[Federal Register: September 14, 1999 (Volume 64, Number 177)]
[Rules and Regulations]
[Page 49652-49655]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14se99-9]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 343
[Docket No. 77N-094A]
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products
for Over-the-Counter Human Use; Final Rule for Professional Labeling of
Aspirin, Buffered Aspirin, and Aspirin in Combination with Antacid Drug
Products; Technical Amendments
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule; technical amendments.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
regulations for internal analgesic, antipyretic, and antirheumatic drug
products for over-the-counter (OTC) use to correct inadvertent errors
and to clarify the labeling for over-the-counter drug products written
for health professionals.
EFFECTIVE DATE: The regulation is effective October 25, 1999.
FOR FURTHER INFORMATION CONTACT: Ida I. Yoder, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
[[Page 49653]]
SUPPLEMENTARY INFORMATION: FDA has discovered that inadvertent errors
were incorporated into the agency's regulations for internal analgesic,
antipyretic, and antirheumatic drug products (21 CFR part 343), that
published on October 23, 1998 (63 FR 56802). This document corrects
those errors and clarifies the labeling for over-the-counter drug
products written for health professionals. Publication of this document
constitutes final action under the Administrative Procedure Act (5
U.S.C. 553). FDA has determined that notice and public comment are
unnecessary because this amendment is nonsubstantive.
List of Subjects in 21 CFR Part 343
    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
343 is amended as follows:
PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
    1. The authority citation for 21 CFR part 343 continues to read as
follows:
    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 343.80 is amended by revising paragraph (a)(1) to read
as follows:
Sec. 343.80  Professional labeling.
    (a) * * *
    (1) The labeling contains the following prescribing information
under the heading ``Comprehensive Prescribing Information'' and the
subheadings ``Description,'' ``Clinical Pharmacology,'' ``Clinical
Studies,'' ``Animal Toxicology,'' ``Indications and Usage,''
``Contraindications,'' ``Warnings,'' ``Precautions,'' ``Adverse
Reactions,'' ``Drug Abuse and Dependence,'' ``Overdosage,'' ``Dosage
and Administration,'' and ``How Supplied'' in the exact language and
the exact order provided as follows:
COMPREHENSIVE PRESCRIBING INFORMATION
DESCRIPTION
    (Insert the proprietary name and the established name (if any)
of the drug, type of dosage form (followed by the phrase ``for oral
administration''), the established name(s) and quantity of the
active ingredient(s) per dosage unit, the total sodium content in
milligrams per dosage unit if the sodium content of a single
recommended dose is 5 milligrams or more, the established name(s)
(in alphabetical order) of any inactive ingredient(s) which may
cause an allergic hypersensitivity reaction, the pharmacological or
therapeutic class of the drug, and the chemical name(s) and
structural formula(s) of the drug.) Aspirin is an odorless white,
needle-like crystalline or powdery substance. When exposed to
moisture, aspirin hydrolyzes into salicylic and acetic acids, and
gives off a vinegary-odor. It is highly lipid soluble and slightly
soluble in water.
CLINICAL PHARMACOLOGY
Mechanism of Action
     Aspirin is a more potent inhibitor of both prostaglandin synthesis
and platelet aggregation than other salicylic acid derivatives. The
differences in activity between aspirin and salicylic acid are thought
to be due to the acetyl group on the aspirin molecule. This acetyl
group is responsible for the inactivation of cyclo-oxygenase via
acetylation.
Pharmacokinetics
    Absorption: In general, immediate release aspirin is well and
completely absorbed from the gastrointestinal (GI) tract. Following
absorption, aspirin is hydrolyzed to salicylic acid with peak plasma
levels of salicylic acid occurring within 1-2 hours of dosing (see
Pharmacokinetics--Metabolism). The rate of absorption from the GI
tract is dependent upon the dosage form, the presence or absence of
food, gastric pH (the presence or absence of GI antacids or
buffering agents), and other physiologic factors. Enteric coated
aspirin products are erratically absorbed from the GI tract.
