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Salicylates (Systemic)

This monograph includes information on the following:

1) Aspirin
2) Aspirin, Buffered
3) Choline Salicylate  
4) Choline and Magnesium Salicylates
5) Magnesium Salicylate
6) Salsalate
7) Sodium Salicylate

VA CLASSIFICATION
Aspirin
Tablets
Primary: CN103
Secondary: CN104; CN850; MS101 ; BL117

Chewable Tablets
Primary: CN103
Secondary: CN104; CN850; MS101; BL117

Chewing Gum Tablets
Primary: CN103

Delayed-release Tablets
Primary: CN103
Secondary: CN104; CN850; MS101; BL117

Extended-release Tablets
Primary: CN103
Secondary: CN104; CN850; MS101

Suppositories
Primary: CN103
Secondary: CN104; CN850; MS101


Aspirin and Caffeine
Primary: CN103
Secondary: CN104; CN850; MS101

Aspirin, Buffered
Primary: CN103
Secondary: CN104; CN850; MS101; BL117

Aspirin and Caffeine, Buffered
Primary: CN103
Secondary: CN104; CN850 ; MS101; BL117

Choline Salicylate
Primary: CN103
Secondary: CN104; CN850; MS101

Choline and Magnesium Salicylates
Primary: CN103
Secondary: CN104; CN850 ; MS101

Magnesium Salicylate
Primary: CN103
Secondary: CN104; CN850; MS101

Salsalate
Primary: MS101
Secondary: CN103; CN104; CN850

Sodium Salicylate
Primary: CN103
Secondary: CN104; CN850; MS101



Note: For information on a buffered aspirin product that is used for its antacid as well as its analgesic and antithrombotic effects, see Aspirin, Sodium Bicarbonate, and Citric Acid (Systemic) .

Commonly used brand name(s): 2171; 217 Strong1; Acuprin 811; Amigesic6; Anacin1; Anacin Caplets1; Anacin Extra Strength1; Anacin Maximum Strength1; Anacin Tablets1; Anaflex 7506; Antidol1; Apo-ASA1; Apo-ASEN1; Arco Pain Tablet1; Arthrisin1; Arthritis Pain Ascriptin2; Arthritis Pain Formula2; Arthritis Strength Bufferin2; Arthropan3; Artria S.R1; Aspergum1; Aspir-Low1; Aspirin Caplets1; Aspirin Children's Tablets1; Aspirin Plus Stomach Guard Extra Strength2; Aspirin Plus Stomach Guard Regular Strength2; Aspirin Regimen Bayer Adult Low Dose1; Aspirin Regimen Bayer Regular Strength Caplets1; Aspirin Tablets1; Aspirin, Coated1; Aspirtab1; Aspirtab-Max1; Astone1; Astrin1; Backache Caplets5; Bayer Children's Aspirin1; Bayer Select Maximum Strength Backache Pain Relief Formula5; Bufferin Caplets2; Bufferin Extra Strength Caplets2; Bufferin Tablets2; Buffex2; Buffinol2; Buffinol Extra2; C21; C2 Buffered2; CMT4; Calmine1; Cama Arthritis Pain Reliever2; Cope2; Coryphen1; Disalcid6; Doan's Backache Pills5; Doan's Regular Strength Tablets5; Dodd's Extra Strength7; Dodd's Pills7; Dolomine1; Easprin1; Ecotrin Caplets1; Ecotrin Tablets1; Empirin1; Entrophen 10 Super Strength Caplets1; Entrophen 15 Maximum Strength Tablets1; Entrophen Caplets1; Entrophen Extra Strength1; Entrophen Tablets1; Extended-release Bayer 8-Hour1; Extra Strength Bayer Arthritis Pain Formula Caplets1; Extra Strength Bayer Aspirin Caplets1; Extra Strength Bayer Aspirin Tablets1; Extra Strength Bayer Plus Caplets2; Gensan1; Genuine Bayer Aspirin Caplets1; Genuine Bayer Aspirin Tablets1; Gin Pain Pills7; Halfprin1; Headache Tablet1; Healthprin Adult Low Strength1; Healthprin Full Strength1; Healthprin Half-Dose1; Herbopyrine1; Instantine1; Kalmex1; Magan5; Magnaprin2; Marthritic6; Maximum Strength Arthritis Foundation Safety Coated Aspirin1; Maximum Strength Ascriptin2; Maximum Strength Doan's Analgesic Caplets5; Mobidin5; Mono-Gesic6; Nervine1; Norwich Aspirin1; Novasen1; Novasen Sp.C1; P-A-C Revised Formula1; PMS-ASA1; Pain Aid1; Regular Strength Ascriptin2; Salflex6; Salsitab6; Sero-Gesic5; Sloprin1; St. Joseph Adult Chewable Aspirin1; Tri-Buffered ASA2; Tricosal4; Trilisate4; ZORprin1.

Other commonly used names are
Acetylsalicylic Acid —Aspirin
ASA —Aspirin
Choline Magnesium Trisalicylate —Choline and Magnesium Salicylates
Salicylsalicylic Acid —Salsalate

  Aspirin is a brand name in Canada; acetylsalicylic acid is the generic name. ASA, a commonly used designation for aspirin (or acetylsalicylic acid) in both the U.S. and Canada, is the term used in Canadian product labeling.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:

Note: All of the salicylates have analgesic, anti-inflammatory, and antipyretic actions; however, clinical uses among specific agents or dosage formulations may vary because of actual pharmacokinetic differences, lack of specific testing, and/or lack of clinical-use data.



Analgesic—Aspirin; Aspirin, Buffered; Choline Salicylate; Choline and Magnesium Salicylates; Magnesium Salicylate; [Salsalate]; Sodium Salicylate;

Anti-inflammatory (nonsteroidal)—Aspirin; Aspirin, Buffered; Choline Salicylate; Choline and Magnesium Salicylates; Magnesium Salicylate; [Salsalate]; Sodium Salicylate;

Antipyretic—Aspirin; Aspirin, Buffered; Choline Salicylate; Choline and Magnesium Salicylates; [Magnesium Salicylate]; [Salsalate]; Sodium Salicylate;

Antirheumatic (nonsteroidal anti-inflammatory)—Aspirin; Aspirin, Buffered; Choline Salicylate; Choline and Magnesium Salicylates; Magnesium Salicylate; Salsalate; Sodium Salicylate;

Platelet aggregation inhibitor—Aspirin Tablets; Aspirin Tablets (Chewable); Aspirin Delayed-release Tablets; Aspirin, Buffered;

Antithrombotic—Aspirin Tablets; Aspirin Tablets (Chewable); Aspirin Delayed-release Tablets; Aspirin, Buffered;

Myocardial infarction prophylactic—Aspirin Tablets; Aspirin Tablets (Chewable); Aspirin Delayed-release Tablets; Aspirin, Buffered;

Myocardial reinfarction prophylactic—Aspirin Tablets; Aspirin Tablets (Chewable); Aspirin Delayed-release Tablets; Aspirin, Buffered;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Pain (treatment) or
Fever (treatment)—Salicylates are indicated to relieve mild to moderate pain such as headache, toothache, and menstrual cramps and to reduce fever. These medications provide only symptomatic relief; additional therapy to treat the cause of the pain or fever should be instituted when necessary. However, the presence of an illness that may predispose toward Reye"s syndrome (i.e., an acute febrile illness, especially influenza or varicella) should be ruled out before salicylate therapy is initiated in a pediatric or adolescent patient. {38} {39}
—Salicylates are recommended for relief of mild to moderate bone pain caused by metastatic neoplastic disease. However, careful patient selection is necessary, especially in patients receiving chemotherapy, because of the platelet aggregation–inhibiting effect of aspirin and because salicylates may cause hypoprothrombinemia or gastrointestinal or renal toxicity. {30} {40}
—Delayed-release formulations containing aspirin or sodium salicylate may not be as useful as immediate-release formulations for single-dose administration for analgesia or antipyresis because the delayed absorption prolongs the onset of action.

Note: The FDA has proposed that caffeine (present as an analgesic adjuvant in some aspirin products) be classified as a Category III ingredient (i.e., lacking documentation of efficacy) in OTC analgesic/antipyretic medications. {01}


Inflammation, nonrheumatic (treatment)—Salicylates are indicated to relieve myalgia, musculoskeletal pain, and other symptoms of nonrheumatic inflammatory conditions such as athletic injuries, bursitis, capsulitis, tendinitis, and nonspecific acute tenosynovitis.

Arthritis, rheumatoid (treatment)
Arthritis, juvenile (treatment) or
Osteoarthritis (treatment)—Salicylates are indicated for the symptomatic relief of acute and chronic rheumatoid arthritis, juvenile arthritis, osteoarthritis, and related rheumatic diseases. Aspirin is usually the first agent to be used and may be the drug of choice in patients able to tolerate prolonged therapy with high doses. These agents do not affect the progressive course of rheumatoid arthritis.
—Concurrent treatment with a glucocorticoid or a disease-modifying antirheumatic agent may be needed, depending on the condition being treated and patient response.
—[Salicylates are also used to reduce arthritic complications associated with systemic lupus erythematosus.]

Rheumatic fever (treatment)—Salicylates are indicated to reduce fever and inflammation in rheumatic fever. However, they do not prevent cardiac or other complications associated with this condition. Sodium salicylate should be avoided in rheumatic fever if congestive cardiac complications are present because of its sodium content. Also, large doses of any salicylate should be avoided in rheumatic fever if severe carditis is present because of possible adverse cardiovascular effects.

