[Federal Register Volume 64, Number 177 (Tuesday, September 14, 1999)]
[Rules and Regulations]
[Pages 49652-49655]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-23684]


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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 
(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 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 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.
    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 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.

    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