ANALYSIS OF POISON CONTROL CENTER DATA FOR

ACETAMINOPHEN-CONTAINING PRODUCTS

1998-2000

Prepared by Julie A. Skare, PhD.

Health Care Research Center

The Procter & Gamble Company

8700 Mason-Montgomery Road

Mason, OH 45040

August 20, 2002

TABLE OF CONTENTS

+--------------------------------------------------------------+---+---+
|                                                              | # |   |
|                                                              |   |   |
|                                                              | P |   |
|                                                              | a |   |
|                                                              | g |   |
|                                                              | e |   |
+--------------------------------------------------------------+---+---+
| 1\. Executive Summary                                        | 1 |   |
+--------------------------------------------------------------+---+---+
| 2\. Background                                               | 4 |   |
+--------------------------------------------------------------+---+---+
| 3\. Methods                                                  | 4 |   |
+--------------------------------------------------------------+---+---+
| 4\. Results                                                  | 8 |   |
+--------------------------------------------------------------+---+---+
| 4.1 APAP-Containing Cough and Cold Medications               | 8 |   |
+--------------------------------------------------------------+---+---+
| 4.1.1 Medical Outcome and Reason for Exposure - All Cases    | 8 |   |
+--------------------------------------------------------------+---+---+
| 4.1.2 Clinical Effects -- All Cases                          | 9 |   |
+--------------------------------------------------------------+---+---+
| 4.1.3 Medical Outcome and Reasons for Exposure -- Hepatic    | 1 |   |
| Effect Cases                                                 | 0 |   |
+--------------------------------------------------------------+---+---+
| 4.1.4 Demographics of Cases Involving Hepatic Effects        | 1 |   |
|                                                              | 3 |   |
+--------------------------------------------------------------+---+---+
| 5.  Products Involved in Hepatic Effect Cases -- Cough and   | 1 |   |
|     Cold                                                     | 4 |   |
|                                                              |   |   |
| > Medications                                                |   |   |
+--------------------------------------------------------------+---+---+
| 4.2 APAP-Containing Analgesics                               | 1 |   |
|                                                              | 5 |   |
+--------------------------------------------------------------+---+---+
| 4.2.1 Medical Outcome and Reason for Exposure -- All Cases   | 1 |   |
|                                                              | 5 |   |
+--------------------------------------------------------------+---+---+
| 4.2.2 Clinical Effects -- All Cases                          | 1 |   |
|                                                              | 6 |   |
+--------------------------------------------------------------+---+---+
| 4.2.3 Medical Outcome and Reason for Exposure -- Hepatic     | 1 |   |
| Effect Cases                                                 | 7 |   |
+--------------------------------------------------------------+---+---+
| 4.  Comparison of Hepatic Effect Cases for APAP-Containing   | 2 |   |
|     Cough                                                    | 0 |   |
|                                                              |   |   |
| > and Cold Medications and Analgesics                        |   |   |
+--------------------------------------------------------------+---+---+
| 4.2.5 Demographics of Cases Involving Hepatic Effects        | 2 |   |
|                                                              | 1 |   |
+--------------------------------------------------------------+---+---+
| 4.2.6 Products Involved in Hepatic Effect Cases --           | 2 |   |
| Analgesics                                                   | 2 |   |
+--------------------------------------------------------------+---+---+
| 4.3 Products Involved in Hepatic Effect Cases -- All         | 2 |   |
| APAP-Containing Products                                     | 3 |   |
+--------------------------------------------------------------+---+---+
| 4.4 Cough and Cold Medications without Analgesic             | 2 |   |
|                                                              | 6 |   |
+--------------------------------------------------------------+---+---+
| 4.4.1 Medical Outcome and Reason for Exposure -- All Cases   | 2 |   |
|                                                              | 6 |   |
+--------------------------------------------------------------+---+---+
| 4.4.2 Clinical Effects -- All Cases                          | 2 |   |
|                                                              | 7 |   |
+--------------------------------------------------------------+---+---+
| 4.4.3 Medical Outcome and Reason for Exposure -- Hepatic     | 2 |   |
| Effect Cases                                                 | 8 |   |
+--------------------------------------------------------------+---+---+
| 5\. Discussion and Conclusions                               | 2 |   |
|                                                              | 9 |   |
+--------------------------------------------------------------+---+---+
| References                                                   | 3 |   |
|                                                              | 1 |   |
+--------------------------------------------------------------+---+---+
| Appendix A                                                   |   |   |
+--------------------------------------------------------------+---+---+
| Appendix B                                                   |   |   |
+--------------------------------------------------------------+---+---+
| Appendix C                                                   |   |   |
+--------------------------------------------------------------+---+---+

**ANALYSIS OF POISON CONTROL CENTER DATA FOR**

**ACETAMINOPHEN-CONTAINING PRODUCTS\***

**1998-2000**

**1. Executive Summary**

Acetaminophen (APAP) is an effective OTC analgesic/antipyretic agent
with a long history of widespread use in over-the-counter medications
including both single ingredient products for pain relief/fever
reduction and combination multiple symptom relief cough and cold
products. When used according to label directions, APAP has an
outstanding safety profile. Under circumstances of overdose of APAP,
hepatotoxicity may occur due to the formation of an excess of a highly
reactive metabolite by hepatic P450 enzymes. In order to respond to the
FDA's request for information to better understand the root causes of
incidents involving hepatotoxic outcomes, an analysis of poison control
center data for all APAP-containing cough and cold products and
APAP-containing analgesics has been completed. The Toxic Exposure
Surveillance System (TESS) established by the American Association of
Poison Control Centers (AAPCC) is a well recognized source of
post-marketing surveillance data that has contributed to decisions
related to the safety of many types of products including drugs. Poison
control centers participating in TESS serve approximately 96% of the
U.S. population.

For this analysis AAPCC TESS data for three classes of products were
purchased for the years 1998-2000. These three data sets include:

A)  All APAP-containing multisymptom relief cough and cold products
    (N=60612 cases)

B)  All APAP-containing analgesic products (N=316371 cases)

C)  All multisymptom relief cough and cold products that do not contain
    an analgesic (N=206428 cases)

The AAPCC TESS data were analyzed to determine medical outcome as a
function of reason for exposure for all cases in each of the three data
sets. For each of the three data sets, the profile of all reported
clinical effects was examined as a function of reason for exposure.
Specifically focusing on only those cases involving hepatic effects,
each of the three data sets was then analyzed to determine the number of
cases involving hepatic effects as a function of the reason for exposure
and as a function of the severity of the medical outcome. Cases
involving hepatic effects were identified by searching for cases in
which the following clinical effects were reported:
100\<AST/ALT[\<]{.underline}1000, AST/ALT\>1000, bilirubin increased,
disseminated intravascular coagulation, PT prolonged, other
coagulopathy, or other liver function test (LFT) abnormality. Only those
cases in which one or more of these clinical effects was judged by the
poison control center to be related to or of unknown relationship to the
exposure were counted. Cases in which the hepatic clinical effect(s) was
judged by the poison control center to be not related to the exposure
were excluded.

\*The content of this report does not necessarily reflect the opinions
or conclusions of the American Association of Poison Control Centers.

For the two data sets involving APAP-containing products, information on
the type of APAP-containing product used and whether or not more than
one APAP-containing product was used was also analyzed as a function of
the reason for exposure for all hepatic effects cases excluding
suspected suicide attempts.

The following observations can be made from the analysis of the data
presented in this report.

-   For all three data sets, the majority of cases handled by the poison
    control centers involved no clinical effects (25-29%), minor effects
    (\~15%) (typical symptoms were drowsiness, nausea, vomiting), or
    received no or minimal follow-up because the quantities ingested
    were expected to result in no or minimal clinical effects (38-49%).

-   For the APAP-containing cough and cold products data set, less than
    0.3% of the total number of cases involved hepatic effects, and the
    majority of these (66%) were suspected suicide attempts. For the
    APAP-containing analgesics data set, 2% of the total number of cases
    involved hepatic effects and the majority of these (70%) were
    suspected suicide attempts. An extremely small fraction (0.006%) of
    cases involving cough and cold medications without analgesic
    involved hepatic effects, and approximately half of these were
    suspected suicide attempts.

-   Excluding suspected suicide attempts, hepatotoxicity cases with
    serious medical outcomes (i.e., major effects and deaths) accounted
    for 35% (19/54) of the total number of hepatotoxicity cases for the
    APAP-containing cough and cold products data set and for 41%
    (768/1877) of the total number of hepatotoxicity cases for the
    APAP-containing analgesics data set.

-   Hepatotoxicity cases were divided approximately evenly between
    unintentional reasons for exposure and intentional reasons for
    exposure, excluding suspected suicide attempts. This was true for
    both the APAP-containing analgesics and the APAP-containing cough
    and cold products.