Platelet aggregation (prophylaxis)—Aspirin (tablets, chewable tablets, delayed-release capsules or tablets, and buffered formulations) is indicated as a platelet aggregation inhibitor in the following:
Ischemic attacks, transient, in males (prophylaxis)
Thromboembolism, cerebral (prophylaxis) or
[Thromboembolism, cerebral, recurrence (prophylaxis)]1—Aspirin is indicated in the treatment of men who have had transient brain ischemia due to fibrin platelet emboli to reduce the recurrence of transient ischemic attacks (TIAs) and the risk of stroke and death. {01}
—[Aspirin is also used in the treatment of women with transient brain ischemia due to fibrin platelet emboli. However, its efficacy in preventing stroke and death in female patients has not been established. ]1
—[Aspirin is also indicated in the treatment of patients with documented, unexplained TIAs associated with mitral valve prolapse. However, if TIAs continue to occur after an adequate trial of aspirin therapy, aspirin should be discontinued and an oral anticoagulant administered instead.]1 {02}
—[Aspirin is also indicated to prevent initial or recurrent cerebrovascular embolism, TIAs, and stroke following carotid endarterectomy. ] {03} {07}
—[Aspirin is indicated in the treatment of patients who have had a completed thrombotic stroke, to prevent a recurrence.]1 {04}

Myocardial infarction (prophylaxis) or
Myocardial reinfarction (prophylaxis)—Aspirin is indicated to prevent myocardial infarction in patients with unstable angina pectoris and to prevent recurrence of myocardial infarction in patients with a history of myocardial infarction. {01} {05} {07}
—In one study, aspirin significantly reduced the rate of reocclusion, reinfarction, stroke, and death when a single dose was administered within a few hours after the onset of symptoms of acute myocardial infarction and daily thereafter. The benefit of early treatment with aspirin was additive to that of streptokinase. Therefore, it is recommended that aspirin therapy be initiated as soon as possible after the onset of symptoms, even if the patient is receiving thrombolytic therapy. {06} {09}
—[One study has shown that aspirin may also prevent myocardial infarction in individuals 50 years of age and older who have no history of unstable angina pectoris or myocardial infarction. However, the incidence of hemorrhagic stroke (but not the total number of hemorrhagic plus thrombotic strokes) was slightly increased in subjects receiving aspirin. Also, the incidence of myocardial infarction, although higher in the placebo group than in the aspirin group, was low in both groups. Therefore, aspirin"s benefit in apparently healthy individuals has not been established. However, aspirin may be indicated for prevention of an initial myocardial infarction in selected patients, especially those who may be at risk because of the presence of chronic stable coronary artery disease (as shown by exertional or episodic angina pectoris, abnormal coronary arteriogram, or positive stress test) and/or other risk factors.]1 {05}

[Thromboembolism (prophylaxis)]—Aspirin is used in low doses to decrease the risk of thromboembolism following orthopedic (hip) surgery (especially total hip replacement) and in patients with arteriovenous shunts. {15}
—Platelet aggregation inhibitors, although not as consistently effective as an anticoagulant or an anticoagulant plus dipyridamole, may provide some protection against the development of thromboembolic complications in patients with mechanical prosthetic heart valves. Therefore, administration of aspirin, alone or in combination with dipyridamole, may be considered if anticoagulant therapy is contraindicated for these patients. {06} Patients with bioprosthetic cardiac valves who are in normal sinus rhythm generally do not require prolonged antithrombotic therapy, but long-term aspirin administration may be considered on an individual basis.1 {06}
—Aspirin is also indicated, alone1 or in combination with dipyridamole, to reduce the risk of thrombosis and/or reocclusion of saphenous vein aortocoronary bypass grafts following coronary bypass surgery. {06} {08}
—Aspirin is also indicated, alone or in combination with dipyridamole, to reduce the risk of thrombosis and/or reocclusion of prosthetic or saphenous vein femoral popliteal bypass grafts.1 {03}
—Because the patient may be at risk for thromboembolic complications, including myocardial infarction and stroke, long-term aspirin therapy may also be indicated for maintaining patency following coronary or peripheral vascular angioplasty and for treating patients with peripheral vascular insufficiency caused by arteriosclerosis.1 {03}
—Prolonged antithrombotic therapy is generally not needed to maintain vessel patency following vascular reconstruction procedures in high-flow, low-resistance arteries larger than 6 mm in diameter. However, long-term aspirin therapy may be indicated, because patients requiring such procedures may be at risk for other thrombotic complications.1 {03}

[Kawasaki disease (treatment)]1—Aspirin is indicated for its anti-inflammatory, antipyretic, and antithrombotic effects in the treatment of Kawasaki disease (Kawasaki syndrome, mucocutaneous lymph node syndrome) in children. {10} {11} {12} {13} {14} {28} {41} It reduces fever, relieves inflammation (e.g., lymphadenitis, mucositis, conjunctivitis, serositis), {10} {11} {12} {13} {14} {28} and may reduce the occurrence of cardiovascular complications. {10} {14} However, the combination of high-dose intravenous gamma globulin and aspirin has been shown to be more effective than aspirin alone in reducing the formation of coronary artery abnormalities. {12} {13} {42}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Note: Aspirin is an acetylated salicylate; the other salicylates are nonacetylated.

Molecular weight—
{16}    Aspirin: 180.16
    Choline salicylate: 241.29
    Magnesium salicylate: 370.60 (tetrahydrate); 298.53 (anhydrous)
    Salsalate: 258.23
    Sodium salicylate: 160.11

pKa—
    Aspirin: 3.5

Note: The other salicylates are also acidic.


Mechanism of action/Effect:

The analgesic, antipyretic, and anti-inflammatory effects of aspirin are due to actions by both the acetyl and the salicylate portions of the intact molecule as well as by the active salicylate metabolite. The actions of other salicylates are due only to the salicylate portion of the molecule. Aspirin directly inhibits the activity of the enzyme cyclo-oxygenase to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Salicylate may competitively inhibit prostaglandin formation. {21} {43} Although many of the therapeutic and adverse effects of these medications may result from inhibition of prostaglandin synthesis (and consequent reduction of prostaglandin activity) in various tissues, other actions may also contribute significantly to the therapeutic effects.


Analgesic:

Salicylates: Produce analgesia through a peripheral action by blocking pain impulse generation and via a central action, possibly in the hypothalamus. The peripheral action may predominate and probably involves inhibition of the synthesis of prostaglandins, and possibly inhibition of the synthesis and/or actions of other substances, which sensitize pain receptors to mechanical or chemical stimulation.

Caffeine: A mild central nervous system (CNS) stimulant. Caffeine-induced constriction of cerebral blood vessels, which leads to a decrease in cerebral blood flow and in the oxygen tension of the brain, may contribute to relief of some types of headache. It has been suggested that the addition of caffeine to aspirin may provide a more rapid onset of action and/or enhanced pain relief with lower doses of analgesic. However, the FDA has determined that studies performed to date have not demonstrated that caffeine is an effective analgesic adjuvant or that it does not interfere with aspirin's efficacy as an antipyretic. {01}



Anti-inflammatory (nonsteroidal):

Exact mechanisms have not been determined. Salicylates may act peripherally in inflamed tissue, probably by inhibiting the synthesis of prostaglandins and possibly by inhibiting the synthesis and/or actions of other mediators of the inflammatory response. Inhibition of leukocyte migration, inhibition of the release and/or actions of lysosomal enzymes, and actions on other cellular and immunological processes in mesenchymal and connective tissues may be involved.



Antipyretic:

May produce antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation resulting in increased cutaneous blood flow, sweating, and heat loss. The central action may involve inhibition of prostaglandin synthesis in the hypothalamus; however, there is some evidence that fevers caused by endogenous pyrogens that do not act via a prostaglandin mechanism may also respond to salicylate therapy.



Antirheumatic (nonsteroidal anti-inflammatory):

Act via analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation.



Platelet aggregation inhibitor:

The platelet aggregation–inhibiting effect of aspirin specifically involves the compound's ability to act as an acetyl donor to the platelet membrane; the nonacetylated salicylates have no clinically significant effect on platelet aggregation. Aspirin affects platelet function by inhibiting the enzyme prostaglandin cyclooxygenase in platelets, thereby preventing the formation of the aggregating agent thromboxane A 2. This action is irreversible; the effects persist for the life of the platelets exposed. Aspirin may also inhibit formation of the platelet aggregation inhibitor prostacyclin (prostaglandin I 2) in blood vessels; however, this action is reversible. These actions may be dose-dependent. Although there is some evidence that doses lower than 100 mg per day may not inhibit prostacyclin synthesis, optimum dosage that will suppress thromboxane A 2 formation without suppressing prostacyclin generation has not been determined.



Other actions/effects:

It is proposed that the gastrointestinal toxicity of salicylates, especially aspirin, may be caused primarily by reduction of the activity of prostaglandins (which exert a protective effect on the gastrointestinal mucosa) because upper gastrointestinal toxicity has been reported following rectal or parenteral administration of nonsteroidal anti-inflammatory drugs. However, when administered orally, these acidic medications (unless administered in an enteric-coated formulation) probably also exert a direct irritant or erosive effect on the mucosa. {17}

Absorption:


Salicylates:

Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used, dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH.

Food decreases the rate, but not the extent, of absorption.

Absorption from enteric-coated formulations is generally delayed.

Absorption of aspirin from the chewing gum tablet is incomplete as compared with absorption from the oral tablet.

