers) and at what dose?**
**Benefit/risk considerations: will alcohol abusers switch to other ingredients that have equivalent or greater risks? **
**What information should be included (organ-specific, alcohol amount, etc.)?**
**Are data sufficient to support a reduced maximum daily dose (2 gm) for alcohol abusers, if so, what it should be?**

**14**

## NDAC Conclusion (June 1993) 

**Alcohol abusers are at increased risk.**
**Warning should specifically refer to possible liver damage.**
**Warning could cause alcohol abusers to switch to other products with equivalent or greater risks. **
**Should not be implemented until NDAC considers the risk for other analgesic ingredients. **
**Insufficient data to  recommend a reduced maximum daily dose for alcohol abusers**.

**15**

## FDA Conclusions (1997) 

**Chronic heavy alcohol use or abuse has a significant effect on the metabolism and detoxification of  NAPQI.  **
**Alcohol abusers are at increased risk and a warning is warranted for adult products. **
**Organ specific warnings are more effective than general warnings.**
**Insufficient data to  recommend a reduced maximum daily dose for alcohol abusers**.
**Labeling should recommend contact with a physician.**

**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 acetaminophen or other pain relievers/fever reducers.  Acetaminophen may cause liver damage.**

**17**