-   An in depth analysis of products involved in hepatotoxicity cases
    for the year 2000 revealed the following profile:

+--------------------------------------+------------------+------------+
| **Product(s) Used**                  | **Number of      | **% of     |
|                                      | Cases**          | Cases**    |
|                                      |                  |            |
|                                      | **(N=698)**      |            |
+--------------------------------------+------------------+------------+
| One Single Ingredient OTC APAP       | 455              | 65%        |
| Analgesic                            |                  |            |
+--------------------------------------+------------------+------------+
| One Combination Product (Rx or OTC)  | 178              | 26%        |
|                                      |                  |            |
| -   Rx Analgesic Combo               | -   111          | -   16%    |
|                                      |                  |            |
| -   OTC Combo (Not cough/cold)       | -   54           | -   8%     |
|                                      |                  |            |
| -   OTC Combo (Cough/cold)           | -   13           | -   2%     |
+--------------------------------------+------------------+------------+
| Two APAP Products                    | 59               | 8%         |
+--------------------------------------+------------------+------------+
| Three or more APAP Products          | 6                | \<1%       |
+--------------------------------------+------------------+------------+

From these data it is clear that the majority of hepatotoxicity cases
involved the use of one APAP-containing analgesic product, most
frequently a single ingredient OTC analgesic. APAP-containing cough and
cold medications were not a significant contributor to the total number
of poison control center reports of APAP-associated hepatotoxicity.

-   Concomitant use of more than one APAP-containing product was not a
    major root cause of incidents involving hepatotoxicity. Less than
    10% of hepatotoxicity cases involved the use of more than one
    APAP-containing product (see the table above). Among those cases
    involving more than one product, the concomitant use of a single
    ingredient OTC analgesic plus an Rx combination analgesic was the
    most frequently reported (27 cases or \~4% of hepatotoxicity cases).
    The use of an OTC APAP-containing cough and cold product plus one or
    more other APAP-containing product(s) was reported in 8 cases (\~1%
    of hepatotoxicity cases).

-   During the three year period evaluated there were no reported cases
    involving hepatic effects with the use of an APAP-containing cough
    and cold medication as recommended. Such cases would have been
    classified as adverse drug reactions according to AAPCC TESS
    definitions, and none of these were reported. There were a small
    number of adverse drug reactions with hepatic effects reported for
    the APAP-containing analgesic products (36 cases representing 0.01%
    of total cases). However, insufficient information is available on
    these cases to conduct a thorough assessment of causality ruling out
    other possible causes or to reliably document whether or not the
    amount of APAP take was truly within the recommended therapeutic
    dose.

Taken as a whole, these data indicate that cases of hepatotoxicity
associated with APAP-containing products result from the intentional or
unintentional incorrect use of these products. Cases involving hepatic
effects with recommended therapeutic use are very rare and impossible to
confirm given the limitations inherent in data collection. Intentional
or unintentional incorrect use of these products can be addressed by
labeling changes and by public education programs that inform consumers
about products containing APAP and the potential for serious
consequences associated with overdosing.

**2. Background**

The FDA has sought information from the OTC health care industry on the
root causes for cases of hepatotoxicity associated with the use of
acetaminophen (APAP)-containing OTC products so that informed decisions
can be made regarding possible means for decreasing the occurrence of
these incidents. Possible scenarios the FDA has suggested as root causes
for these cases are 1) the consumer ingested more than the recommended
dose of a single APAP-containing product, 2) the consumer used an OTC
combination product containing APAP along with an OTC single ingredient
APAP analgesic product either unintentionally (i.e., not knowing that
they both contain APAP) or intentionally (but without understanding the
possible adverse effects associated with overdose), 3) the consumer used
an Rx product containing APAP along with an OTC single ingredient APAP
analgesic product either unintentionally or intentionally, or 4) the
consumer developed liver toxicity even though he/she followed the label
directions for use. In response to the FDA's request for information,
poison control center data for APAP-containing cough and cold
medications and APAP-containing analgesics have been purchased from the
American Association of Poison Control Centers Toxic Exposure
Surveillance System (AAPCC TESS), and an analysis of cases involving
hepatic effects has been completed. The AAPCC TESS data provide an
additional source of post-marketing adverse event data that can be
evaluated in conjunction with the FDA's AERS database to obtain a more
complete picture of post-marketing adverse event reports of
hepatotoxicity associated with APAP.

**3. Methods**

AAPCC TESS data for three classes of products were purchased for the
years 1998-2000. These three data sets include:

D)  All APAP-containing multisymptom relief cough and cold products

E)  All APAP-containing analgesic products

F)  All multisymptom relief cough and cold products that do not contain
    an analgesic

The subcategories of products that are included in each of these three
data sets are shown in Figures 1 -- 3 below. These subcategories reflect
the classification system used by AAPCC TESS. This classification system
was created several years ago, and there are not necessarily currently
marketed products that fall into each of the subcategories listed in
Figures 1 -- 3.

OTC APAP-containing cough and cold combination products (Figure 1)
typically contain a decongestant plus an antihistamine, and they may
also contain an antitussive (e.g., dextromethorphan). The AAPCC TESS
category of APAP-containing analgesics (Figure 2) includes OTC single
ingredient APAP analgesic products (either an adult formulation, a
pediatric formulation, or unknown whether adult or pediatric), OTC APAP
combination products containing aspirin, Rx combination products
containing an opioid, and other combination products such as OTC
analgesic/sleep aid combination products containing APAP plus
diphenhydramine. Cough and cold products without an analgesic (Figure 3)
typically contain the same types of active ingredients as the
APAP-containing cough and cold combinations except that they do not
contain APAP, aspirin, or any other analgesic.

**Figure 1**

######### AAPCC TESS Classifications for APAP-Containing Cough and Cold Products

> APAP/ASA with decongestant/antihistamine, with phenylpropanolamine,
> and:
>
> Dextromethorphan
>
> Other opioid
>
> Without opioid
>
> APAP/ASA with decongestant /antihistamine, without
> phenylpropanolamine, and:
>
> Dextromethorphan
>
> Other opioid
>
> Without opioid
>
> APAP with decongestant/antihistamine, with phenylpropanolamine, and:
>
> Codeine
>
> Dextromethorphan
>
> Other opioid
>
> Without opioid
>
> APAP with decongestant/antihistamine, without phenylpropanolamine
>
> Codeine
>
> Dextromethorphan
>
> Other opioid
>
> Without opioid
>
> APAP/dextromethorphan
>
> **Figure 2**

**AAPCC TESS Classifications for Acetaminophen-Containing Analgesics**

Acetaminophen only

Adult formulation

Pediatric formulation

Unknown formulation

Acetaminophen in combination with:

Aspirin with other ingredient

Aspirin without other ingredient

Codeine

Hydrocodone

Oxycodone

Propoxyphene

Other opioid

Other drug: adult formulation

########  Other drug: pediatric formulation

**Figure 3**

**AAPCC TESS Classifications for Cough and Cold Products Without
Analgesic**

Antihistamine/decongestant, with phenylpropanolamine:

> Codeine

Dextromethorphan

Other opiod

Without opioid

Antihistamine/decongestant, without phenylpropanolamine:

> Codeine

Dextromethorphan

Other opioid

Without opioid

Other dextromethorphan

> Other phenylpropanolamine
>
> Other

The AAPCC TESS data were analyzed to determine medical outcome as a
function of reason for exposure for all cases in each of the three data
sets. Within each data set, medical outcome as a function of reason for
exposure was also evaluated for three different age groups: 1) \< 6
years of age, 2) 6-12 years of age, and 3) \>12 years of age. The AAPCC
TESS definitions for reasons for exposure and medical outcome are
provided below (Figures 4 and 5).

For each of the three data sets, the profile of all reported clinical
effects was examined as a function of reason for exposure. Specifically
focusing on hepatoxicity, each of the three data sets was also analyzed
to determine the number of cases involving hepatic effects as a function
of the reason for exposure and as a function of the severity of the
medical outcome. The data were analyzed by age group as described above.
Cases involving hepatic effects were identified by searching for cases
in which the following clinical effects were reported:
100\<AST/ALT[\<]{.underline}1000, AST/ALT\>1000, bilirubin increased,
disseminated intravascular coagulation, PT prolonged, other
coagulopathy, or other liver function test (LFT) abnormality. Only those
cases in which one or more of these clinical effects was judged by the
poison control center to be related to or of unknown relationship to the
exposure were counted. Cases in which the hepatic clinical effect(s) was
judged by the poison control center to be not related to the exposure
were excluded.

For the two data sets involving APAP-containing products, information on
the type of APAP-containing product used and whether or not more than
one APAP-containing product was used was also analyzed as a function of
the reason for exposure for all hepatic effects cases excluding
suspected suicide attempts. For the APAP-containing cough and cold
products, the analysis of products used covered all three years
(1998-2000). The year 2000 was the first year that the AAPCC TESS system
captured data on the use of more than two substances per case.
Nevertheless, all three years were included in this analysis because the
total number of hepatic effects cases was relatively small for the
APAP-containing cough and cold products data set. For the larger number
of cases involving the APAP-containing analgesic products, the analysis
of products used was limited to the year 2000.

####### **Figure 4**

####### **AAPCC TESS Definitions**

**Medical Outcome**

No Effect: The patient developed no signs or symptoms as a result of the
exposure

Minor Effect: The patient developed some signs or symptoms as a result
of the exposure, but they were minimally bothersome and generally
resolved rapidly.

Moderate Effect: The patient exhibited signs or symptoms as a result of
the exposure that were more pronounced, more prolonged, or more of a
systemic nature than minor symptoms. Symptoms were not life-threatening,
and the patient has no residual disability. Usually some form of
treatment is indicated.