Following rectal administration of aspirin, absorption is delayed and incomplete as compared with absorption following oral administration of equal doses.

Absorption of aspirin is impaired during the early febrile stage of Kawasaki disease, then increases toward normal in the convalescent stage. {28}



Caffeine:

Well absorbed from the gastrointestinal tract.


Distribution:


In breast milk:

Aspirin: Peak salicylate concentrations of 173 to 483 mcg per mL have been measured 5 to 8 hours after maternal ingestion of a single 650-mg dose.

Sodium salicylate: A total of 3 to 4 mg of salicylate is excreted following maternal ingestion of a single dose of 20 mg per kg of body weight (mg/kg).


Protein binding:

Salicylate—High (to albumin); decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration or renal dysfunction, and during pregnancy.

Caffeine—Low.

Biotransformation:

Salicylate compounds are largely hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, which is further metabolized primarily in the liver.

Caffeine—Hepatic.

Half-life:


Aspirin:

15 to 20 minutes (for intact molecule); rapidly hydrolyzed to salicylate.

In breast milk (as salicylate)—3.8 to 12.5 hours (average 7.1 hours) following a single 650-mg dose of aspirin.



Salicylate:

Dependent on dose and on urinary pH; about 2 to 3 hours with low or single doses and 20 hours or longer with very high doses; with repeated dosing using antirheumatic doses, may range from 5 to 18 hours.



Caffeine:

3 to 4 hours.


Time to peak plasma concentration

Generally 1 to 2 hours with single doses; may be more rapid with liquid dosage forms; may be delayed with salsalate (as compared with aspirin) or with delayed-release tablet or capsule formulations.

Time to steady-state plasma concentration

Increases as daily dosage and plasma concentrations are increased; with large (antirheumatic) doses of aspirin, may require up to 7 days.

Therapeutic plasma concentration


Salicylate:

Analgesic and antipyretic: 25 to 50 mcg per mL (2.5 to 5 mg per 100 mL); these concentrations are generally reached with single analgesic/antipyretic doses.

Anti-inflammatory/antirheumatic: 150 to 300 mcg per mL (15 to 30 mg per 100 mL). Steady-state plasma concentrations within this range are usually reached with therapeutic antirheumatic doses. However, because of interindividual differences in salicylate kinetics, wide variations in steady-state plasma concentrations may be produced in different patients by the same dose. Also, with large or repeated doses, major metabolic pathways become saturated; small changes in dosage may result in large changes in plasma concentration.


Time to peak effect

Antirheumatic—May require 2 to 3 weeks or more of continuous therapy.

Elimination:


Aspirin and salicylate salts—
        Renal; primarily as free salicylic acid and conjugated metabolites.



Salsalate—
        About 13% of a dose excreted as conjugated salsalate; small amounts also excreted unchanged. The remainder of the dose is excreted as free or conjugated salicylate.

Note: Total salicylate excretion does not increase proportionately with dose, but excretion of unmetabolized salicylic acid is increased with higher doses; also, there are large interindividual differences in elimination kinetics. In addition, the rate of excretion of total salicylate and the quantity of free salicylic acid eliminated are increased in alkaline urine and decreased in acidic urine.




In dialysis—Salicylate—
        Hemodialysis—Clearances of 35 to 100 mL per minute have been reported.
        Peritoneal dialysis—Removed more slowly than with hemodialysis; clearances of 45 to 90 mL per hour have been reported in infants.
        Caffeine—Renal; primarily as metabolites. About 1 to 2% of a dose is excreted unchanged. {22}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one salicylate, including methyl salicylate (oil of wintergreen), or to other nonsteroidal anti-inflammatory drugs (NSAIDs) may be sensitive to other salicylates also.

Patients sensitive to aspirin may not necessarily be sensitive to nonacetylated salicylates.

Patients sensitive to tartrazine dye may be sensitive to aspirin also, and vice versa.

Cross-sensitivity between aspirin and other NSAIDs that results in bronchospastic or cutaneous reactions may be eliminated if the patient undergoes a desensitization procedure (See General Dosing Information ).

Patients sensitive to other xanthines (aminophylline, dyphylline, oxtriphylline, theobromine, theophylline) may be sensitive to caffeine also. {22}

Pregnancy/Reproduction
Fertility—
Salicylates have caused increased numbers of fetal resorptions in animal studies.

Pregnancy—

First trimester

For salicylates—Salicylates readily cross the placenta. Although it has been reported that salicylate use during pregnancy may increase the risk of birth defects in humans, controlled studies using aspirin have not shown proof of teratogenicity. Studies in humans with other salicylates have not been done. Studies in animals have shown that salicylates cause birth defects including fissure of the spine and skull; facial clefts; eye defects; and malformations of the CNS, viscera, and skeleton (especially the vertebrae and ribs). (Aspirin extended-release tablets: FDA Pregnancy Category D; {37} Magnesium salicylate and salsalate: FDA Pregnancy Category C.)

For caffeine—Caffeine crosses the placenta and achieves blood and tissue concentrations similar to maternal concentrations. Studies in humans have not shown that caffeine causes birth defects. However, studies in animals have shown that caffeine causes skeletal abnormalities in the digits and phalanges (when given in doses equivalent to the caffeine content of 12 to 24 cups of coffee daily throughout pregnancy or when given in very large single doses, i.e., 50 to 100 mg per kg of body weight [mg/kg]) and retarded skeletal development (when given in lower doses).



Third trimester

Chronic, high-dose salicylate therapy may result in prolonged gestation, increased risk of postmaturity syndrome (fetal damage or death due to decreased placental function if pregnancy is greatly prolonged), and increased risk of maternal antenatal hemorrhage. Also, ingestion of salicylates, especially aspirin, during the last 2 weeks of pregnancy may increase the risk of fetal or neonatal hemorrhage. The possibility that regular use late in pregnancy may result in constriction or premature closure of the fetal ductus arteriosus, possibly leading to persistent pulmonary hypertension and heart failure in the neonate, must also be considered. Overuse or abuse of aspirin late in pregnancy has been reported to increase the risk of stillbirth or neonatal death, possibly because of antenatal hemorrhage or premature ductus arteriosus closure, and to decrease birthweight; however, studies using therapeutic doses of aspirin have not shown these adverse effects. Pregnant women should be advised not to take aspirin during the last trimester of pregnancy unless such therapy is prescribed and monitored by a physician. {44}



Labor and delivery—

Chronic, high-dose salicylate therapy late in pregnancy may result in prolonged labor, complicated deliveries, and increased risk of maternal or fetal hemorrhage.

Breast-feeding


For salicylates:

Problems in humans with usual analgesic doses have not been documented. However, salicylate is distributed into breast milk; with chronic, high-dose use, intake by the infant may be high enough to cause adverse effects.

In one study, peak salicylate concentrations of 173 to 483 mcg per mL were measured in breast milk 5 to 8 hours after maternal ingestion of a single dose of 650 mg of aspirin. The half-life in breast milk was 3.8 to 12.5 hours (average 7.1 hours).

Following maternal ingestion of 20 mg/kg of sodium salicylate, a total of 3 to 4 mg of salicylate is distributed into breast milk.



For caffeine:

Caffeine is distributed into breast milk in very small amounts; at recommended dosages, concentration in the infant is considered to be insignificant.


Pediatrics


For salicylates:

Aspirin use may be associated with the development of Reye's syndrome in children and teenagers with acute febrile illnesses, especially influenza and varicella. It is recommended that salicylate therapy not be initiated in febrile pediatric or adolescent patients until after the presence of such an illness has been ruled out. Also, it is recommended that chronic salicylate therapy in these patients be discontinued if a fever occurs, and not resumed until it has been determined that an illness that may predispose to Reye's syndrome is not present or has run its course. {38} Other forms of salicylate toxicity may also be more prevalent in pediatric patients, especially children who have a fever or are dehydrated.

Especially careful monitoring of the serum salicylate concentration is recommended in pediatric patients with Kawasaki disease. Absorption of aspirin is impaired during the early febrile stage of the disease; therapeutic anti-inflammatory plasma salicylate concentrations may be extremely difficult to achieve. Also, as the febrile stage passes, absorption is improved; salicylate toxicity may occur if dosage is not readjusted. {28} {46}



For caffeine:

Pediatric patients are especially susceptible to overdose of caffeine and its adverse CNS effects. {22} {47}



Geriatrics


Geriatric patients may be more susceptible to the toxic effects of salicylates, possibly because of decreased renal function. Lower doses than those usually recommended for adults, especially for long-term use or for use of long-acting salicylates (such as choline and magnesium salicylates and salsalate), may be required.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
In addition to the interactions listed below, the possibility should be considered that additive or multiple effects leading to impaired blood clotting and/or increased risk of bleeding may occur if a salicylate, especially aspirin, is used concurrently with any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.