    Distribution: Salicylic acid is widely distributed to all
tissues and fluids in the body including the central nervous system
(CNS), breast milk, and fetal tissues. The highest concentrations
are found in the plasma, liver, renal cortex, heart, and lungs. The
protein binding of salicylate is concentration-dependent, i.e.,
nonlinear. At low concentrations (< 100 micrograms/milliliter
(<greek-m>g/mL)), approximately 90 percent of plasma salicylate is
bound to albumin while at higher concentrations (> 400 <greek-m>g/
mL), only about 75 percent is bound. The early signs of salicylic
overdose (salicylism), including tinnitus (ringing in the ears),
occur at plasma concentrations approximating 200 <greek-m>g/mL.
Severe toxic effects are associated with levels > 400 <greek-m>g/mL.
(See Adverse Reactions and Overdosage.)
    Metabolism: Aspirin is rapidly hydrolyzed in the plasma to
salicylic acid such that plasma levels of aspirin are essentially
undetectable 1-2 hours after dosing. Salicylic acid is primarily
conjugated in the liver to form salicyluric acid, a phenolic
glucuronide, an acyl glucuronide, and a number of minor metabolites.
Salicylic acid has a plasma half-life of approximately 6 hours.
Salicylate metabolism is saturable and total body clearance
decreases at higher serum concentrations due to the limited ability
of the liver to form both salicyluric acid and phenolic glucuronide.
Following toxic doses (10-20 grams (g)), the plasma half-life may be
increased to over 20 hours.
    Elimination: The elimination of salicylic acid follows zero
order pharmacokinetics; (i.e., the rate of drug elimination is
constant in relation to plasma concentration). Renal excretion of
unchanged drug depends upon urine pH. As urinary pH rises above 6.5,
the renal clearance of free salicylate increases from < 5 percent to
> 80 percent. Alkalinization of the urine is a key concept in the
management of salicylate overdose. (See Overdosage.) Following
therapeutic doses, approximately 10 percent is found excreted in the
urine as salicylic acid, 75 percent as salicyluric acid, and 10
percent phenolic and 5 percent acyl glucuronides of salicylic acid.
Pharmacodynamics
    Aspirin affects platelet aggregation by irreversibly inhibiting
prostaglandin cyclo-oxygenase. This effect lasts for the life of the
platelet and prevents the formation of the platelet aggregating factor
thromboxane A2. Nonacetylated salicylates do not inhibit this enzyme
and have no effect on platelet aggregation. At somewhat higher doses,
aspirin reversibly inhibits the formation of prostaglandin
I<INF>2</INF> (prostacyclin), which is an arterial vasodilator and
inhibits platelet aggregation.
    At higher doses aspirin is an effective anti-inflammatory agent,
partially due to inhibition of inflammatory mediators via cyclo-
oxygenase inhibition in peripheral tissues. In vitro studies suggest
that other mediators of inflammation may also be suppressed by
aspirin administration, although the precise mechanism of action has
not been elucidated. It is this nonspecific suppression of cyclo-
oxygenase activity in peripheral tissues following large doses that
leads to its primary side effect of gastric irritation. (See Adverse
Reactions.)
CLINICAL STUDIES
    Ischemic Stroke and Transient Ischemic Attack (TIA): In clinical
trials of subjects with TIA's due to fibrin platelet emboli or
ischemic stroke, aspirin has been shown to significantly reduce the
risk of the combined endpoint of stroke or death and the combined
endpoint of TIA, stroke, or death by about 13-18 percent.
    Suspected Acute Myocardial Infarction (MI): In a large, multi-
center study of aspirin, streptokinase, and the combination of
aspirin and streptokinase in 17,187 patients with suspected acute
MI, aspirin treatment produced a 23-percent reduction in the risk of
vascular mortality. Aspirin was also shown to have an additional
benefit in patients given a thrombolytic agent.