Major Effect: The patient exhibited signs or symptoms as a result of the
exposure that were life-threatening or resulted in significant residual
disability or disfigurement

Death: Only those deaths which are probably or undoubtedly related to
the exposure are coded here.

No Follow-Up, Nontoxic Exposure: Follow-up calls were limited because
the substance implicated was nontoxic or the amount was insignificant

No Follow-Up, Minimal Effects Possible: Follow-up calls were limited
because the exposure was likely to result in only minimal toxicity.

Unable to Follow, Potentially toxic: The exposure was significant and
may have resulted in a moderate, major or fatal outcome, but the patient
could not be followed

Unrelated Effect: The exposure was probably not responsible for the
effect.

**Figure 5**

####### **AAPCC TESS Definitions**

**Reasons for Exposure**

Unintentional General: All unintentional exposures not specifically
defined below. Most unintentional exposures in children are captured
here.

Therapeutic Error: An unintentional deviation from a proper therapeutic
regimen that results in the wrong dose, incorrect route of
administration, administration to the wrong person, or administration of
the wrong substance. Only exposures to medications or products
substituted for medications are included. Drug interactions resulting
from unintentional administration of drugs or foods which are known to
interact are also included.

Unintentional Misuse: Unintentional improper or incorrect use of a
nonpharmaceutical substance. (In the data sets included in this
analysis, cases coded as Unintentional Misuse most likely represent
Therapeutic Error cases that have been misclassified since the
substances involved are pharmaceutical substances.)

Unintentional Unknown: An exposure determined to be unintentional but
the exact reason is unknown

Suspected Suicidal: Inappropriate use of a substance for reasons which
are suspected to be self destructive or manipulative.

Intentional Misuse: Intentional improper or incorrect use of a substance
for reasons other than the pursuit of a psychotropic effect.

Intentional Abuse: Intentional improper or incorrect use of a substance
to achieve a euphoric or psychotropic effect. All recreational use of
substances for any effect is included.

Adverse Reaction: An adverse event occurring with normal, prescribed,
labeled or recommended use of the product, as opposed to overdose,
misuse, or abuse.

Other: Several categories from the AAPCC TESS definitions were combined
together into one "Other" category. These include: Environmental,
Occupational, Bite/Sting, Food Poisoning, Contaminant/Tampering,
Malicious, Adverse Reaction to Food

**4. Results**

For all of the data discussed below, summary tables and figures are
provided in the text and more detailed tables are included in Appendices
A - C.

**4.1 APAP-Containing Cough and Cold Medications**

**4.1.1 Medical Outcome and Reason for Exposure -- All Cases (Tables
A1-A4, Appendix A)**

There were a total of \~20,000 reports per year for products included in
this data set resulting in a total of over 60,000 cases during the three
year period. The majority of cases involved no clinical effects (\~25%),
minor effects (\~16%), or received no or minimal follow-up because the
quantities ingested were expected to result in no or minimal clinical
effects (\~47%). Serious medical outcomes (i.e., major effects and
deaths) accounted for \~0.3% of cases, and the majority of these (\~84%)
were associated with intentional exposures, predominantly
suicides/suicide attempts (see Table A1, Appendix A).

The predominant reason for exposure for all cases involving
APAP-containing cough and cold products reported to poison control
centers during 1998-2000 varied among the three different age groups
evaluated (see Figure 6 below and Tables A2-A4, Appendix A). Among
children \<6 years of age, unintentional general cases (i.e., accidental
ingestions) predominated (75% of cases), and therapeutic
errors/unintentional misuse accounted for most of the remaining cases
(24%). Among children 6--12 years of age, therapeutic
errors/unintentional misuse were the most frequently reported reason
(\~60%), and unintentional general cases were the second most frequently
reported reason (\~31%). Among those age \>12 years, suspected suicide
attempts (\~32%) and therapeutic errors/unintentional misuse (\~29%)
were the most frequently reported reasons.

**Figure 6**

#### **APAP-Containing Cough and Cold Medications**

#### **Reason for Exposure -- All Cases**

![](media/image1.wmf){width="7.875694444444444in" height="2.46875in"}

**4.1.2 Clinical Effects -- All Cases (Table A5, Appendix A)**

The total number of clinical effects reported by body system was
evaluated by broad category of reason for exposure (i.e., unintentional,
intentional, adverse drug reaction, other, unknown) and these data are
summarized in Table 1 below. Only clinical effects judged by the poison
control center to be related or of unknown relationship to the exposure
were counted. Clinical effects judged by the poison control center to be
not related to the exposure were excluded. The most frequently reported
clinical effects (see Table A5, Appendix A) were drowsiness/lethargy
(15.5% of cases), tachycardia (4.1%), vomiting (3.3%),
agitation/irritability (3.2%), dizziness/vertigo (2.8%), and nausea
(2.2%). One or more hepatic effects were observed in 0.27% of cases
(162/60612) (see Table A6, Appendix A).

### Table 1

### APAP-Containing Cough and Cold Medications

### Summary of Clinical Effects by Reason for Exposure\*

## **1998-2000 -- All Cases, All Ages**

+---------------+----------+----------+-------+------+-------+-------+
|               | **Number |          |       |      |       |       |
|               | of       |          |       |      |       |       |
|               | Clinical |          |       |      |       |       |
|               | E        |          |       |      |       |       |
|               | ffects** |          |       |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+
| **Body        | *        | **I      | **Ad  | *    | *     | **To  |
| System**      | *Uninten | ntention | verse | *Oth | *Unkn | tal** |
|               | tional** | al\*\*** | Drug  | er** | own** |       |
|               |          |          | React |      |       | **(N= |
|               | **       | **       | ion** | **(N | **(   | 60612 |
|               | (N=46181 | (N=11853 |       | =130 | N=187 | Cas   |
|               | Cases)** | Cases)** | **(N  | Case | Cas   | es)** |
|               |          |          | =2261 | s)** | es)** |       |
|               |          |          | Cas   |      |       |       |
|               |          |          | es)** |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+
| C             | 579      | 2613     | 234   | 6    | 33    | 3465  |
| ardiovascular |          |          |       |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+
| Dermal        | 178      | 120      | 506   | 0    | 4     | 808   |
+---------------+----------+----------+-------+------+-------+-------+
| Gas           | 1435     | 2313     | 292   | 8    | 21    | 4069  |
| trointestinal |          |          |       |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+
| Hepatic/      | 48       | 224      | 1\    | 0    | 0     | 273   |
| Hematological |          |          | *\*\* |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+
| Neurological  | 8190     | 6412     | 1109  | 21   | 111   | 15843 |
+---------------+----------+----------+-------+------+-------+-------+
| Ocular        | 289      | 529      | 75    | 8    | 4     | 905   |
+---------------+----------+----------+-------+------+-------+-------+
| Renal         | 14       | 51       | 2     | 0    | 0     | 67    |
+---------------+----------+----------+-------+------+-------+-------+
| Respiratory   | 94       | 167      | 69    | 2    | 8     | 340   |
+---------------+----------+----------+-------+------+-------+-------+
| Miscellaneous | 920      | 954      | 445   | 4    | 39    | 2362  |
+---------------+----------+----------+-------+------+-------+-------+
| **Total       | *        | *        | **2   | **   | **    | **28  |
| Number of     | *11747** | *13383** | 733** | 49** | 220** | 132** |
| Clinical      |          |          |       |      |       |       |
| Effects**     |          |          |       |      |       |       |
+---------------+----------+----------+-------+------+-------+-------+

\*More than one clinical effect may be reported per case

\*\*Includes suspected suicide attempts

\*\*\*Reported clinical effect was hemolysis

**4.1.3 Medical Outcome and Reason for Exposure -- Hepatic Effect Cases
(Tables A6-**

**A7a-h, Appendix A)**

> Cases involving hepatic effects were tabulated according to medical
> outcome and reason for exposure. The majority of these cases (107/162,
> \~66%) involved suspected suicide attempts (see Figure 7 below and
> Table A6, Appendix A). Other intentional reasons for exposure (i.e.,
> intentional abuse, intentional misuse) accounted for \~18% of cases.
> Therapeutic errors/unintentional misuse accounted for 8% of cases, and
> unintentional general cases represented 6.8% of cases. There were no
> cases involving hepatic effects when label directions were followed
> (i.e., adverse drug reactions). Because there were only two cases
> involving children \<12 years of age, Figure 7 includes all ages but
> does not display reason for exposure by age group.

#### **Figure 7**

#### **APAP-Containing Cough and Cold Medications**

**Reason for Exposure -- Hepatic Effect Cases**

![](media/image2.wmf){width="4.229861111111111in"
height="2.4895833333333335in"}

For the APAP-containing cough and cold medications, there were 25 cases
with hepatic effects that involved unintentional exposures (i.e., taking
too much by mistake) and 29 cases with hepatic effects (excluding
suicide attempts) that involved intentional exposures (i.e., taking too
much on purpose) (see Tables 2a and 2b below). Among these 54 cases,
there was 1 death (a therapeutic error in a 78 year old female) and 18
cases with major medical outcomes. Among these 19 serious cases, 9
involved unintentional reasons for exposure and 10 involved intentional
reasons for exposure. Although the total number of hepatic effects cases
was comparable for unintentional and intentional reasons for exposure
(25 vs. 29), the percentage of cases with hepatic effects (0.05% vs.
0.8%) and the percentage of cases with serious medical outcomes
involving hepatic effects (deaths plus major effect medical outcomes)
(0.02% vs. 0.3%) was much lower for unintentional reasons for exposure
in comparison to intentional reasons for exposure. Two of the cases
classified as unintentional general cases involved two year olds, and
most likely involved accidental ingestions by unattended children.
Neither of these cases involved a serious medical outcome although one
of them was not followed. There were no other hepatic effect cases
involving children \<12 years of age. A listing of the 54 cases
involving hepatic effects that provides information on age, gender,
medical outcome, reason for exposure, reported clinical effects, and
substances used is found in Tables A7a-h, Appendix A.