For all salicylates
Acetaminophen    (prolonged concurrent use of acetaminophen with a salicylate is not recommended because chronic, high-dose administration of the combined analgesics [1.35 grams daily, or cumulative ingestion of 1 kg annually, for 3 years or longer] significantly increases the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal disease, and cancer of the kidney or urinary bladder; also, it is recommended that for short-term use the combined dose of acetaminophen plus a salicylate not exceed that recommended for acetaminophen or a salicylate given individually)


Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid (Vitamin C)
Potassium or sodium phosphates    (acidification of the urine by these medications decreases salicylate excretion, leading to increased salicylate plasma concentrations; initiation of therapy with these medications in patients stabilized on a salicylate may lead to toxic salicylate concentrations)

    (aspirin may increase urinary excretion of ascorbic acid; clinical significance is unclear, but some clinicians recommend ascorbic acid supplementation in patients receiving prolonged high-dose aspirin therapy)


Alcohol or
» Nonsteroidal anti-inflammatory drugs (NSAIDs), other    (concurrent use of these medications with a salicylate may increase the risk of gastrointestinal side effects, including ulceration and gastrointestinal blood loss; also, concurrent use of a salicylate with an NSAID may increase the risk of severe gastrointestinal side effects without providing additional symptomatic relief and is therefore not recommended)

    (aspirin may decrease the bioavailability of many NSAIDs, including diflunisal, fenoprofen, indomethacin, meclofenamate, piroxicam [to 80% of the usual plasma concentration], and the active sulfide metabolite of sulindac; aspirin has also been shown to decrease the protein binding and increase the plasma clearance of ketoprofen, and to decrease the formation and excretion of ketoprofen conjugates)

    (concurrent use of other NSAIDs with aspirin may also increase the risk of bleeding at sites other than the gastrointestinal tract because of additive inhibition of platelet aggregation)


» Alkalizers, urinary, such as:
Carbonic anhydrase inhibitors
Citrates
Sodium bicarbonate or
Antacids, chronic high-dose use, especially calcium- and/or magnesium-containing    (alkalinization of the urine by these medications increases salicylate excretion, leading to decreased salicylate plasma concentrations, reduced effectiveness, and shortened duration of action; also, withdrawal of a urinary alkalizer from a patient stabilized on a salicylate may increase the plasma salicylate concentration to a toxic level; however, the antacids present in buffered aspirin formulations may not be present in sufficient quantity to alkalinize the urine)

    (metabolic acidosis induced by carbonic anhydrase inhibitors may increase penetration of salicylate into the brain and increase the risk of salicylate toxicity in patients taking large [antirheumatic] doses of salicylate; if acetazolamide is used to produce forced alkaline diuresis in the treatment of salicylate poisoning, the increased risk of severe metabolic acidosis and increased salicylate toxicity must be considered and an alkaline intravenous solution given concurrently)


» Anticoagulants, coumarin- or indandione-derivative or
» Heparin or
» Thrombolytic agents, such as:
Alteplase
Anistreplase
Streptokinase
Urokinase    (salicylates may displace a coumarin- or indandione-derivative anticoagulant from its protein-binding sites, and, in high doses, may cause hypoprothrombinemia, leading to increased anticoagulation and risk of bleeding)

    (the potential occurrence of gastrointestinal ulceration or hemorrhage during salicylate, especially aspirin, therapy may cause increased risk to patients receiving anticoagulant or thrombolytic therapy)

    (because aspirin-induced inhibition of platelet function may lead to prolonged bleeding time and increased risk of hemorrhage, concurrent use of aspirin with an anticoagulant or a thrombolytic agent is recommended only within a carefully monitored antithrombotic regimen; although a recent study has shown that initiation of therapy with 160 mg of aspirin a day concurrently with short-term [1-hour] intravenous infusion of streptokinase in patients with acute coronary arterial occlusion significantly decreases the risk of reocclusion, reinfarction, stroke, and death without increasing the risk of adverse effects [as compared with streptokinase alone], other studies using higher doses of aspirin and/or more prolonged administration of a thrombolytic agent have demonstrated an increased risk of bleeding)


Anticonvulsants, hydantoin    (salicylates may decrease hydantoin metabolism, leading to increases in hydantoin plasma concentrations, efficacy, and/or toxicity; adjustment of hydantoin dosage may be required when chronic salicylate therapy is initiated or discontinued {23} {48})


» Antidiabetic agents, oral or
Insulin    (effects of these medications may be increased by large doses of salicylates; dosage adjustments may be necessary; potentiation of oral antidiabetic agents may be caused partially by displacement from serum proteins; glipizide and glyburide, because of their nonionic binding characteristics, may not be affected as much as the other oral agents; however, caution in concurrent use is recommended)


Antiemetics, including antihistamines and phenothiazines    (antiemetics may mask the symptoms of salicylate-induced ototoxicity, such as dizziness, vertigo, and tinnitus)


Bismuth subsalicylate    (ingestion of large repeated doses as for traveler's diarrhea may produce substantial plasma salicylate concentrations; concurrent use with large doses of analgesic salicylates may increase the risk of salicylate toxicity)


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin or
» Valproic acid    (these medications may cause hypoprothrombinemia; in addition, plicamycin or valproic acid may inhibit platelet aggregation; concurrent use with aspirin may increase the risk of bleeding because of additive interferences with blood clotting)

    (hypoprothrombinemia induced by large doses of salicylates, and the potential occurrence of gastrointestinal ulceration or hemorrhage during salicylate, especially aspirin, therapy, may increase the risk of bleeding complications in patients receiving these medications)

    (concurrent use of aspirin with valproic acid has also been reported to increase the plasma concentration of valproic acid and induce valproic acid toxicity {29} {48})


Corticosteroids or
Corticotropin (ACTH), chronic therapeutic use of    (corticosteroids or corticotropin may increase salicylate excretion, resulting in lower plasma concentrations and increased salicylate dosage requirements; salicylism may result when corticosteroids or corticotropin dosage is subsequently decreased or discontinued, especially in patients receiving large [antirheumatic] doses of salicylate; also, the risk of gastrointestinal side effects, including ulceration and gastrointestinal blood loss, may be increased; however, concurrent use in the treatment of arthritis may provide additive therapeutic benefit and permit reduction of corticosteroid or corticotropin dosage)

    (because corticosteroids and corticotropin may cause sodium and fluid retention, caution in concurrent use with large doses of sodium salicylate is recommended)


Furosemide    (in addition to increasing the risk of ototoxicity, concurrent use of furosemide with high doses of salicylate may lead to salicylate toxicity because of competition for renal excretory sites)


Laxatives, cellulose-containing    (concurrent use may reduce the salicylate effect because of physical binding or other absorptive hindrance; medications should be administered 2 hours apart)


» Methotrexate    (salicylates may displace methotrexate from its binding sites and decrease its renal clearance, leading to toxic methotrexate plasma concentrations; if they are used concurrently, methotrexate dosage should be decreased, the patient observed for signs of toxicity, and/or methotrexate plasma concentration monitored; also, it is recommended that salicylate therapy be discontinued 24 to 48 hours prior to administration of a high-dose methotrexate infusion, and not resumed until the plasma methotrexate concentration has decreased to a nontoxic level [usually at least 12 hours postinfusion])


Ototoxic medications, other (See Appendix II ), especially
» Vancomycin    (concurrent or sequential administration of these medications with a salicylate should be avoided because the potential for ototoxicity may be increased; hearing loss may occur and may progress to deafness even after discontinuation of the medication; these effects may be reversible, but usually are permanent)


» Platelet aggregation inhibitors (See Appendix II )    (concurrent use with aspirin is not recommended, except in a monitored antithrombotic regimen, because the risk of bleeding may be increased)

    (the potential occurrence of gastrointestinal ulceration or hemorrhage during salicylate therapy, and the hypoprothrombinemic effect of large doses of salicylate, may cause increased risk to patients receiving a platelet aggregation inhibitor {48} {49})


» Probenecid or
» Sulfinpyrazone    (concurrent use of a salicylate is not recommended when these medications are used to treat hyperuricemia or gout, because the uricosuric effect of these medications may be decreased by doses of salicylates that produce serum salicylate concentrations above 5 mg per 100 mL; also, these medications may inhibit the uricosuric effect achieved when serum salicylate concentrations are above 10 to 15 mg per 100 mL)

    (probenecid may decrease renal clearance and increase plasma concentrations and toxicity of salicylates)

    (sulfinpyrazone may decrease salicylate excretion and/or displace salicylate from its protein binding sites, possibly leading to increased salicylate concentrations and toxicity)

    (although low doses of sulfinpyrazone and aspirin have been used concurrently to provide additive inhibition of platelet aggregation, the efficacy of the combination has not been established and the increased risk of bleeding must be considered; also, concurrent use of sulfinpyrazone with aspirin may increase the risk of gastrointestinal ulceration or hemorrhage)


Salicylic acid or other salicylates, topical    (concurrent use with systemic salicylates may increase the risk of salicylate toxicity if significant quantities are absorbed)


Vitamin K    (requirements for this vitamin may be increased in patients receiving high doses of salicylate)


Zidovudine    (in theory, aspirin may competitively inhibit the hepatic glucuronidation and decrease the clearance of zidovudine, leading to potentiation of zidovudine toxicity; the possibility must be considered that aspirin toxicity may also be increased)


For buffered aspirin formulations, choline and magnesium salicylates, and magnesium salicylate (in addition to those interactions listed above as applying to all salicylates) {50}
» Ciprofloxacin or{15}
» Enoxacin or{16}
» Itraconazole or{17}
» Ketoconazole or{18}
» Lomefloxacin or{24}
» Norfloxacin or{111}
» Ofloxacin or{112}
» Tetracyclines, oral{18}    (antacids present in buffered aspirin formulations, and the magnesium in choline and magnesium salicylates or magnesium salicylate, interfere with absorption of these medications; if used concurrently, the interacting salicylate should be taken at least 6 hours before or 2 hours after ciprofloxacin or lomefloxacin, 8 hours before or 2 hours after enoxacin, 2 hours after itraconazole, 3 hours before or after ketoconazole, 2 hours before or after norfloxacin or ofloxacin, and 3 to 4 hours before or after a tetracycline)