    Prevention of Recurrent MI and Unstable Angina Pectoris: These
indications are supported by the results of six large, randomized,
multi-center, placebo-controlled trials of predominantly male post-
MI subjects and one randomized placebo-controlled study of men with
unstable angina pectoris. Aspirin therapy in MI subjects was
associated with a significant reduction (about 20 percent) in the
risk of the combined endpoint of subsequent death and/or nonfatal
reinfarction in these patients. In aspirin-treated unstable angina
patients the event rate was reduced to 5 percent from the 10 percent
rate in the placebo group.
[[Page 49654]]
    Chronic Stable Angina Pectoris: In a randomized, multi-center,
double-blind trial designed to assess the role of aspirin for
prevention of MI in patients with chronic stable angina pectoris,
aspirin significantly reduced the primary combined endpoint of
nonfatal MI, fatal MI, and sudden death by 34 percent. The secondary
endpoint for vascular events (first occurrence of MI, stroke, or
vascular death) was also significantly reduced (32 percent).
    Revascularization Procedures: Most patients who undergo coronary
artery revascularization procedures have already had symptomatic
coronary artery disease for which aspirin is indicated. Similarly,
patients with lesions of the carotid bifurcation sufficient to
require carotid endarterectomy are likely to have had a precedent
event. Aspirin is recommended for patients who undergo
revascularization procedures if there is a preexisting condition for
which aspirin is already indicated.
    Rheumatologic Diseases: In clinical studies in patients with
rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing
spondylitis and osteoarthritis, aspirin has been shown to be
effective in controlling various indices of clinical disease
activity.
ANIMAL TOXICOLOGY
    The acute oral 50 percent lethal dose in rats is about 1.5 g/
kilogram (kg) and in mice 1.1 g/kg. Renal papillary necrosis and
decreased urinary concentrating ability occur in rodents chronically
administered high doses. Dose-dependent gastric mucosal injury
occurs in rats and humans. Mammals may develop aspirin toxicosis
associated with GI symptoms, circulatory effects, and central
nervous system depression. (See Overdosage.)
INDICATIONS AND USAGE
    Vascular Indications (Ischemic Stroke, TIA, Acute MI, Prevention
of Recurrent MI, Unstable Angina Pectoris, and Chronic Stable Angina
Pectoris): Aspirin is indicated to: (1) Reduce the combined risk of
death and nonfatal stroke in patients who have had ischemic stroke
or transient ischemia of the brain due to fibrin platelet emboli,
(2) reduce the risk of vascular mortality in patients with a
suspected acute MI, (3) reduce the combined risk of death and
nonfatal MI in patients with a previous MI or unstable angina
pectoris, and (4) reduce the combined risk of MI and sudden death in
patients with chronic stable angina pectoris.
    Revascularization Procedures (Coronary Artery Bypass Graft
(CABG), Percutaneous Transluminal Coronary Angioplasty (PTCA), and
Carotid Endarterectomy): Aspirin is indicated in patients who have
undergone revascularization procedures (i.e., CABG, PTCA, or carotid
endarterectomy) when there is a preexisting condition for which
aspirin is already indicated.
    Rheumatologic Disease Indications (Rheumatoid Arthritis,
Juvenile Rheumatoid Arthritis, Spondyloarthropathies,
Osteoarthritis, and the Arthritis and Pleurisy of Systemic Lupus
Erythematosus (SLE)): Aspirin is indicated for the relief of the
signs and symptoms of rheumatoid arthritis, juvenile rheumatoid
arthritis, osteoarthritis, spondyloarthropathies, and arthritis and
pleurisy associated with SLE.
CONTRAINDICATIONS
    Allergy: Aspirin is contraindicated in patients with known
allergy to nonsteroidal anti-inflammatory drug products and in
patients with the syndrome of asthma, rhinitis, and nasal polyps.
Aspirin may cause severe urticaria, angioedema, or bronchospasm
(asthma).
    Reye's Syndrome: Aspirin should not be used in children or
teenagers for viral infections, with or without fever, because of
the risk of Reye's syndrome with concomitant use of aspirin in
certain viral illnesses.