**Table 2a**

**APAP-Containing Cough and Cold Medications**

**Medical Outcome for Cases Involving Hepatic Effects**

**Unintentional Exposures**

\*Includes one case involving a two year old child in each of these
categories.

###### Table 2b

###### APAP-Containing Cough and Cold Medications

**Medical Outcome for Cases Involving Hepatic Effects**

# Intentional Exposures (Excluding Suicides)

+-----------------+---------+-----------+------------+---------------+
| Minor           | 1       | 1         | 1          | 3             |
|                 |         |           |            |               |
| Effect          |         |           |            | (0.08)        |
+-----------------+---------+-----------+------------+---------------+
| Moderate        | 5       | 8         | 1          | 14            |
|                 |         |           |            |               |
| Effect          |         |           |            | (0.4)         |
+-----------------+---------+-----------+------------+---------------+
| Major           | 5       | 5         | 0          | 10            |
|                 |         |           |            |               |
| Effect          |         |           |            | (0.3)         |
+-----------------+---------+-----------+------------+---------------+
| Death           | 0       | 0         | 0          | 0             |
+-----------------+---------+-----------+------------+---------------+
| No              | 0       | 0         | 0          | 0             |
| F/U-Minimally   |         |           |            |               |
| Toxic           |         |           |            |               |
+-----------------+---------+-----------+------------+---------------+
| No              | 2       | 0         | 0          | 2(0.05)       |
| F/U-Potentially |         |           |            |               |
| Toxic           |         |           |            |               |
+-----------------+---------+-----------+------------+---------------+
| Total Cases     | 13      | 14        | 2          | 29            |
| with Hepatic    |         |           |            |               |
| Effects         |         |           |            | (0.8)         |
+-----------------+---------+-----------+------------+---------------+
| TOTAL CASES     | 1888    | 1402      | 478        | 3768          |
+-----------------+---------+-----------+------------+---------------+

**4.1.4 Demographics of Cases Involving Hepatic Effects**

Age and gender distribution were examined for hepatic effect cases
involving unintentional or intentional (excluding suicides) reasons for
exposure (see Table 3 below). There appeared to be a larger proportion
of males in cases involving intentional reasons for exposure, although
the total number of cases was too small to draw firm conclusions.

**Table 3**

**APAP-Containing Cough/Cold Medications**

### Demographics for Cases Involving Hepatic Effects

**1998-2000**

+---------------------+-------+------+----------------+---------------+
| **Reason for        | ### N |      | **Mean Age     | **Gender**    |
| Exposure**          |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | SD (Range)**   |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 11    |      | 29             | 6M/5F         |
| General             |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 16.2 (2-48)    |               |
+---------------------+-------+------+----------------+---------------+
| Therapeutic Error   | 9     |      | 56             | 3M/6F         |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 17.1 (21-78)   |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 4     |      | 42             | 2M/2F         |
| Misuse              |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 3.7 (37-46)    |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 1     |      | 19             | F             |
| Unknown             |       |      |                |               |
+---------------------+-------+------+----------------+---------------+
| #####               | *     |      | **40           | **11M/14F**   |
| Total Unintentional | *25** |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 16.1 (2-78)**  |               |
+---------------------+-------+------+----------------+---------------+
| Intentional Misuse  | 13    |      | 32             | 11M/2F        |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 10.3 (17-50)   |               |
+---------------------+-------+------+----------------+---------------+
| Intentional Abuse   | 14    |      | 27             | 10M/4F        |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 16.4 (13-70)   |               |
+---------------------+-------+------+----------------+---------------+
| Intentional Unknown | 2     |      | 16             | 1M/1F         |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 0              |               |
+---------------------+-------+------+----------------+---------------+
| #####               | *     |      | **27           | **22M/7F**    |
| Total Intentional\* | *29** |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 8.2 (13-70)**  |               |
+---------------------+-------+------+----------------+---------------+

\*Excludes suspected suicide attempts

**4.1.5 Products Involved in Hepatic Effect Cases -- Cough and Cold
Medications (Tables A8-A10, Appendix A)**

> Hepatic effects cases involved only one APAP-containing cough and cold
> product and no other APAP-containing product in 18/25 cases and 21/29
> cases for the unintentional and intentional reasons for exposure,
> respectively (Table 4 and Tables A8 and A9, Appendix A). When there
> was another APAP product involved, it was most often a single
> ingredient OTC analgesic (9 cases). In two of the cases involving
> intentional reasons for exposure, three APAP-containing products were
> used. The cases included in the data set for APAP-containing cough and
> cold medications that also involved use of an APAP-containing
> analgesic are also found in the data set for the APAP-containing
> analgesics discussed in the Section 4.2 below.
>
> The number of APAP-containing products used was also evaluated by
> medical outcome (Table A10, Appendix A) in order to determine whether
> or not there appeared to be a trend for multiple product use to result
> in more significant medical outcomes involving hepatic effects.
> However, the number of hepatic effects cases in the cough and cold
> medications data set was too small to draw any conclusions regarding
> this question.

**Table 4**

# Products Used in Hepatic Effect Cases

###### APAP-Containing Cough and Cold Medications Data Set

**1998-2000**

  ----------------- ----------------- ------------ ------------ ----------------- ------------ ------------ -----------
                    **No. of Cases**  **No. of                                                 **No. of     
                                      Cases**                                                  Cases**      

  **Reason for      **One             **Two APAP                                               **Three APAP **Total**
  Exposure**        APAP-Containing   Products**                                               Products**   
                    Cough/Cold                                                                              
                    Product**                                                                               

                                      Cough/Cold   Cough/Cold   Cough/Cold        Two          Any Three    
                                      Product +    Product +Rx  Product +         Cough/Cold   Products     
                                      OTC          Analgesic    Analgesic/Sleep   Products                  
                                      Analgesic                 Aid                                         

  Unintentional     9                 1            1            0                 0            0            11
  General                                                                                                   

  Therapeutic Error 6                 1            1            0                 1            0            9

  Unintentional     3                 1            0            0                 0            0            4
  Misuse                                                                                                    

  Unintentional     0                 1            0            0                 0            0            1
  Unknown                                                                                                   

  **Subtotal        **18**            **4**        **2**        **0**             **1**        **0**        **25**
  Unintentional**                                                                                           

  Intentional       8                 4            0            0                 0            1            13
  Misuse                                                                                                    

  Intentional Abuse 11                1            0            1                 0            1            14

  Intentional       2                 0            0            0                 0            0            2
  Unknown                                                                                                   

  **Subtotal        **21**            **5**        **0**        **1**             **0**        **2**        **29**
  Intentional\***                                                                                           

  **Total**         **39**            **9**        **2**        **1**             **1**        **2**        **54**
  ----------------- ----------------- ------------ ------------ ----------------- ------------ ------------ -----------

\*Excludes suspected suicide attempts

**4.2 APAP-Containing Analgesics**

**4.2.1 Medical Outcome and Reason for Exposure -- All Cases (Tables
B1-B4, Appendix B)**

There were a total of \~100,000 reports per year for products included
in this data set resulting in a total of over 300,000 cases during the
three year period. Similar to the APAP-containing cough and cold
medications, the majority of cases involved no clinical effects (\~27%),
minor effects (\~15%), or received no or minimal follow-up because the
quantities ingested were expected to result in no or minimal clinical
effects (\~38%). Serious medical outcomes (major effects and deaths)
accounted for \~1.8% of cases, which represents a notably higher
percentage than the APAP-containing cough and cold products (\~0.3%).
The majority of these serious outcomes (\~87%) were associated with
intentional exposures, predominantly suicides/suicide attempts (see
Table B1, Appendix B).

> As with the APAP-containing cough and cold medications, the
> predominant reason for exposure for all cases reported to poison
> control centers varied among different age groups (see Figure 8 below
> and Tables B2-B4, Appendix B). Among children \<6 years of age,
> unintentional general cases (i.e., accidental ingestions) predominated
> (\~82% of cases) and therapeutic errors/unintentional misuse accounted
> for most of the remaining cases (\~17%). Among children 6-12 years of
> age, therapeutic errors/unintentional misuse were the most frequently
> reported reason (\~47%), and unintentional general cases were the
> second most frequently reported reason (\~37%). Among those age \>12
> years, suspected suicide attempts were the most frequently reported
> and accounted for a higher percentage of total cases (\~56%) than for
> the APAP-containing cough and cold medications. Therapeutic
> errors/unintentional misuse (\~15%) were the second most frequently
> reported reason.

