US Pharm.
2008;33(5):18-21.
Community pharmacists field
hundreds of self-care questions yearly on the topic of pain management. Many
concern minor pains, such as headaches, toothaches, and muscle pains. For this
reason, it is vital to understand the labeling of the various nonprescription
internal analgesic products and the decision points in recommending them. This
allows the pharmacist to identify appropriate products for each patient, as
well as to offer justifiable referrals to the physician or other prescriber
when the patient's situation requires it.
Age Limitations
There are several
age restrictions that must be considered when recommending internal analgesics.
1 The lowest age that is safe for self-care (without a physician
recommendation) varies according to the specific ingredient. For instance,
aspirin is contraindicated for those younger than 3 years of age. On the other
hand, acetaminophen (e.g., Tylenol), commonly abbreviated as APAP, can be
given down to the age of 2 years. Ibuprofen (e.g., Advil, Motrin) is safe for
patients as young as 6 months, unless the infant has a sore throat, when it
should not be given under the age of 3 years. However, naproxen (e.g., Aleve)
must not be recommended for self-care in patients under the age of 12 years.
Interestingly, ibuprofen products carry a warning against use for patients
over the age of 65 years, unless a physician advises them to do so.1
Several points are important
to consider in making age-specific recommendations. The specific dosage form
is also critical. For instance, although ibuprofen may be recommended down to
the age of 6 months, the only product to carry this labeling is infants'
concentrated drops (e.g., Infants' Motrin Concentrated Drops).1
Children's Motrin Suspension carries an age cut-off of 2 years (3 years for
sore throat).1 Thus, the pharmacist must scan each product label to
make sure it carries labeling appropriate for the age of the patient.
Another issue concerns that of
manufacturer-supplied pediatric dosing charts. For many years, various
manufacturers have created dosage charts purporting to allow pharmacists to
make dosing recommendations below the FDA-approved age cut-offs. In the case
of Tylenol, dosage charts suggested giving the products to patients as young
as 0 months of age, essentially to newborns.1 The FDA has never
approved labeling on acetaminophen packages for patients under the age of 2
years.2 Pharmacists should not rely on these unapproved doses and
should refer questions about dosing at these ages to the patient's physician.
Duration of the Pain
Another factor that
determines whether pain is self-treatable is how long it has lasted.
Generally, if pain has persisted for longer than 10 days in adults, the
patient should be referred to a physician.1 Pain may be
self-treated for five days in children, when using aspirin or acetaminophen,
but self-treatment in children is only safe for three days when ibuprofen is
used. However, if the pain is due to sore throat, the patient may only
self-treat for two days with any internal analgesic before a physician's
advice is required.1
Alcohol Use
All internal
analgesics warn against concurrent use with alcohol unless a physician is
consulted first. The exact wording is important: "Alcohol Warning: If you
consume 3 or more alcoholic drinks every day, ask your doctor whether you
should take [insert name of ingredient] or other pain relievers/fever
reducers."1 If the product contains aspirin, magnesium
salicylate, ibuprofen, or naproxen, the label states that stomach bleeding may
occur. If the product contains acetaminophen, the label states that
acetaminophen may cause liver damage. Thus, the pharmacist should strive to
discover whether the patient is a habitual, daily user of any type of
alcoholic beverage, stressing to these patients the risks associated with
unsupervised use of internal analgesics.
New FDA Labeling Proposals
As of this writing,
the most recent FDA action in regard to internal analgesics is a set of
proposed rules published in the Federal Register in December 2006, as a
result of a meeting held in September 2002.2 If these guidelines
are finalized, they will affect internal analgesic labeling in several
important ways. The FDA justified the proposed changes by describing the
accumulating mass of serious adverse event reports, such as unintentional
acetaminophen hepatotoxicity and nonsteroidal anti-inflammatory drug
(NSAID)–related gastrointestinal bleeding and renal toxicity. The agency
stressed that these events are rare in relation to their extensive use, but
also asserted that labeling changes could reduce morbidity.
Acetaminophen labeling was
scrutinized carefully. In the 2002 meeting, William M. Lee, MD, of
Southwestern Medical Center at Dallas explained that acetaminophen causes
1,000 to 2,000 cases of acute liver failure (ALF) yearly in the United States.
2 In a prospective study, he found that over 40% of cases of ALF were
caused by acetaminophen toxicity.2 Concurrent alcohol use was a
factor in over half of the cases.
FDA staff examined its adverse
event reporting system (AERS) for spontaneous reports of hepatotoxicity in
which one or more acetaminophen products had been ingested (without suicidal
intent), finding a total of 282 adult cases and 25 pediatric cases (patients
aged 1 day to 8 years) from January 1998 to July 2001.2
For pediatric cases where
gender was reported to the FDA's AERS system, 70% of the patients were males.