For enteric-coated formulations (in addition to those interactions listed above as applying to all salicylates)
Antacids or
Histamine H 2-receptor antagonists    (concurrent administration of these medications, which increase intragastric pH, with an enteric-coated medication may cause premature dissolution, and loss of the protective effect, of the enteric coating)


For formulations containing caffeine (in addition to those interactions listed above as applying to all salicylates)
CNS stimulation–producing medications, other (See Appendix II )    (concurrent use with caffeine may result in excessive CNS stimulation, which may cause unwanted effects such as nervousness, irritability, insomnia, or possibly convulsions or cardiac arrhythmias; close observation is recommended)


Lithium    (caffeine increases urinary excretion of lithium, thereby possibly reducing its therapeutic effect)


Monoamine oxidase (MAO) inhibitors, including furazolidone, pargyline, and procarbazine    (concurrent use of large amounts of caffeine with MAO inhibitors may produce dangerous cardiac arrhythmias or severe hypertension because of the sympathomimetic side effects of caffeine)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results

For all salicylates:
Copper sulfate urine sugar tests    (false-positive test results may occur with chronic use of salicylates in doses equivalent in salicylate content to 2.4 grams or more of aspirin a day, i.e., 3.2 grams of choline salicylate, 2.4 grams of choline and magnesium salicylates, 2 grams of magnesium salicylate, 1.8 grams of salsalate, or 2.4 grams of sodium salicylate a day)


Gerhardt test for urine aceto-acetic acid    (interference may occur because reaction with ferric chloride produces a reddish color that persists after boiling)


Glucose enzymatic urine sugar tests    (false-negative test results may occur with chronic use of salicylates in doses equivalent in salicylate content to 2.4 grams or more of aspirin a day, i.e., 3.2 grams of choline salicylate, 2.4 grams of choline and magnesium salicylates, 2 grams of magnesium salicylate, 1.8 grams of salsalate, or 2.4 grams of sodium salicylate a day)


Renal function test using phenolsulfonphthalein (PSP)    (salicylate may competitively inhibit renal tubular secretion of PSP, thereby decreasing urinary PSP concentration and invalidating test results)


Serum uric acid determinations    (falsely increased values may occur with colorimetric assay methods when plasma salicylate concentrations exceed 13 mg per 100 mL; the uricase assay method is not affected)


Thyroid imaging, radionuclide    (chronic salicylate administration may depress thyroid function; salicylate therapy should be discontinued at least 1 week prior to administration of the radiopharmaceutical; however, a rebound effect may occur following discontinuation of salicylate therapy, resulting in a period of 3 to 10 days of increased thyroidal uptake {26} {51})


Urine vanillylmandelic acid (VMA) determinations    (values may be falsely increased or decreased, depending on method used)


For aspirin only (in addition to those interferences listed above for all salicylates):
Protirelin-induced thyroid-stimulating hormone (TSH) release determinations    (TSH response to protirelin may be decreased by 2 to 3.6 grams of aspirin daily; peak TSH concentrations occur at the same time after administration, but are reduced {25} {51})


Urine 5-hydroxyindoleacetic acid (5-HIAA) determinations    (aspirin may alter results when fluorescent method is used)


For caffeine-containing formulations (in addition to the diagnostic interferences listed above):
Myocardial perfusion imaging, radionuclide, when adenosine or dipyridamole is used as an adjunct to the radiopharmaceutical    (caffeine may reverse the effects of adenosine or dipyridamole on myocardial blood flow, thereby interfering with test results; patients should be advised to avoid caffeine for at least 8 to 12 hours prior to the test {27} {51})

With physiology/laboratory test values

For all salicylates
Liver function tests, including:
Serum alanine aminotransferase (ALT [SGPT]) and
Serum alkaline phosphatase and
Serum aspartate aminotransferase (AST [SGOT])    (abnormalities may occur, especially in patients with juvenile rheumatoid arthritis, systemic lupus erythematosus, or pre-existing history of liver disease, or when plasma salicylate concentrations exceed 25 mg per 100 mL; liver function test values may return to normal despite continued use or when dosage is decreased; however, if severe abnormalities occur, or if there is evidence of active liver disease, the medication should be discontinued and used with caution in the future)


Prothrombin time    (may be prolonged with large doses of salicylates, especially if plasma concentrations exceed 30 mg per 100 mL)


Serum cholesterol concentrations    (may be decreased by chronic use of salicylates in doses equivalent in salicylate content to 5 grams or more of aspirin per day, i.e., 6.7 grams of choline salicylate, 5 grams of choline and magnesium salicylates, 4.1 grams of magnesium salicylate, 3.8 grams of salsalate, or 5 grams of sodium salicylate a day)


Serum potassium concentrations    (may be decreased because of increased potassium excretion caused by direct effect on renal tubules)


Serum thyroxine (T 4) concentrations and
Serum triiodothyronine (T 3) concentrations    (may be decreased when determined by radioimmunoassay—with large doses of salicylates)


Serum uric acid concentrations    (may be increased or decreased, depending on salicylate dosage; plasma salicylate concentrations below 10 to 15 mg per 100 mL increase serum uric acid concentrations and higher plasma salicylate concentrations decrease uric acid concentrations)


T 3 resin uptake    (may be increased with large doses of salicylates)


For aspirin only (in addition to the interferences listed above)
Bleeding time    (may be prolonged by aspirin for 4 to 7 days because of suppressed platelet aggregation; as little as 40 mg of aspirin affects platelet function for at least 96 hours following administration; however, clinical bleeding problems have not been reported with small doses [150 mg or less])


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For all salicylates:
» Bleeding ulcers or
» Hemorrhagic states, other active    (may be exacerbated, especially by aspirin)


» Hemophilia or other bleeding problems, including coagulation or platelet function disorders    (increased risk of hemorrhage, especially with aspirin)


For aspirin only (in addition to the contraindications listed above for all salicylates):
» Angioedema, anaphylaxis, or other severe sensitivity reaction induced by aspirin or other NSAIDs, history of or
» Nasal polyps associated with asthma, induced or exacerbated by aspirin    (high risk of severe sensitivity reaction to aspirin)


» Thrombocytopenia    (increased risk of bleeding because aspirin inhibits platelet aggregation)


For choline and magnesium salicylates and for magnesium salicylate only (in addition to the contraindications listed above for all salicylates):
» Renal insufficiency, chronic advanced    (risk of hypermagnesemic toxicity)


Risk-benefit should be considered when the following medical problems exist

For all salicylates:
Anemia    (may be exacerbated by gastrointestinal blood loss during salicylate, especially aspirin, therapy; also, salicylate-induced peripheral vasodilation may lead to pseudoanemia)


Conditions predisposing to fluid retention, such as:
Compromised cardiac function or
Hypertension    (in patients with carditis, high doses of salicylates may precipitate congestive heart failure or pulmonary edema)

    (patients with congestive heart disease may be more susceptible to adverse renal effects)

    (sodium content of sodium salicylate may be detrimental to these patients when large doses are administered chronically)


» Gastritis, erosive or
» Peptic ulcer    (may be exacerbated because of ulcerogenic effects, especially with aspirin; risk of gastrointestinal bleeding is increased)


Gout    (salicylates may increase serum uric acid concentrations and may interfere with efficacy of uricosuric agents)


Hepatic function impairment    (salicylates metabolized hepatically; also, patients with decompensated hepatic cirrhosis may be more susceptible to adverse renal effects)

    (in severe hepatic impairment, inhibition of platelet function by aspirin may increase the risk of hemorrhage)


Hypoprothrombinemia or
Vitamin K deficiency    (increased risk of bleeding because of antiplatelet action of aspirin and the hypoprothrombinemic effect of high doses of salicylates)


Renal function impairment    (salicylate elimination may be reduced; also, the risk of renal adverse effects may be increased)

    (choline and magnesium salicylates or magnesium salicylate should be used with caution in patients with mild or moderate renal impairment because of the risk of hypermagnesemic toxicity; however, as stated above, these medications should not be used if chronic advanced renal insufficiency is present)


Sensitivity reaction, mild, to aspirin or other NSAIDs, history of    (risk of sensitivity reaction, especially with aspirin)


Symptoms of nasal polyps associated with bronchospasm, or angioedema, anaphylaxis, or other severe allergic reactions induced by aspirin or other NSAIDs    (although cross-sensitivity leading to severe reactions occurs very rarely with the nonacetylated salicylates, caution is recommended; however, as indicated above, aspirin should not be used)


Thyrotoxicosis    (may be exacerbated by large doses)


For aspirin only (in addition to those listed above for all salicylates):
» Asthma    (increased risk of bronchospastic sensitivity reaction)


Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (rarely, aspirin has caused hemolytic anemia in these patients)


For formulations containing caffeine {37}:
Cardiac disease, severe    (high doses of caffeine may increase risk of tachycardia or extrasystoles, which may lead to heart failure)


Sensitivity to caffeine, history of    (risk of allergic reaction)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For all salicylates
Hematocrit determinations    (may be required at periodic intervals during prolonged high-dose therapy because of the possibility of gastrointestinal blood loss, especially with aspirin)


Hepatic function determinations    (may be required prior to initiation of antirheumatic therapy and if symptoms of hepatotoxicity occur during therapy; salicylate-induced hepatotoxicity may be especially likely to occur in patients, especially children, with rheumatic fever, systemic lupus erythematosus, juvenile arthritis, or pre-existing hepatic disease)