###### Figure 8

**APAP-Containing Analgesics**

**Reason for Exposure -- All Cases**

![](media/image3.wmf){width="7.0993055555555555in"
height="2.1034722222222224in"}

**4.2.2 Clinical Effects -- All Cases (Table B5, Appendix B)**

> The total number of clinical effects reported by body system was
> evaluated by broad category of reason for exposure (i.e.,
> unintentional, intentional, adverse drug reaction, other, unknown) and
> these data are summarized in Table 5 below. Only clinical effects
> judged by the poison control center to be related or of unknown
> relationship to the exposure were counted. Clinical effects judged by
> the poison control center to be not related to the exposure were
> excluded. The most frequently reported clinical effects were
> drowsiness/lethargy (13.7% of cases), vomiting (8.3%), nausea (5.1%),
> tachycardia (3.4%), abdominal pain (2.2%), and agitation/irritability
> (2.0%) (see Table B5, Appendix B). Although these were generally
> similar to the most frequently reported clinical effects for the
> APAP-containing cough and cold medications (see Section 4.1.2), one
> notable difference was that the frequency of hepatic effects was
> greater for the APAP-containing analgesics. One or more hepatic
> effect(s) were observed in 2.0% (6360/316371) of cases (see Table B6,
> Appendix B) compared to 0.27% (162/60612) of cases for the
> APAP-containing cough and cold products (see Section 4.1.2).

**Table 5**

**APAP-Containing Analgesics**

### Summary of Clinical Effects by Reason for Exposure\*

## **1998-2000 - All Ages**

+---------------+----------+---------+------+------+-------+--------+
|               | **Number |         |      |      |       |        |
|               | of       |         |      |      |       |        |
|               | Clinical |         |      |      |       |        |
|               | E        |         |      |      |       |        |
|               | ffects** |         |      |      |       |        |
+---------------+----------+---------+------+------+-------+--------+
| **Body        | *        | **Int   | *    | *    | *     | **T    |
| System**      | *Uninten | entiona | *Adv | *Oth | *Unkn | otal** |
|               | tional** | l\*\*** | erse | er** | own** |        |
|               |          |         | Drug |      |       | **(N=  |
|               | **(      | **(N    | Re   | **(N | **(N  | 316371 |
|               | N=178206 | =127772 | acti | =569 | =1535 | Ca     |
|               | Cases)** | C       | on** | Case | Cas   | ses)** |
|               |          | ases)** |      | s)** | es)** |        |
|               |          |         | *    |      |       |        |
|               |          |         | *(N= |      |       |        |
|               |          |         | 8289 |      |       |        |
|               |          |         | Case |      |       |        |
|               |          |         | s)** |      |       |        |
+---------------+----------+---------+------+------+-------+--------+
| C             | 1530     | 16013   | 401  | 3    | 223   | 18170  |
| ardiovascular |          |         |      |      |       |        |
+---------------+----------+---------+------+------+-------+--------+
| Dermal        | 786      | 976     | 2077 | 4    | 22    | 3865   |
+---------------+----------+---------+------+------+-------+--------+
| Gas           | 10776    | 37454   | 3113 | 58   | 276   | 51677  |
| trointestinal |          |         |      |      |       |        |
+---------------+----------+---------+------+------+-------+--------+
| Hepatic/      | 1587     | 10298   | 86   | 7    | 282   | 12260  |
| Hematological |          |         |      |      |       |        |
+---------------+----------+---------+------+------+-------+--------+
| Neurological  | 14727    | 58426   | 3368 | 41   | 890   | 77452  |
+---------------+----------+---------+------+------+-------+--------+
| Ocular        | 506      | 2215    | 109  | 3    | 52    | 2285   |
+---------------+----------+---------+------+------+-------+--------+
| Renal         | 156      | 1174    | 29   | 2    | 61    | 1422   |
+---------------+----------+---------+------+------+-------+--------+
| Respiratory   | 566      | 3755    | 350  | 1    | 123   | 4795   |
+---------------+----------+---------+------+------+-------+--------+
| Miscellaneous | 3143     | 11401   | 1568 | 13   | 280   | 16405  |
+---------------+----------+---------+------+------+-------+--------+
| **Total       | *        | **1     | *    | **1  | **2   | **18   |
| Number of     | *33777** | 41712** | *111 | 32** | 209** | 8931** |
| Clinical      |          |         | 01** |      |       |        |
| Effects**     |          |         |      |      |       |        |
+---------------+----------+---------+------+------+-------+--------+

\*More than one clinical effect may be reported per case

\*\*Includes suspected suicide attempts

**4.2.3 Medical Outcome and Reason for Exposure -- Hepatic Effects Cases
(Tables B6-B11, Appendix B)**

Cases with hepatic effects were tabulated according to medical outcome
and reason for exposure. The vast majority of cases with hepatic effects
(6285/6360, \~99%) involved subjects \>12 years of age (see Tables
B6-B9, Appendix B). There were 30 cases involving children \< 6 years of
age and 45 cases involving children 6-12 years of age.

> Reasons for exposure among cases with hepatic effects varied for the
> three different age groups evaluated (see Figure 9 below and Tables
> B7-B9, Appendix B). Among children \<6 years of age, unintentional
> general exposures (i.e., accidental ingestions) accounted for \~72% of
> hepatic effect cases (21 cases). Therapeutic errors/unintentional
> misuse accounted for \~17% of cases (5 cases). There were 2 cases
> classified as adverse drug reactions. One case was coded as a
> suspected suicide attempt and probably represents a coding error.

Among children 6-12 years of age, suicide attempts account for \~85% of
hepatic effect cases (39 cases). There were 3 therapeutic
error/unintentional misuse cases, 2 intentional abuse cases, and 1 case
classified as an adverse drug reaction.

Among those age \>12 years, suspected suicide attempts accounted for the
majority of hepatic effect cases (\~71%) and other intentional reasons
for exposure accounted for \~14% of cases. Therapeutic
error/unintentional misuse and unintentional general cases each
accounted for \~6% of cases. Approximately 0.5% of cases were classified
as adverse drug reactions (33 cases).

#### **Figure 9**

**APAP-Containing Analgesics**

**Reason for Exposure --Hepatic Effect Cases**

![](media/image4.wmf){width="7.302083333333333in"
height="2.4381944444444446in"}

Among all age groups there were 853 cases that involved unintentional
exposures and 866 cases that involved intentional exposures (excluding
suicides) (see Tables 6a and 6b below). There were 20 deaths associated
with therapeutic errors and 3 deaths categorized as unintentional
unknown. A listing of the 20 therapeutic error cases that provides
information on age, gender, medical outcome, reported clinical effects,
and substances used is found in Table B10, Appendix B. All of these
cases involved subjects \>12 years of age. There were 102 deaths
associated with intentional reasons for exposure excluding suicides, and
the majority of these (61/102) were attributed to intentional misuse.
The vast majority of serious cases (i.e., major effects and deaths) with
hepatic effects involved subjects \>12 years of age even when
suicides/suicide attempts were excluded (758/768 cases) (see Tables
B7-B9, Appendix B). Although the total number of hepatic effect cases
was comparable for the intentional and unintentional reasons for
exposure (853 vs. 866), the percentage of cases with hepatic effects
(0.48 vs. 3.5%) and the percentage of cases with serious medical
outcomes involving hepatic effects (deaths plus major effects) (0.17 vs.
1.52%) was much lower for unintentional reasons for exposure in
comparison to intentional reasons for exposure.

There were also a total of 36 cases classified as adverse drug reactions
(33 in subjects \>12 years of age and 3 in children), including 2 deaths
and 16 major effects (see Table B6, Appendix B). However, the
information collected by poison control centers in managing phone calls
is typically insufficient to reliably document whether or not the amount
taken was truly the recommended therapeutic dose. A listing of these 36
cases classified as adverse drug reactions that provides information on
age, gender, medical outcome, reported clinical effects, and substances
used is found in Table B11, Appendix B.

**Table 6a**

**APAP-Containing Analgesics**

**Medical Outcome for Cases Involving Hepatic Effects**

**Unintentional Exposures**

# Table 6b

###### APAP-Containing Analgesics

###### Medical Outcome for Cases Involving Hepatic Effects

# Intentional Exposures (Excluding Suicides)

+---------+------------+------------+-------------+------------------+
| Minor   | 32         | 15         | 7           | 54               |
|         |            |            |             |                  |
| Effect  |            |            |             | (0.22)           |
+---------+------------+------------+-------------+------------------+
| M       | 220        | 93         | 55          | 368              |
| oderate |            |            |             |                  |
|         |            |            |             | (1.5)            |
| Effect  |            |            |             |                  |
+---------+------------+------------+-------------+------------------+
| Major   | 153        | 68         | 52          | 273              |
|         |            |            |             |                  |
| Effect  |            |            |             | (1.1)            |
+---------+------------+------------+-------------+------------------+
| Death   | 61         | 17         | 24          | 102              |
|         |            |            |             |                  |
|         |            |            |             | (0.42)           |
+---------+------------+------------+-------------+------------------+
| No F/U- | 9          | 3          | 1           | 13               |
|         |            |            |             |                  |
| Mi      |            |            |             | (0.053)          |
| nimally |            |            |             |                  |
|         |            |            |             |                  |
| Toxic   |            |            |             |                  |
+---------+------------+------------+-------------+------------------+
| No F/U- | 36         | 11         | 9           | 56               |
|         |            |            |             |                  |
| Pote    |            |            |             | (0.23)           |
| ntially |            |            |             |                  |
|         |            |            |             |                  |
| Toxic   |            |            |             |                  |
+---------+------------+------------+-------------+------------------+
| Total   | 511        | 207        | 148         | 866              |
| Cases   |            |            |             |                  |
| with    |            |            |             | (3.5)            |
| Hepatic |            |            |             |                  |
| Effects |            |            |             |                  |
+---------+------------+------------+-------------+------------------+
| TOTAL   | 14937      | 5644       | 3819        | 24400            |
+---------+------------+------------+-------------+------------------+

There were a total of 113 cases with an unknown reason for exposure,
including 29 deaths and 39 major effects (see Table B6, Appendix B). All
of these cases involved subjects \>12 years of age. As shown in Table
B6, Appendix B, there were also 9 cases with a reason for exposure
categorized as "Other" (see definitions in Section 3, Figure 5). These
cases included 2 major effects, including one case categorized as
Malicious that involved a child under 6 years of age.