WARNINGS
    Alcohol Warning: Patients who consume three or more alcoholic
drinks every day should be counseled about the bleeding risks
involved with chronic, heavy alcohol use while taking aspirin.
    Coagulation Abnormalities: Even low doses of aspirin can inhibit
platelet function leading to an increase in bleeding time. This can
adversely affect patients with inherited (hemophilia) or acquired
(liver disease or vitamin K deficiency) bleeding disorders.
    GI Side Effects: GI side effects include stomach pain,
heartburn, nausea, vomiting, and gross GI bleeding. Although minor
upper GI symptoms, such as dyspepsia, are common and can occur
anytime during therapy, physicians should remain alert for signs of
ulceration and bleeding, even in the absence of previous GI
symptoms. Physicians should inform patients about the signs and
symptoms of GI side effects and what steps to take if they occur.
    Peptic Ulcer Disease: Patients with a history of active peptic
ulcer disease should avoid using aspirin, which can cause gastric
mucosal irritation and bleeding.
PRECAUTIONS
General
    Renal Failure: Avoid aspirin in patients with severe renal
failure (glomerular filtration rate less than 10 mL/minute).
    Hepatic Insufficiency: Avoid aspirin in patients with severe
hepatic insufficiency.
    Sodium Restricted Diets: Patients with sodium-retaining states,
such as congestive heart failure or renal failure, should avoid
sodium-containing buffered aspirin preparations because of their
high sodium content.
Laboratory Tests
    Aspirin has been associated with elevated hepatic enzymes, blood
urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and
prolonged bleeding time.
Drug Interactions
    Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic
and hypotensive effects of ACE inhibitors may be diminished by the
concomitant administration of aspirin due to its indirect effect on
the renin-angiotensin conversion pathway.
    Acetazolamide: Concurrent use of aspirin and acetazolamide can
lead to high serum concentrations of acetazolamide (and toxicity)
due to competition at the renal tubule for secretion.
    Anticoagulant Therapy (Heparin and Warfarin): Patients on
anticoagulation therapy are at increased risk for bleeding because
of drug-drug interactions and the effect on platelets. Aspirin can
displace warfarin from protein binding sites, leading to
prolongation of both the prothrombin time and the bleeding time.
Aspirin can increase the anticoagulant activity of heparin,
increasing bleeding risk.
    Anticonvulsants: Salicylate can displace protein-bound phenytoin
and valproic acid, leading to a decrease in the total concentration
of phenytoin and an increase in serum valproic acid levels.
    Beta Blockers: The hypotensive effects of beta blockers may be
diminished by the concomitant administration of aspirin due to
inhibition of renal prostaglandins, leading to decreased renal blood
flow, and salt and fluid retention.
    Diuretics: The effectiveness of diuretics in patients with
underlying renal or cardiovascular disease may be diminished by the
concomitant administration of aspirin due to inhibition of renal
prostaglandins, leading to decreased renal blood flow and salt and
fluid retention.
    Methotrexate: Salicylate can inhibit renal clearance of
methotrexate, leading to bone marrow toxicity, especially in the
elderly or renal impaired.
    Nonsteroidal Anti-inflammatory Drugs (NSAID's): The concurrent
use of aspirin with other NSAID's should be avoided because this may
increase bleeding or lead to decreased renal function.
    Oral Hypoglycemics: Moderate doses of aspirin may increase the
effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
    Uricosuric Agents (Probenecid and Sulfinpyrazone): Salicylates
antagonize the uricosuric action of uricosuric agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility
     Administration of aspirin for 68 weeks at 0.5 percent in the
feed of rats was not carcinogenic. In the Ames Salmonella assay,
aspirin was not mutagenic; however, aspirin did induce chromosome
aberrations in cultured human fibroblasts. Aspirin inhibits
ovulation in rats. (See Pregnancy.)
Pregnancy
     Pregnant women should only take aspirin if clearly needed.
Because of the known effects of NSAID's on the fetal cardiovascular
system (closure of the ductus arteriosus), use during the third
trimester of pregnancy should be avoided. Salicylate products have
also been associated with alterations in maternal and neonatal
hemostasis mechanisms, decreased birth weight, and with perinatal
mortality.