Serum salicylate concentrations    (monitoring required at periodic intervals during prolonged high-dose therapy as a guide to dosage, safety, and efficacy, especially in children; because aspirin absorption in children with Kawasaki disease is erratic and varies at different stages of the disease, monitoring of plasma salicylate concentration in these patients is critical {28})


For choline and magnesium salicylates and magnesium salicylate only (in addition to those listed above for all salicylates)
Serum magnesium concentration    (monitoring recommended during therapy with large doses in patients with renal insufficiency because of the possibility of hypermagnesemic toxicity)




Side/Adverse Effects

Note: Salicylates may decrease renal function, especially when serum salicylate concentrations reach 250 mcg per mL (25 mg per 100 mL). However, the risk of complications due to this action appears minimal in patients with normal renal function.
Aspirin-induced bronchospasm is most likely to occur in patients with the triad of asthma, allergies, and nasal polyps induced by aspirin. Nonacetylated salicylates may rarely cause bronchospastic reactions in susceptible people when very large doses are given.
Angioedema or urticaria may be more likely to occur in patients with a history of recurrent idiopathic angioedema or urticaria.
Gastrointestinal side effects are more likely to occur with aspirin than with other salicylates; also, they may be more likely to occur with chronic, high-dose administration than with occasional use. Use of enteric-coated formulations may reduce the potential for gastrointestinal side effects.
Adverse effects are more likely to occur at serum salicylate concentrations of 300 mcg per mL (30 mg per 100 mL) or above; however, they may also occur at lower serum concentrations, especially in patients 60 years of age or older. Serum concentrations at which adverse or toxic effects have been reported during chronic therapy include:

Salicylate
Concentration
(mcg per mL/
mg per 100 mL)
Effect
195–210/
19.5–21
Mild toxicity (tinnitus, decreased hearing)
250/25
Hepatotoxicity (abnormal liver function tests)
250/25
Decreased renal function
300/30
Decreased prothrombin time
310/31
Deafness
350/35
Hyperventilation
> 400/40
Metabolic acidosis, other signs of severe toxicity


The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Anaphylactoid reaction (bluish discoloration or flushing or redness of skin; coughing; difficulty in swallowing; dizziness or feeling faint, severe; skin rash, hives [may include giant urticaria], and/or itching; stuffy nose; swelling of eyelids, face, or lips; tightness in chest, troubled breathing, and/or wheezing, especially in asthmatic patients)
    
anemia (unusual tiredness or weakness)—for aspirin or buffered aspirin only; may occur secondary to gastrointestinal microbleeding
    
anemia, hemolytic (troubled breathing, exertional; unusual tiredness or weakness)—reported with aspirin only, almost always in patients with glucose-6-phosphate (G6PD) deficiency{35}{52}
    
bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
    
dermatitis, allergic (skin rash, hives, or itching)
    
gastrointestinal ulceration, possibly with bleeding (bloody or black, tarry stools; stomach pain, severe; vomiting of blood or material that looks like coffee grounds)

Incidence unknown
    
Rectal irritation —for aspirin suppository dosage form



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent with aspirin; less frequent with enteric-coated or buffered formulations and with other salicylates
    
Gastrointestinal irritation (mild stomach pain; heartburn or indigestion; nausea with or without vomiting){53}

Incidence less frequent
For caffeine-containing formulations
    
CNS stimulation (trouble in sleeping, nervousness, or jitters)






Overdose
For specific information on the agents used in the management of salicylate overdose, see:
   • Vitamin K 1—Phytonadione in Vitamin K (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
Mild overdose
    
Salicylism (Continuing ringing or buzzing in ears or hearing loss; confusion; severe or continuing diarrhea, stomach pain, and or headache; dizziness or lightheadedness; severe drowsiness; fast or deep breathing; continuing nausea and/or vomiting; uncontrollable flapping movements of the hands, especially in elderly patients; increased thirst; vision problems)—tinnitus and/or headache may be the earliest symptoms of salicylism

Severe overdose
    
Bloody urine
convulsions
hallucinations
severe nervousness, excitement, or confusion
shortness of breath or troubled breathing
unexplained fever


Note: In young children, the only signs of an overdose may be changes in behavior, severe drowsiness or tiredness, and/or fast or deep breathing.
Laboratory findings in overdose may indicate encephalographic abnormalities, alterations in acid-base balance (especially respiratory alkalosis and metabolic acidosis), hyperglycemia or hypoglycemia (especially in children), ketonuria, hyponatremia, hypokalemia, and proteinuria.



Treatment of overdose
To decrease absorption—Emptying the stomach via induction of emesis (taking care to guard against aspiration) {54} or gastric lavage.

Administering activated charcoal.

To enhance elimination—Inducing forced alkaline diuresis to increase salicylate excretion. However, bicarbonate should not be administered orally for this purpose because salicylate absorption may be increased. Also, if acetazolamide is used, the increased risk of severe metabolic acidosis and salicylate toxicity (caused by increased penetration of salicylate into the brain because of metabolic acidosis) must be considered. Some emergency care practitioners recommend that acetazolamide not be used at all in the treatment of salicylate overdose. {21} Others state that acetazolamide may be used, provided that precautions are taken to prevent systemic metabolic acidosis, such as concurrent administration of an alkaline intravenous solution, e.g., one that contains sodium bicarbonate or sodium lactate. {34}

Institution of exchange transfusion, hemodialysis, peritoneal dialysis, or hemoperfusion as needed in severe overdose.

Specific treatment—Administering blood or vitamin K 1 if necessary to treat hemorrhaging.

Monitoring—Monitoring for pulmonary edema and convulsions and instituting appropriate therapy if required.

Monitoring serum salicylate concentration until it is apparent that the concentration is decreasing to the nontoxic range. When a large single dose of an immediate-release formulation has been ingested, salicylate {55} concentrations of 500 mcg per mL (50 mg per 100 mL; 3.62 mmol/L) 2 hours after ingestion indicate serious toxicity; salicylate concentrations above 800 mcg per mL (80 mg per 100 mL; 5.79 mmol/L) 2 hours after ingestion indicate possible fatality. In addition, prolonged monitoring may be necessary in massive overdosage because absorption may be delayed; if a determination performed prior to 6 hours after ingestion fails to show a toxic salicylate concentration, the determination should be repeated. {31} Although the following values are not reliable for predicting the severity of toxicity after chronic or repeated ingestions, or after ingestion of a large single dose of a delayed-release (enteric-coated) or extended-release formulation, {55} salicylate concentrations considered indicative of varying degrees of toxicity are as follows {31} {32} {33} {56}:

Time After
Ingestion
Salicylate Concentration
mcg/mL
mg/100 mL
mmol/L
Mild toxicity
     
6 hr
450–650
45–65
3.26–4.71
12 hr
350–550
35–55
2.53–3.98
Moderate toxicity
     
6 hr
650–900
65–90
4.71–6.52
12 hr
550–750
55–75
3.98–5.43
Severe toxicity
     
6 hr
> 900
> 90
> 6.52
12 hr
> 750
> 75
> 5.43


Supportive care—Monitoring and supporting vital functions. Correcting hyperthermia; fluid, electrolyte, and acid-base imbalances; ketosis; and plasma glucose concentration as needed. Patients in whom intentional overdose is known or suspected should be referrred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Salicylates (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any of the salicylates, including methyl salicylate, or nonsteroidal anti-inflammatory drugs (NSAIDs), history of

Pregnancy—Salicylates and caffeine (present in some formulations) cross the placenta; high-dose chronic use or abuse of aspirin in the third trimester may be hazardous to the mother as well as the fetus and/or neonate, causing heart problems in fetus or neonate and/or bleeding in mother, fetus, or neonate; high-dose chronic use or abuse of any salicylate late in pregnancy may also prolong and complicate labor and delivery; not taking aspirin during the third trimester unless prescribed by physician





Breast-feeding—Salicylates and caffeine (present in some formulations) are excreted in breast milk




Use in children and teenagers—Checking with physician before giving to children or teenagers with symptoms of acute febrile illness, especially influenza or varicella, because of the risk of Reye's syndrome; determining ahead of time what physician wants done if a child receiving chronic therapy develops fever or other symptoms of acute illness that may predispose to Reye's syndrome; also, increased susceptibility to salicylate toxicity in children, especially with fever and dehydration






Use in the elderly—Increased susceptibility to salicylate toxicity
Other medications, especially anticoagulants, antidiabetic agents (oral), those cephalosporins that may cause hypoprothrombinemia, plicamycin, valproic acid, methotrexate, NSAIDs, platelet aggregation inhibitors, probenecid, sulfinpyrazone, urinary alkalizers, and vancomycin; also, for buffered aspirin, choline and magnesium salicylates, and magnesium salicylate: fluoroquinolone antibiotics, itraconazole, ketoconazole, and oral tetracyclines
Other medical problems, especially coagulation or platelet function disorders, gastrointestinal problems such as ulceration or erosive gastritis (especially a bleeding ulcer), thyrotoxicosis, and (for choline and magnesium salicylates and for magnesium salicylate) chronic advanced renal insufficiency



Diet
Sodium content of sodium salicylate must be considered for patients on a sodium-restricted diet, especially with chronic use of antirheumatic doses

Proper use of this medication
» Taking nonenteric-coated oral dosage forms after meals or with food to minimize stomach irritation