**4.2.4 Comparison of Hepatic Effect Cases for APAP-Containing Cough and
Cold Medications and Analgesics**

There were many more hepatic effect cases reported for the
APAP-containing analgesics than for the APAP-containing cough and cold
products, even when suicide attempts were excluded (see Figure 10
below). This large difference is not accounted for by the difference in
the number of total cases reported to poison control centers each year
for these two classes of products. The total number of cases reported
each year is 5 fold larger for the APAP-containing analgesic data set
(\~300,000 cases) compared to the APAP-containing cough and cold
medications data set (\~60,000 cases). However, there is a
disproportionately greater difference in the number of cases with
hepatic effects for the analgesic products versus the cough and cold
products across all reasons for exposure for both total hepatic effect
cases (\~34 fold difference) and for hepatic effect cases with serious
outcomes, i.e., deaths and major medical outcomes (\~40 fold
difference). These fold differences would become even larger if
duplicate cases (i.e., those found in both data sets because they
involved use of both a cough and cold product and an analgesic) were
eliminated from the cough and cold products data set (see footnotes to
Figure 10 for numbers of duplicate cases).

#### **Figure 10**

**Comparison of Hepatic Effect Cases**

**APAP-Containing Cough and Cold Products and Analgesics**

![](media/image5.wmf){width="5.802777777777778in"
height="4.094444444444444in"}**1998-2000**

######## 

######## **4.2.5 Demographics of Cases Involving Hepatic Effects**

Age and gender distribution were examined for hepatic effects cases
involving unintentional and intentional reasons for exposure (excluding
suicides), for adverse drug reactions, and for cases with unknown reason
for exposure (see Table 7 below). This analysis was completed only for
the year 2000. There appeared to be a trend for more females than males
involved across all reasons for exposure, although the magnitude of the
gender difference varied among individual categories of reason for
exposure.

**Table 7**

**APAP-Containing Analgesics**

### Demographics for Cases Involving Hepatic Effects

**2000**

+---------------------+-------+------+----------------+---------------+
| **Reason for        | ### N |      | **Mean Age     | **Gender**    |
| Exposure**          |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | SD (Range)**   |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 145   |      | 28.9           | 70M/75F       |
| General             |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 18.9 (1 day -- |               |
|                     |       |      | 83 yrs.)       |               |
+---------------------+-------+------+----------------+---------------+
| Therapeutic Error   | 52    |      | 46.5           | 24M/28F       |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 24.9 (1 day -- |               |
|                     |       |      | 89 yrs.)       |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 78    |      | 40.2           | 33M/45F       |
| Misuse              |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 17.6 (12-89    |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+
| Unintentional       | 17    |      | 39.4           | 4M/13F        |
| Unknown             |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 27.4 (3 -- 87  |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+
| **Total             | **    |      | # ND           | **131M/161F** |
| Unintentional**     | 292** |      |                |               |
+---------------------+-------+------+----------------+---------------+
| Intentional Misuse  | 189   |      | 37.6           | ### 70M/119F  |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 16.2 (12 - 85  |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+
| #######             | 84    |      | 34.9           | 35M/49F       |
| # Intentional Abuse |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 13.2 (10 -- 79 |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+
| Intentional Unknown | 54    |      | 37.8           | 23M/31F       |
|                     |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 17.7 (13 -- 85 |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+
| **Total             | **    |      | # ND           | **128M/199F** |
| Intentional\***     | 392** |      |                |               |
+---------------------+-------+------+----------------+---------------+
| ##### Ad            | 15    |      | 39.2           | ### 5M/10F    |
| verse Drug Reaction |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 25.2 (7 mo. -- |               |
|                     |       |      | 79 yrs.)       |               |
+---------------------+-------+------+----------------+---------------+
| #                   | 50    |      | 42.8           | ### 12M/38F   |
| #### Unknown Reason |       |      | [              |               |
|                     |       |      | +]{.underline} |               |
|                     |       |      | 17.5 (14 -- 83 |               |
|                     |       |      | yrs.)          |               |
+---------------------+-------+------+----------------+---------------+

\*Excludes suspected suicide attempts

ND -- Not Determined

**4.2.6 Products Involved in Hepatic Effect Cases - Analgesics (Tables
B12a,b-B20a,b, Appendix B)**

Tables B12a,b-B20a,b in Appendix B provide a detailed tabulation of the
types of products involved in hepatic effects cases for the analgesics
data set for the year 2000. The vast majority of cases (85-96%,
depending on the reason for exposure) involved the use of only one
APAP-containing analgesic product. There did not appear to be a trend
for use of more than one APAP-containing product to result in more
significant medical outcomes, but the numbers of cases involving more
than one product were relatively small. The products used are discussed
more thoroughly in Section 4.3 below where the data for hepatic effects
cases involving APAP-containing cough and cold medications and/or
APAP-containing analgesics are combined in order to evaluate the profile
of product use for all APAP-containing products.

**4.3 Products Involved in Hepatic Effect Cases -- All APAP-Containing
Products (Tables 8**

**and 8a)**

> A complete picture of hepatic effect cases for the year 2000 for all
> APAP-containing products (i.e., those found in either the
> APAP-containing analgesics data set or the APAP-containing cough and
> cold products data set) is presented in Table 8 below. Duplicate cases
> (i.e., those that were found in both data sets because they involved
> both an analgesic and a cough and cold medication) have been
> eliminated from this table. Across all reasons for exposure (excluding
> suicide attempts) over 90% of the cases involved the use of only one
> APAP-containing product, and in 65% of cases the product involved was
> a single ingredient OTC analgesic. Rx analgesic combination products
> accounted for 16% of cases across all reasons for exposure.
> Intentional abuse cases showed a higher percentage of cases involving
> an Rx combination analgesic (33%) and a lower percentage of cases
> involving a single ingredient OTC analgesic (42%) compared to all
> other reasons for exposure. Use of an APAP-containing OTC cough and
> cold product as the only APAP-containing product accounted for 2% of
> all cases. Less than 10% of cases involved concomitant use of more
> than one APAP-containing product. Among those cases, the concomitant
> use of a single ingredient OTC analgesic plus an Rx analgesic
> combination product was the most frequently reported (4% of cases).
> Two percent of cases (18 cases) involved the use of any two OTC
> APAP-containing products. The types of OTC products involved in these
> cases are shown in Table 8a. One percent of cases involved the use of
> two Rx analgesic combination products. Less than 1% of cases involved
> the use of three or more APAP-containing products, and none of these
> cases involved unintentional exposures.

# Table 8

# Acetaminophen-Containing Products Used in Cases With Hepatic Effects

**2000**

  ----------------- ------------ ----------- ------------ ------------ ------------- ---------- ----------- ----------- ------------ -----------
                    **No. of                                           **No. of                                         **No. of     
                    Cases (% of                                        Cases (% of                                      Cases (% of  
                    Cases)**                                           Cases)**                                         Cases)**     

  **Reason for      **One APAP                                         **Two APAP                                       **Three or   **Total**
  Exposure**        Product**                                          Products**                                       More APAP    
                                                                                                                        Products**   

                    Single       Rx          OTC Combo    OTC Combo    OTC           Any Two    Rx          Two Rx      Any Three or 
                    Ingredient   Analgesic   Not          Cough/Cold   Analgesic +   OTC        Analgesic   Analgesic   More         
                    OTC          Combo       Cough/Cold                Rx Analgesic  Products   Combo + Any Combos      Products     
                    Analgesic                                          Combo                    OTC Combo                            

  Unintentional     103 (70%)    16 (11%)    16 (11%)     2 (1%)       6 (4%)        1 (\<1%)   0           3 (2%)      0            147
  General                                                                                                                            

  Therapeutic Error 34 (61%)     9 (16%)     1 (2%)       3 (5%)       6 (11%)       1 (2%)     2 (4%)      0           0            56

  Unintentional     55 (68%)     6 (7%)      7 (8%)       3 (4%)       5 (6%)        5 (6%)     0           0           0            81
  Misuse                                                                                                                             

  Unintentional     13 (76%)     2 (12%)     1 (6%)       0            0             1 (6%)     0           0           0            17
  Unknown                                                                                                                            