2 Fifteen of the 25 pediatric cases involved liver injury that was
severe and life-threatening. Ten of the 25 patients died and 21 required
hospitalization. The FDA mentioned a possible safe dose of APAP as 75
mg/kg/day. For 10 of the pediatric cases, the estimated doses administered
were 106 to 375 mg/kg/day. In 20 cases, one or more medication errors
contributed to the hepatotoxicity. In three, infants' concentrated drops were
given instead of the less concentrated children's liquid formulation. In four
cases, the dose was measured using household teaspoons rather than the
recommended measuring device.2
The lessons for pharmacists
are clear when selling these products for use in pediatric patients. It is
vital to stress to parents that dosing instructions must be followed exactly
and that the dropper or other dosage device that came with the product is the
only measuring device that can be safely used to deliver a dose. Furthermore,
parents must be taught to follow the age-related instructions without
deviation, using only the label on the specific product. Finally, they must be
taught that different products have different concentrations and that a given
volume of infants' concentrated drops contains a greater amount of APAP than
standard liquid children's formulations.
In adult cases reported to the
FDA's AERS system, 25% involved use of more than one APAP-containing product.
2 The typical scenario involved use of a narcotic/APAP combination along
with a nonprescription APAP product. Patients often exceeded maximum
recommended doses; the 65 patients with severe liver injury took an average of
7.1 g daily (as opposed to the FDA-approved maximum safe adult dose of 4 g
daily). One hundred and sixteen of the 282 cases involved alcohol use. It
reached the extent of abuse or overt alcoholism in 64 cases. Seventy-four
percent of the 116 patients developed severe liver injury.2
The lessons for pharmacists
are also quite clear for adult patients contemplating use of acetaminophen. At
the point of sale, pharmacists must stress not to combine the product with any
other analgesic containing APAP, to follow the dosing instructions exactly,
and to heed the alcohol warning on the label.
A manufacturer present at the
FDA meeting questioned the nature of APAP advertising. "Advertising portrays
acetaminophen as a totally safe ingredient. This portrayal may exacerbate use
and contribute to the silent danger resulting from overdose."2
Indeed, one company's Web site contains the following statement: "When taken
as directed, according to the package label and dosing instructions, Tylenol
(acetaminophen) does not cause liver damage."3 This statement
must be examined closely as it shifts the blame for liver damage to the
patient, clearly stating that following the label and dosing correctly will
invariably prevent liver damage.
Is the patient always at fault
when liver damage occurs, as the above statement implies? Part of this hinges
on the question, "Do patients risk liver damage with normal doses of APAP?"
The FDA stated: "Twenty-three of the 65 cases with severe liver injury
reported doses of less than 4 g/day."2 (The FDA-approved,
safe adult dose of APAP is 4 g daily.) The FDA also conducted an analysis of
APAP-associated hepatotoxicity cases, discovering that patients ingested more
than 4 g of APAP daily in 70% of cases; 32% ingested more than 10 g daily.
Apparently, 30% of patients experienced hepatotoxicity with the recommended
daily doses.2
The manufacturer must address
these cases in which patients apparently taking labeled doses of acetaminophen
nevertheless experienced liver damage. It should demonstrate in each case in
the FDA files how the patient was at fault; i.e., did not take the product
according to the package label. If each case of liver failure cannot be
explained in this manner, the manufacturer should modify its categorical
assertion of safety in regard to liver damage. If the manufacturer chooses to
responsibly undertake this examination of the serious liver injury cases, it
may help the FDA determine how to mandate more complete warning labels on APAP
packages in order to prevent liver damage to other patients.
As a result of the 2002
meeting, the FDA proposed to change APAP labeling to reduce the risk of
adverse events. The FDA would require a new liver warning for all
APAP-containing products. The agency would also remove the current alcohol
warning and incorporate a new alcohol warning in the proposed liver warning.
The following label modifications were proposed for adult acetaminophen
products:
"Liver warning: This product
contains acetaminophen. Severe liver damage may occur if you take:
•
More than [insert maximum number of daily dosage units] in 24 hours
•
With other drugs containing acetaminophen
•
Three or more alcoholic drinks every day while using this product
Do not use with any other drug containing
acetaminophen (prescription or nonprescription). Ask a doctor or pharmacist
before using with other drugs if you are not sure. Ask a doctor before use if
you have liver disease."2
The FDA's proposed changes would also
require that the ingredient acetaminophen be prominently identified on the
product's principal display panel of the immediate container as well as the
outer carton when applicable. These proposed updates should help both the
pharmacist and the patient to better understand the necessary precautions to
take when using OTC pain relievers.
REFERENCES
1. Pray WS.
Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott
Williams & Wilkins; 2006.
2. Internal analgesic,
antipyretic, and antirheumatic drug products for over-the-counter human use;
proposed amendment of the tentative final monograph; required warnings and
other labeling. Fed Regist. 2006;71:77314-77352.
3. Tylenol. Frequently
asked questions.
www.tylenol.com/print.jhtml?id=tylenol/headbody/exlpfaqprint.inc#3_f. Accessed
March 27, 2008.
4. Raymond J. Parents
say acet aminophen killed student. The Oklahoman. February 29,
2008:1-2.
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