» Taking all tablet or capsule dosage forms with a full glass of water and not lying down for 15 to 30 minutes after taking

» Not taking aspirin or buffered aspirin if it has a strong vinegar-like odor

Not chewing aspirin or buffered aspirin dosage forms within 7 days after tonsillectomy, tooth extraction, or other oral surgery

Not placing aspirin or buffered aspirin tablet directly on tooth or gum surface, to prevent tissue damage

Proper administration of

Aspirin
Chewable tablets—May be chewed, dissolved in liquid, crushed, or swallowed whole

Delayed-release tablets—Must be swallowed whole

Extended-release tablets—May be broken or crumbled (but not ground up) if necessary, unless specified by manufacturer to be swallowed whole; see manufacturer's prescribing information

Suppository—Proper administration technique

Choline and magnesium salicylates oral solution
Liquid may be mixed with fruit juice just prior to taking, if desired

Sodium salicylate delayed-release tablets
Tablets must be swallowed whole
Importance of not taking more medication than prescribed by physician or dentist or recommended on package label

Unless otherwise directed by physician, children not taking more often than 5 times daily

Compliance with therapy (for arthritis); may take 2 to 3 weeks or longer for maximum effectiveness

» Proper dosing
Missed dose: If on scheduled dosing regimen—taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Possibility of overdose if other medications containing aspirin or other salicylates (possibly including topical products) are used

» Regular visits to physician to check progress if long-term or high-dose therapy is prescribed

Checking with physician if
Taking for pain or fever, and pain persists for longer than 10 days for adults or 5 days for children, fever persists for longer than 3 days, condition becomes worse, new symptoms occur, or redness or swelling is present

Taking for sore throat, and sore throat is severe, persists for longer than 2 days, or occurs together with or is followed by fever, headache, rash, nausea, or vomiting

Symptoms of ringing or buzzing in ears or headache occur during long-term therapy

Patients taking aspirin as a platelet aggregation inhibitor
» Taking only the amount of aspirin prescribed; checking with prescribing physician about proper medication to use for relief of pain, fever, or arthritis

» Not discontinuing treatment for any reason without first consulting prescribing physician
» Not taking acetaminophen, ibuprofen, or other NSAIDs concurrently with salicylates for longer than a few days, unless specifically prescribed by physician or dentist, especially if using salicylates on a long-term and/or high-dose basis

Diabetics

Possibility of false urine sugar test results with prolonged use (per day) of—
8 or more 325-mg (5-grain), 4 or more 500-mg or 650-mg (10-grain), 3 or more 800-mg or 975-mg (15-grain) doses of aspirin

8 or more 325-mg (5-grain) or 4 or more 500-mg or 650-mg (10-grain) doses of buffered aspirin or sodium salicylate

4 or more 870-mg doses of choline salicylate

5 or more 500-mg, 4 or more 750-mg, or 2 or more 1000-mg, doses of choline and magnesium salicylates

7 or more regular strength, or 4 or more extra-strength, tablets of magnesium salicylate

4 or more 500-mg, or 3 or more 750-mg, doses of salsalate
Checking with physician, nurse, or pharmacist if unsure of daily dose being taken, if changes in urine sugar test results occur, or if any other questions, especially if diabetes not well-controlled
Caution if any kind of surgery is required; not taking aspirin for 5 days prior to surgery unless otherwise directed by physician or dentist because of risk of bleeding

Checking with health care professional before using buffered aspirin, choline and magnesium salicylates, or magnesium salicylate concurrently with a fluoroquinolone antibiotic, itraconazole, ketoconazole, or an oral tetracycline; these salicylate formulations may interfere with absorption of the anti-infective agent

Not taking a cellulose-containing laxative within 2 hours of a salicylate

Alcohol consumption may increase probability of stomach problems (for oral dosage forms only)

Checking with physician if rectal irritation occurs with aspirin suppositories

Caution if any laboratory tests required; possible interference with some test results by salicylates; possible interference with dipyridamole-assisted myocardial imaging by formulations containing caffeine

» Suspected overdose: Getting emergency help immediately


Side/adverse effects
Signs of potential side effects, especially allergic reactions, anemia, and gastrointestinal toxicity and, with aspirin suppositories, rectal irritation


General Dosing Information
A reduction in initial dosage is recommended for geriatric patients, especially those receiving long-acting salicylates (e.g., choline and magnesium salicylates, salsalate) or prolonged therapy. These patients may be more susceptible to salicylate toxicity, especially if accumulation occurs because of impaired renal function. If the reduced dosage is not effective, dosage may gradually be increased as tolerated.

For treatment of arthritis, dosage is usually increased gradually until symptoms are relieved, therapeutic plasma concentrations are achieved, or signs of toxicity, such as tinnitus or headache, occur. If these signs should appear, dosage should be reduced. However, tinnitus is not a reliable index of maximum salicylate tolerance, especially in very young or geriatric patients or those with impaired hearing.

For treatment of arthritis, dosage adjustments should not be made more frequently than once weekly, unless a reduction in dosage is required because of side effects, because up to 7 days may be required to achieve steady-state plasma concentrations.

The risk of Reye's syndrome must be considered when salicylates are administered to children and teenagers. It is recommended that salicylates be withheld from pediatric and adolescent patients with a fever or other symptoms of an illness that may predispose to Reye's syndrome until it has been determined that such an illness is not present or has run its course. {38}

Dosage should be reduced if fever or illness causes fluid depletion, especially in children.

In general, it is recommended that aspirin therapy be discontinued 5 days before surgery to prevent possible occurrence of bleeding problems.

Patients who experience bronchospastic or cutaneous allergic reactions to aspirin may be desensitized to these effects by administration of initially small and gradually increasing doses of aspirin. Desensitization must be carried out only by clinicians who are familiar with the technique, and only in a facility having trained personnel, medications, and equipment immediately available for treating any adverse reaction to the medication (especially anaphylaxis or severe bronchospasm). This procedure also desensitizes the patient to other nonsteroidal anti-inflammatory drugs (NSAIDs). However, unless aspirin or another NSAID is then administered on a daily basis, sensitivity to these medications redevelops within a few days.

For oral dosage forms only
These medications (except enteric-coated formulations) should be administered after meals or with food to lessen gastric irritation.

It is recommended that tablet and capsule dosage forms of these medications always be administered with a full glass (240 mL) of water and that the patient remain in an upright position for 15 to 30 minutes after administration. These measures may reduce the risk of the medication becoming lodged in the esophagus, which has been reported to cause prolonged esophageal irritation and difficulty in swallowing in some patients receiving NSAIDs.

It is recommended that aspirin or buffered aspirin products not be chewed before swallowing for at least 7 days following tonsillectomy or oral surgery because of possible injury to oral tissues from prolonged contact with aspirin.

Aspirin or buffered aspirin tablets should not be placed directly on a tooth or gum surface because of possible injury to tissues.

Concurrent use of an antacid and/or a histamine (H 2)-receptor antagonist (cimetidine, famotidine, or ranitidine) may protect against salicylate-induced gastric irritation or ulceration. However, the fact that chronic, high-dose antacid use may alkalinize the urine and increase salicylate excretion must be considered. Also, because these medications may cause premature dissolution, and loss of the protective effect, of enteric coatings, they will not provide additive protection against gastric irritation when administered concurrently with enteric-coated dosage forms.

ASPIRIN

Summary of Differences


Category/indications:
Aspirin (tablets, chewable tablets, and delayed-release tablets) also indicated as a platelet aggregation inhibitor.



Pharmacology/pharmacokinetics:
Aspirin irreversibly inhibits platelet aggregation.



Precautions:


Cross-sensitivity and/or related problems—
Risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs) significantly greater than with other salicylates.



Drug interactions and/or related problems—
May increase ascorbic acid requirement (prolonged high-dose use).

Theoretically, may decrease zidovudine clearance.

Higher risk of bleeding (compared with other salicylates) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.



Laboratory value alterations—
Interferes with urine 5-hydroxyindoleacetic acid determinations.

Interferes with protirelin-induced thyroid-stimulating hormone release determinations.

Prolongs bleeding time.



Medical considerations/contraindications—
Should not be used in patients with a history of severe sensitivity reactions to aspirin, other NSAIDs, nasal polyps and asthma, or thrombocytopenia

Should be used with caution in patients with asthma or glucose-6-phosphate dehydrogenase (G6PD) deficiency.




Side/adverse effects:
More ulcerogenic than other salicylates.

Rarely, causes hemolytic anemia (in patients with G6PD deficiency).

Suppository dosage form may cause rectal bleeding.



Additional Dosing Information
See also General Dosing Information.

Salicylate toxicity requiring treatment generally occurs with doses of 200 mg per kg of body weight (mg/kg), especially in children.

The general doses for aspirin products other than aspirin chewing gum tablets are based on the FDA's dosing recommendations for aspirin. The dosage unit of 80 mg (1.23 grains) is used for pediatric doses; the dosage unit of 325 mg (5 grains) is used for adult doses. The conversion factor of 1 grain equal to 65 mg is used. Strengths of specific products may vary, depending on the manufacturer.

The extended-release tablet, the suppository, and the chewing gum tablet dosage forms may give incomplete or unreliable absorption.

Chewable aspirin tablets may be chewed, dissolved in liquid, or swallowed whole.

The delayed-release tablets must be swallowed whole.