  **Subtotal        **205        **33        **25 (8%)**  **8 (3%)**   **17 (6%)**   **8 (3%)** **2         **3 (2%)**  **0**        **301**
  Unintentional**   (68%)**      (11%)**                                                        (\<1%)**                             

  Intentional       136 (72%)    28 (15%)    7 (4%)       0            8 (4%)        5 (3%)     1 (\<1%)    2 (1%)      2 (1%)       189
  Misuse                                                                                                                             

  Intentional Abuse 37 (42%)     29 (33%)    9 (10%)      5 (6%)       2 (2%)        3 (3%)     1 (1%)      2 (2%)      1 (1%)       89

  Intentional       34 (63%)     9 (17%)     6 (11%)      0            0             2 (4%)     1 (2%)      1 (2%)      1 (2%)       54
  Unknown                                                                                                                            

  **Subtotal        **207        **66        **22 (7%)**  **5 (1.5%)** **10 (3%)**   **10       **3 (1%)**  **5         **4 (1%)**   **332**
  Intentional**     (62%)**      (20%)**                                             (3%)**                 (1.5%)**                 

  Adverse Drug      12 (80%)     2 (13%)     0            0            0             0          0           1 (7%)      0            15
  Reaction                                                                                                                           

  Unknown           31 (62%)     10 (20%)    7 (14%)      0            0             0          0           0           2 (4%)       50

  **Total**         **455        **111       **54 (8%)**  **13 (2%)**  **27 (4%)**   **18       **5         **9 (1%)**  **6 (\<1%)** **698**
                    (65%)**      (16%)**                                             (3%)**     (\<1%)**                             
  ----------------- ------------ ----------- ------------ ------------ ------------- ---------- ----------- ----------- ------------ -----------

**Table 8a**

**Acetaminophen-Containing Products Used in Cases with Hepatic Effects**

**That Involved Two OTC Products (Expanded From Table 8)**

+--------+------+---------+---------+--------+----------+-------+---+
|        | ##   |         |         |        |          |       |   |
|        | #### |         |         |        |          |       |   |
|        |  Num |         |         |        |          |       |   |
|        | ber  |         |         |        |          |       |   |
|        | of C |         |         |        |          |       |   |
|        | ases |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| **     | Two  | Single  | Single  | APAP   | Single   | Two   | T |
| Reason | Si   | Ing     | Ing     | /Other | In       | OTC   | o |
| for    | ngle | redient | redient | Active | gredient | Cough | t |
| Expo   | In   | OTC     | OTC     | C      | OTC      | /Cold | a |
| sure** | gred | Anal    | Anal    | ombo + | Ana      | C     | l |
|        | ient | gesic + | gesic + | AP     | lgesic + | ombos |   |
|        | OTC  | APA     | A       | AP/ASA | OTC      |       |   |
|        | An   | P/Other | PAP/ASA | Plus   | Co       |       |   |
|        | alge | Active  | Plus    | Other  | ugh/Cold |       |   |
|        | sics | Combo\* | Other   | Active | Combo    |       |   |
|        |      |         | Active  | Combo  |          |       |   |
|        |      |         | Co      |        |          |       |   |
|        |      |         | mbo\*\* |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| U      | 1    | 0       | 0       | 0      | 0        | 0     | 1 |
| ninten |      |         |         |        |          |       |   |
| tional |      |         |         |        |          |       |   |
| G      |      |         |         |        |          |       |   |
| eneral |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| Thera  | 0    | 0       | 0       | 0      | 0        | 1     | 1 |
| peutic |      |         |         |        |          |       |   |
| Error  |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| U      | 1    | 3       | 0       | 0      | 1        | 0     | 5 |
| ninten |      |         |         |        |          |       |   |
| tional |      |         |         |        |          |       |   |
| Misuse |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| U      | 0    | 0       | 0       | 0      | 1        | 0     | 1 |
| ninten |      |         |         |        |          |       |   |
| tional |      |         |         |        |          |       |   |
| U      |      |         |         |        |          |       |   |
| nknown |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| **Su   | *    | **3**   | **0**   | **0**  | **2**    | **1** | * |
| btotal | *2** |         |         |        |          |       | * |
| Uni    |      |         |         |        |          |       | 8 |
| ntenti |      |         |         |        |          |       | * |
| onal** |      |         |         |        |          |       | * |
+--------+------+---------+---------+--------+----------+-------+---+
| Inten  | 1    | 0       | 1       | 1      | 2        | 0     | 5 |
| tional |      |         |         |        |          |       |   |
| Misuse |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| Inten  | 0    | 0       | 3       | 0      | 0        | 0     | 3 |
| tional |      |         |         |        |          |       |   |
| Abuse  |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| Inten  | 0    | 0       | 1       | 1      | 0        | 0     | 2 |
| tional |      |         |         |        |          |       |   |
| U      |      |         |         |        |          |       |   |
| nknown |      |         |         |        |          |       |   |
+--------+------+---------+---------+--------+----------+-------+---+
| **Su   | *    | **0**   | **5**   | **2**  | **2**    | **0** | * |
| btotal | *1** |         |         |        |          |       | * |
| I      |      |         |         |        |          |       | 1 |
| ntenti |      |         |         |        |          |       | 0 |
| onal** |      |         |         |        |          |       | * |
|        |      |         |         |        |          |       | * |
+--------+------+---------+---------+--------+----------+-------+---+
| **T    | *    | **3**   | **5**   | **2**  | **4**    | **1** | * |
| otal** | *3** |         |         |        |          |       | * |
|        |      |         |         |        |          |       | 1 |
|        |      |         |         |        |          |       | 8 |
|        |      |         |         |        |          |       | * |
|        |      |         |         |        |          |       | * |
+--------+------+---------+---------+--------+----------+-------+---+

\*APAP/Other Active Combo -- A common example of products in this
category is an APAP/Diphenhydramine (i.e., Analgesic/Sleep Aid) combo.

\*\*APAP/ASA Plus Other Active Combo -- A common example of products in
this category is an APAP/Aspirin/Caffeine combination product

**4.4 Cough and Cold Medications Without Analgesic**

Data for cough and cold products without an analgesic were analyzed and
compared to the data for the APAP-containing cough and cold products in
order to assess the relative contribution of the presence of APAP to the
overall profile of toxicity for the latter. The cough and cold products
without an analgesic typically contain the same types of active
ingredients (e.g., decongestant, antihistamine, antitussive,
expectorant) as the APAP-containing cough and cold combinations except
that they do not contain APAP, aspirin, or any other analgesic.

**4.4.1 Medical Outcome and Reason for Exposure -- All Cases (Tables
C1-C4, Appendix C)**

There were a total of \~65,000-70,000 reports per year for products
included in this data set resulting in a total of over 200,000 cases
over the three year period. Similar to the APAP-containing cough and
cold medications, the majority of cases involved no clinical effects
(\~29%), minor effects (\~14%), or received no or minimal follow-up
because the quantities ingested were expected to result in no or minimal
clinical effects (\~49%). Serious medical outcomes (i.e., major effects
and deaths) accounted for \~0.2% of cases, and the majority of these
(\~72%) were associated with intentional exposures, predominantly
suicide attempts (see Table C1, Appendix C). These findings are
comparable to the profile for the APAP-containing cough and cold
products where \~0.3% of cases involved serious medical outcomes (see
Section 4.1.1).

The profile of reasons for exposure for the three different age ranges
evaluated (see Figure 11 below and Tables C2-C4, Appendix C) was
generally comparable to the APAP-containing cough and cold medications
(see Section 4.1.1). Among children \<6 years of age, unintentional
general cases (i.e., accidental ingestions) predominated (\~68% of
cases), and therapeutic error/unintentional misuse accounted for most of
the remaining cases (\~30%). Among children 6-12 years of age,
therapeutic errors/unintentional misuse were the most frequently
reported reason (\~65%), and unintentional general cases were the second
most frequently reported reason (\~29%). Among those age \>12 years,
therapeutic errors/unintentional misuse were more frequently reported
for the cough and cold medications without analgesic compared to the
APAP-containing cough and cold medications (\~41% vs. \~29%), and
suicide attempts were less frequently reported (\~22% vs. \~32%) (see
Figure 6, Section 4.1.1 and Figure 11 below).

###### Figure 11

#### **Cough and Cold Medications Without Analgesic**

#### **Reason for Exposure -- All Cases**

![](media/image6.wmf){width="7.552083333333333in" height="2.46875in"}

**4.4.2 Clinical Effects -- All Cases (Table C5, Appendix C)**

> The total number of clinical effects reported by body system was
> evaluated by broad category of reason for exposure (i.e.,
> unintentional, intentional, adverse drug reaction, other, unknown) and
> is summarized in Table 9 below. Only clinical effects judged by the
> poison control center to be related or of unknown relationship to the
> exposure were counted. Clinical effects judged by the poison control
> center to be not related to the exposure were excluded. For
> hepatic/hematological effects, only those effects that were reported
> in cases that did not involve concomitant exposure to an
> APAP-containing product were included. Cases that involved concomitant
> exposure to an APAP-containing product were excluded. The latter cases
> are captured in one or both of the other two data sets evaluated in
> this report.
>
> The most frequently reported clinical effects for the cough and cold
> medications without analgesic were similar to those reported for the
> APAP-containing cough and cold medications (see Section 4.1.2). These
> included drowsiness/lethargy (14.2% of cases), agitation/irritability
> (3.1%), tachycardia (2.6%), vomiting (2.1%), and dizziness/vertigo
> (1.8%) (see Table C5, Appendix C). Hepatic effects were extremely rare
> and were reported in only 13 cases (0.006%) after excluding cases that
> also involved an APAP-containing product (see Table C6, Appendix C).