Labor and Delivery
     Aspirin should be avoided 1 week prior to and during labor and
delivery because it can result in excessive blood loss at delivery.
Prolonged gestation and prolonged labor due to prostaglandin
inhibition have been reported.
[[Page 49655]]
Nursing Mothers
    Nursing mothers should avoid using aspirin because salicylate is
excreted in breast milk. Use of high doses may lead to rashes,
platelet abnormalities, and bleeding in nursing infants.
Pediatric Use
    Pediatric dosing recommendations for juvenile rheumatoid
arthritis are based on well-controlled clinical studies. An initial
dose of 90-130 mg/kg/day in divided doses, with an increase as
needed for anti-inflammatory efficacy (target plasma salicylate
levels of 150-300 <greek-m>g/mL) are effective. At high doses (i.e.,
plasma levels of greater than 200 <greek-m>g/mL), the incidence of
toxicity increases.
ADVERSE REACTIONS
    Many adverse reactions due to aspirin ingestion are dose-
related. The following is a list of adverse reactions that have been
reported in the literature. (See Warnings.)
    Body as a Whole: Fever, hypothermia, thirst.
    Cardiovascular: Dysrhythmias, hypotension, tachycardia.
    Central Nervous System: Agitation, cerebral edema, coma,
confusion, dizziness, headache, subdural or intracranial hemorrhage,
lethargy, seizures.
    Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic
acidosis, respiratory alkalosis.
    Gastrointestinal: Dyspepsia, GI bleeding, ulceration and
perforation, nausea, vomiting, transient elevations of hepatic
enzymes, hepatitis, Reye's Syndrome, pancreatitis.
    Hematologic: Prolongation of the prothrombin time, disseminated
intravascular coagulation, coagulopathy, thrombocytopenia.
    Hypersensitivity: Acute anaphylaxis, angioedema, asthma,
bronchospasm, laryngeal edema, urticaria.
    Musculoskeletal: Rhabdomyolysis.
    Metabolism: Hypoglycemia (in children), hyperglycemia.
    Reproductive: Prolonged pregnancy and labor, stillbirths, lower
birth weight infants, antepartum and postpartum bleeding.
    Respiratory: Hyperpnea, pulmonary edema, tachypnea.
    Special Senses: Hearing loss, tinnitus. Patients with high
frequency hearing loss may have difficulty perceiving tinnitus. In
these patients, tinnitus cannot be used as a clinical indicator of
salicylism.
    Urogenital: Interstitial nephritis, papillary necrosis,
proteinuria, renal insufficiency and failure.
DRUG ABUSE AND DEPENDENCE
    Aspirin is nonnarcotic. There is no known potential for
addiction associated with the use of aspirin.
OVERDOSAGE
    Salicylate toxicity may result from acute ingestion (overdose)
or chronic intoxication. The early signs of salicylic overdose
(salicylism), including tinnitus (ringing in the ears), occur at
plasma concentrations approaching 200 <greek-m>g/mL. Plasma
concentrations of aspirin above 300 <greek-m>g/mL are clearly toxic.
Severe toxic effects are associated with levels above 400
<greek-m>g/mL. (See Clinical Pharmacology.) A single lethal dose of
aspirin in adults is not known with certainty but death may be
expected at 30 g. For real or suspected overdose, a Poison Control
Center should be contacted immediately. Careful medical management
is essential.
    Signs and Symptoms: In acute overdose, severe acid-base and
electrolyte disturbances may occur and are complicated by
hyperthermia and dehydration. Respiratory alkalosis occurs early
while hyperventilation is present, but is quickly followed by
metabolic acidosis.
    Treatment: Treatment consists primarily of supporting vital
functions, increasing salicylate elimination, and correcting the
acid-base disturbance. Gastric emptying and/or lavage is recommended
as soon as possible after ingestion, even if the patient has vomited
spontaneously. After lavage and/or emesis, administration of
activated charcoal, as a slurry, is beneficial, if less than 3 hours
have passed since ingestion. Charcoal adsorption should not be
employed prior to emesis and lavage.
