[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR343.80]
[Page 253-259]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--Continued
PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents
Subpart C--Labeling
Sec. 343.80 Professional labeling.
The labeling of an over-the-counter drug product written for health
professionals (but not for the general public) shall consist of the
following:
(a) For products containing aspirin identified in Secs. 343.12 and
343.13 or permitted combinations identified in Sec. 343.22. (These
products must meet United States Pharmacopeia (USP) standards for
dissolution or drug release in Sec. 343.90.)
(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)
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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 (g/mL)),
approximately 90 percent of plasma salicylate is bound to albumin while
at higher concentrations (> 400 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 g/mL. Severe toxic effects are associated
with levels > 400 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 I2 (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
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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.
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.
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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.
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 g/mL) are effective. At high doses (i.e., plasma
levels of greater than 200 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.
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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 g/mL. Plasma concentrations of
aspirin above 300 g/mL are clearly toxic. Severe toxic effects
are associated with levels above 400 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
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anti-inflammatory efficacy with target plasma salicylate levels of 150-
300 g/mL. At high doses (i.e., plasma levels of greater than
200 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 g/mL. At high doses
(i.e., plasma levels of greater than 200 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 g/mL. At high doses
(i.e., plasma levels of greater than 200 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.
(2) In addition to, and immediately preceding, the labeling required
under paragraph (a)(1) of this section, the professional labeling may
contain the following highlights of prescribing information in the exact
language and exact format provided, but only when accompanied by the
comprehensive prescribing information required in paragraph (a)(1) of
this section.
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[GRAPHIC] [TIFF OMITTED] TR01DE98.008
(b) [Reserved]
[63 FR 56814, Oct. 23, 1998; 63 FR 66015, 66016, Dec. 1, 1998, as
amended at 64 FR 49653, Sept. 14, 1999]