**Table 9**

**Cough and Cold Medications Without Analgesic**

### Summary of Clinical Effects by Reason for Exposure

## **1998-2000 - All Ages**

+-----------------+----------+--------+------+------+-------+--------+
|                 | **Number |        |      |      |       |        |
|                 | of       |        |      |      |       |        |
|                 | Clinical |        |      |      |       |        |
|                 | E        |        |      |      |       |        |
|                 | ffects** |        |      |      |       |        |
+-----------------+----------+--------+------+------+-------+--------+
| **Body System** | *        | **Int  | *    | *    | *     | **T    |
|                 | *Uninten | ention | *Adv | *Oth | *Unkn | otal** |
|                 | tional** | al\*** | erse | er** | own** |        |
|                 |          |        | Drug |      |       | **(N=  |
|                 | **(      | **(N   | Re   | **(N | **(   | 206428 |
|                 | N=183868 | =16860 | acti | =348 | N=300 | Ca     |
|                 | Cases)** | Ca     | on** | Case | Cas   | ses)** |
|                 |          | ses)** |      | s)** | es)** |        |
|                 |          |        | *    |      |       |        |
|                 |          |        | *(N= |      |       |        |
|                 |          |        | 5052 |      |       |        |
|                 |          |        | Case |      |       |        |
|                 |          |        | s)** |      |       |        |
+-----------------+----------+--------+------+------+-------+--------+
| Cardiovascular  | 2582     | 5339   | 536  | 13   | 51    | 8521   |
+-----------------+----------+--------+------+------+-------+--------+
| Dermal          | 728      | 246    | 1029 | 1    | 11    | 2015   |
+-----------------+----------+--------+------+------+-------+--------+
| G               | 4827     | 3111   | 817  | 11   | 32    | 8798   |
| astrointestinal |          |        |      |      |       |        |
+-----------------+----------+--------+------+------+-------+--------+
| Hepatic/He      | 1        | 13     | 5    | 0    | 0     | 19     |
| matological\*\* |          |        |      |      |       |        |
+-----------------+----------+--------+------+------+-------+--------+
| Neurological    | 34012    | 9576   | 2605 | 30   | 168   | 46391  |
+-----------------+----------+--------+------+------+-------+--------+
| Ocular          | 1582     | 975    | 193  | 3    | 15    | 2768   |
+-----------------+----------+--------+------+------+-------+--------+
| Renal           | 43       | 82     | 32   | 0    | 2     | 159    |
+-----------------+----------+--------+------+------+-------+--------+
| Respiratory     | 333      | 319    | 186  | 1    | 10    | 849    |
+-----------------+----------+--------+------+------+-------+--------+
| Miscellaneous   | 3561     | 1801   | 941  | 11   | 29    | 6343   |
+-----------------+----------+--------+------+------+-------+--------+
| **Total Number  | *        | **2    | **63 | **   | **    | **7    |
| of Clinical     | *47672** | 1536** | 44** | 70** | 321** | 5943** |
| Effects**       |          |        |      |      |       |        |
+-----------------+----------+--------+------+------+-------+--------+

\*Includes suspected suicide attempts

\*\* Excludes cases that involved concomitant exposure to an
APAP-containing product

**4.4.3 Medical Outcome and Reason for Exposure - Hepatic Effect Cases
(Table C6-C7, Appendix C)**

> Although not expected with cough and cold medications without
> analgesic, 13 cases involving hepatic effects were reported after
> excluding cases with concomitant use of an APAP-containing product
> (Table C6, Appendix C). Approximately half of these (6/13) involved
> suspected suicide attempts. A listing of the 7 remaining cases
> involving hepatic effects that provides information on age, gender,
> medical outcome, reason for exposure, reported clinical effects, and
> substances used is found in Table C7, Appendix 3. These 7 cases
> included 2 deaths classified as intentional abuse cases and 1 major
> medical outcome classified as an adverse drug reaction. All three of
> these cases involved concomitant use of another drug which probably
> contributed to the major effect outcome or death.

**5. Discussion and Conclusions**

The use of AAPCC TESS data to evaluate post-marketing reports of
hepatotoxicity associated with the use of APAP-containing products
provides a valuable source of information to address questions related
to the root causes of these incidents. The AAPCC TESS database includes
all calls made to phones serving the general public at all poison
control centers participating in TESS. Based on information provided in
the annual reports published by the AAPCC, these poison control centers
serve approximately 96% of the US population (References 1-3).

One advantage offered by the AAPCC TESS data in addressed questions
related to APAP-related hepatotoxicity incidents is the use of
standardized definitions of reasons for exposure and medical outcome by
all participating poison control centers. Another advantage is that the
AAPCC TESS database includes all incidents that involve a call to a
public phone number at a poison control center and therefore is not
dependent upon voluntary reporting of the incident to the FDA or to the
manufacturer.

Limitations of the AAPCC TESS data must also be considered. As with
other post-marketing spontaneous adverse event reports, the accuracy of
the information on each AAPCC TESS case is dependent upon the person
calling the poison control center. The caller may be the subject
involved in the incident, a family member, a child care provider, a
health care professional involved in treating the subject, etc. Another
limitation is that information on the quantity of a drug or other
substance that has been consumed is not available via the standard
report format provided by the AAPCC TESS. From the AAPCC TESS
definitions of reason for exposure, it can be assumed that adverse drug
reactions involve the use of the recommended therapeutic dose, and all
other unintentional and intentional reasons for exposure involve the use
of more than the recommended therapeutic dose. However, the
classification of each case remains dependent upon the information
provided by the caller, which may or may not be accurate. Furthermore,
although a judgment is made by the poison control center staff regarding
whether the clinical effects reported by the caller are related, not
related, or of unknown relationship to the reported exposure, the
information collected by poison control centers is typically
insufficient to conduct a thorough assessment of causality ruling out
other possible causes. Nevertheless, despite these limitations, which
are common to most post-marketing surveillance systems, an analysis of
the AAPCC TESS data for APAP-containing products provides information
that is important to consider in determining how cases of
APAP-associated hepatotoxicity might be reduced.

Several observations can be made from the data presented in this report.
First, the vast majority of reported cases involved an APAP-containing
analgesic product. APAP-containing cough and cold medications were not
an important contributor to poison control center reports of
APAP-associated hepatotoxicity.

In depth analysis of products involved in cases reported in the year
2000 indicates that concomitant use of more than one APAP-containing
product was not a major root cause of incidents involving
hepatotoxicity. Most cases (\>90%) involved a single product, most
frequently an OTC analgesic (65% of cases). APAP-containing Rx
combination analgesics were the second most frequently reported product
category (16% of cases). Less than 10% of cases involved concomitant use
of more than one APAP-containing product. Among those cases, the
concomitant use of a single ingredient OTC analgesic plus an Rx
combination analgesic was the most frequently reported (4% of cases).
These data indicate that there are few incidents of hepatotoxicity
associated with multisymptom cough and cold medications containing APAP
even when considering the scenario of the use of more than one
APAP-containing product.

During the three year period evaluated there were no reported cases
involving hepatic effects with the use of an APAP-containing cough and
cold medication as recommended. Such cases would have been classified as
adverse drug reactions according to AAPCC TESS definitions, and none of
these were reported. There were a small number of adverse drug reactions
with hepatic effects reported for the APAP-containing analgesic products
(36 cases representing 0.01% of total cases). However, insufficient
information is available on these cases to conduct a thorough assessment
of causality ruling out other possible causes or to reliably document
whether or not the amount of APAP take was truly within the recommended
therapeutic dose.

A comparison of the APAP-containing cough and cold medications with the
cough and cold medications without analgesic indicates that both of
these sets of products present quite benign profiles with respect to
medical outcomes and clinical effects. Although the presence of APAP in
cough and cold medications was associated with some reports involving
hepatotoxicity, these were rare in comparison with the APAP-containing
analgesics. A small number of cases involving hepatic effects was also
reported for the cough and cold medications that do not contain an
analgesic, a finding which was unexpected based on the ingredients found
in these products. This could be attributable to the concomitant use of
other drugs or to other factors that cannot be explored due to the
limitations discussed previously that preclude a thorough assessment of
causality.

Taken as a whole, these data indicate that cases of hepatotoxicity
associated with APAP-containing products result from the intentional or
unintentional incorrect use of these products. Cases involving hepatic
effects with recommended therapeutic use are very rare and impossible to
confirm given the limitations inherent in data collection. Intentional
or unintentional incorrect use of these products can be addressed by
labeling changes and by public education programs that inform consumers
about products containing APAP and the potential for serious
consequences associated with overdosing.

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2.  Litovitz TL, Klein-Schwartz W, Shite S, Cobaugh DJ, Youniss J, Drab,
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3.  Litovitz TL, Klein-Schwartz W, White S, Cobaugh D, Youniss J,
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