    Severity of aspirin intoxication is determined by measuring the
blood salicylate level. Acid-base status should be closely followed
with serial blood gas and serum pH measurements. Fluid and
electrolyte balance should also be maintained.
    In severe cases, hyperthermia and hypovolemia are the major
immediate threats to life. Children should be sponged with tepid
water. Replacement fluid should be administered intravenously and
augmented with correction of acidosis. Plasma electrolytes and pH
should be monitored to promote alkaline diuresis of salicylate if
renal function is normal. Infusion of glucose may be required to
control hypoglycemia.
    Hemodialysis and peritoneal dialysis can be performed to reduce
the body drug content. In patients with renal insufficiency or in
cases of life-threatening intoxication, dialysis is usually
required. Exchange transfusion may be indicated in infants and young
children.
DOSAGE AND ADMINISTRATION
    Each dose of aspirin should be taken with a full glass of water
unless patient is fluid restricted. Anti-inflammatory and analgesic
dosages should be individualized. When aspirin is used in high
doses, the development of tinnitus may be used as a clinical sign of
elevated plasma salicylate levels except in patients with high
frequency hearing loss.
    Ischemic Stroke and TIA: 50-325 mg once a day. Continue therapy
indefinitely.
    Suspected Acute MI: The initial dose of 160-162.5 mg is
administered as soon as an MI is suspected. The maintenance dose of
160-162.5 mg a day is continued for 30 days post-infarction. After
30 days, consider further therapy based on dosage and administration
for prevention of recurrent MI.
    Prevention of Recurrent MI: 75-325 mg once a day. Continue
therapy indefinitely.
    Unstable Angina Pectoris: 75-325 mg once a day. Continue therapy
indefinitely.
    Chronic Stable Angina Pectoris: 75-325 mg once a day. Continue
therapy indefinitely.
    CABG: 325 mg daily starting 6 hours post-procedure. Continue
therapy for 1 year post-procedure.
    PTCA: The initial dose of 325 mg should be given 2 hours pre-
surgery. Maintenance dose is 160-325 mg daily. Continue therapy
indefinitely.
    Carotid Endarterectomy: Doses of 80 mg once daily to 650 mg
twice daily, started presurgery, are recommended. Continue therapy
indefinitely.
    Rheumatoid Arthritis: The initial dose is 3 g a day in divided
doses. Increase as needed for anti-inflammatory efficacy with target
plasma salicylate levels of 150-300 <greek-m>g/mL. At high doses
(i.e., plasma levels of greater than 200 <greek-m>g/mL), the
incidence of toxicity increases.
    Juvenile Rheumatoid Arthritis: Initial dose is 90-130 mg/kg/day
in divided doses. Increase as needed for anti-inflammatory efficacy
with target plasma salicylate levels of 150-300 <greek-m>g/mL. At
high doses (i.e., plasma levels of greater than 200 <greek-m>g/mL),
the incidence of toxicity increases.
    Spondyloarthropathies: Up to 4 g per day in divided doses.
    Osteoarthritis: Up to 3 g per day in divided doses.
    Arthritis and Pleurisy of SLE: The initial dose is 3 g a day in
divided doses. Increase as needed for anti-inflammatory efficacy
with target plasma salicylate levels of 150-300 <greek-m>g/mL. At
high doses (i.e., plasma levels of greater than 200 m<greek-m>/mL),
the incidence of toxicity increases.
HOW SUPPLIED
    (Insert specific information regarding, strength of dosage form,
units in which the dosage form is generally available, and
information to facilitate identification of the dosage form as
required under Sec. 201.57(k)(1), (k)(2), and (k)(3).) Store in a
tight container at 25  deg.C (77  deg.F); excursions permitted to
15-30  deg.C (59-86  deg.F).
    REV: October 23, 1998.
    Dated: September 7, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-23684 Filed 9-13-99; 8:45 am]
BILLING CODE 4160-01-F