Some extended-release tablets may be broken or crumbled but must not be ground up before swallowing. Others must be swallowed whole. Consult manufacturers" prescribing information for individual products.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ASPIRIN TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic
Oral, 325 to 500 mg every three hours, 325 to 650 mg every four hours, or 650 mg to 1000 mg every six hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 4 grams, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 3.6 to 5.4 grams a day in divided doses.

Note: In acute rheumatic fever, up to 7.8 grams a day in divided doses may be given.


Platelet aggregation inhibitor
Oral, 80 to 325 mg a day, with the following exceptions

Ischemic attacks, transient, in males or
[Thromboembolism, cerebral, recurrence]1
Oral, 1 gram a day. Dosage may be reduced to 325 mg a day if the patient is unable to tolerate the higher dose.

[Ischemic attacks, transient, occurring in association with mitral valve prolapse]1
Oral, 325 mg to 1 gram a day.

[Prevention of thrombosis or occlusion of coronary bypass graft]
Oral, 325 mg seven hours postoperatively (via a nasogastric tube), then 325 mg three times daily, concurrently with 75 mg of dipyridamole. Dipyridamole may be discontinued one week postoperatively, but aspirin should be continued indefinitely.

Platelet aggregation inhibitor therapy is most effective when it is initiated two days prior to scheduled surgery. However, preoperative administration of aspirin has been shown to increase perisurgical bleeding and is not recommended. Therapy is therefore initiated with dipyridamole (recommended dosage 100 mg four times a day for two days prior to surgery and 100 mg one hour postoperatively [via a nasogastric tube]). Dipyridamole therapy is continued postoperatively (recommended dosage 75 mg seven hours postoperatively, via a nasogastric tube, then 75 mg three times a day, concurrently with aspirin) for at least one week.


Note: Although the doses recommended above for use of aspirin as a platelet aggregation inhibitor have been found effective in clinical studies, optimum dosage has not been established. For indications other than prevention of transient ischemic attacks or recurrence of cerebral thromboembolism, lower doses are often used. A few studies have shown that 160 mg of aspirin every twenty-four hours, or 325 mg every forty-eight hours, may effectively inhibit platelet aggregation while minimizing the risk of aspirin-induced side effects. Other studies have shown that single doses of 40 to 80 mg also inhibit platelet aggregation.



Usual pediatric dose
Analgesic/antipyretic
Oral, 1.5 grams per square meter of body surface a day in four to six divided doses; or for

Children up to 2 years of age: Dosage must be individualized by physician.

Children 2 to 4 years of age: Oral, 160 mg every four hours as needed, while symptoms persist.

Children 4 to 6 years of age: Oral, 240 mg every four hours as needed, while symptoms persist.

Children 6 to 9 years of age: Oral, 320 to 325 mg every four hours as needed, while symptoms persist.

Children 9 to 11 years of age: Oral, 320 to 400 mg every four hours as needed, while symptoms persist.

Children 11 to 12 years of age: Oral, 320 to 480 mg every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.


[Kawasaki disease]1
During the early febrile stage: Oral, 80 to 120 mg (average 100 mg) per kg of body weight a day in four divided doses for fourteen days {10} {11} {12} or until inflammation has subsided. {57} However, absorption may be impaired or erratic during this stage of the illness, and considerably higher doses may be required. {28} It is recommended that dosage be adjusted to achieve and maintain a plasma salicylate concentration of 20 to 30 mg per 100 mL.

During the convalescent stage: Oral, 3 to 5 mg per kg of body weight a day as a single dose. If no coronary artery abnormalities occur, treatment is usually continued for a minimum of eight weeks. If coronary artery abnormalities occur, it is recommended that treatment be continued for at least one year, even if the abnormalities regress, and longer if abnormalities persist. {11}


Strength(s) usually available
U.S.—


81 mg (OTC) [Aspir-Low{62}] [Healthprin Adult Low Strength{63} ( scored)][Generic]{62}


162.5 mg (OTC) [Healthprin Half-Dose{63} ( scored)]


325 mg (OTC) [Aspirtab{62}] [Empirin{64}] [Genuine Bayer Aspirin Caplets{65}] [Genuine Bayer Aspirin Tablets{65}] [Healthprin Full Strength{63} (scored)] [Norwich Aspirin{62}][Generic]{62}


500 mg (OTC) [Aspirtab-Max{62}] [{62}Extra Strength Bayer Aspirin Caplets{66}] [Extra Strength Bayer Aspirin Tablets{66}] [Norwich Aspirin{62}][Generic]{62}


650 mg (OTC)[Generic]{62}

Canada—


300 mg of ASA (OTC) [Headache Tablet{67}]


325 mg of ASA (OTC) [Apo-ASA{67}{68}] [Aspirin Caplets{67}{69}] [Aspirin Tablets{67}{69}] [PMS-ASA{70}][Generic]{67}


500 mg of ASA (OTC) [Aspirin Caplets] [{67}{69}Aspirin Tablets{67}{69}]

Note: Strengths of specific products labeled in grains may vary, depending on the manufacturer.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


ASPIRIN TABLETS (CHEWABLE) USP

Usual adult and adolescent dose
See Aspirin Tablets USP.

Usual pediatric dose
See Aspirin Tablets USP.

Strength(s) usually available
U.S.—


81 mg (OTC) [Bayer Children's Aspirin{71}] [St. Joseph Adult Chewable Aspirin{72}][Generic]{62}

Canada—


80 mg of ASA (OTC) [Aspirin Children's Tablets{67}{69}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • May be chewed.
   • Take with food and a full glass of water.


ASPIRIN CHEWING GUM TABLETS

Usual adult and adolescent dose
Analgesic
Oral, 454 to 650 mg. May be repeated every four hours as needed.


Note: For patient self-medication, it is recommended that a physician be consulted if pain is not relieved within ten days or sore throat within two days.


Usual pediatric dose
Analgesic
Children up to 3 years of age: Dosage must be individualized by physician.

Children 3 to 6 years of age: Oral, 227 mg. May be repeated up to three times a day.

Children 6 to 12 years of age: Oral, 227 to 454 mg. May be repeated up to four times a day.


Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days or sore throat within two days.


Strength(s) usually available
U.S.—


227 mg (OTC) [Aspergum{62}]

Canada—


325 mg of ASA (OTC) [Aspergum{67}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • To be chewed.
   • Take with food.
   • Drink a full glass of water after chewing.


ASPIRIN DELAYED-RELEASE TABLETS USP

Usual adult and adolescent dose
See Aspirin Tablets USP.

Usual pediatric dose
See Aspirin Tablets USP.

Strength(s) usually available
U.S.—


81 mg (OTC) [Acuprin 81{73}] [Aspirin Regimen Bayer Adult Low Dose{74}] [Ecotrin Caplets{75}] [Ecotrin Tablets{75}] [Halfprin{62}][Generic]{62}


162 mg (OTC) [Halfprin{76}]


325 mg (OTC) [Aspirin Regimen Bayer Regular Strength Caplets{74}] [Ecotrin Caplets{75}] [Ecotrin Tablets{75}] [Norwich Aspirin{62}][Generic]{62}


500 mg (OTC) [Ecotrin Caplets{75}] [Ecotrin Tablets{75}] [Extra Strength Bayer Arthritis Pain Formula Caplets{77}] [Maximum Strength Arthritis Foundation Safety Coated Aspirin{78}] [Norwich Aspirin{62}][Generic]{62}


650 mg (OTC)[Generic]{62}


975 mg (Rx) [Easprin{79}][Generic]{62}

Canada—


325 mg of ASA (OTC) [Apo-ASEN] [{67}Aspirin, Coated] [{80}Astrin{67}] [Coryphen] [{67}Entrophen Caplets] [{67}{81}Entrophen Tablets] [{67}{81}Novasen] [Novasen Sp.C{67}{82}][Generic]{67}{82}{67}


500 mg of ASA (OTC) [Aspirin, Coated{80}] [Entrophen Extra Strength{67}]


650 mg of ASA (OTC) [Apo-ASEN{67}] [Coryphen{67}] [Entrophen 10 Super Strength Caplets{67}{81}] [Novasen{67}{82}] [Novasen Sp.C{67}{82}][Generic]{67}


975 mg of ASA (OTC) [Entrophen 15 Maximum Strength Tablets{81}][Generic]{67}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Swallow tablets whole.
   • Take with a full glass of water.


ASPIRIN EXTENDED-RELEASE TABLETS USP

Usual adult and adolescent dose
Analgesic
Oral, 650 mg to 1.3 grams as 650-mg tablets every eight hours, or 1.6 grams as 800-mg tablets twice a day.


Note: The extended-release tablets have not been recommended by FDA for use as a platelet aggregation inhibitor.
For treatment of arthritis, the recommended analgesic dose may be administered initially, then adjusted according to patient requirements and response.


Usual pediatric dose
Pediatric strength not available.

Strength(s) usually available
U.S.—


650 mg (OTC) [Extended-release Bayer 8-Hour (scored)]{83}


800 mg (Rx) [Sloprin{62}] [ZORprin{62}][Generic]{62}


975 mg (Rx)[Generic]{62}

Canada—


325 mg of ASA (OTC) [Arthrisin{67}]


650 mg of ASA (OTC) [Arthrisin{67}] [Artria S.R{67}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.
   • Swallow tablets whole (if specified by manufacturer).


ASPIRIN AND CAFFEINE CAPSULES

Usual adult and adolescent dose
See Aspirin Tablets USP. Dosage is based only on the aspirin component.

Usual pediatric dose
Analgesic/Antipyretic
Children up to 6 years of age: Product of suitable strength not available.

Children 6 years of age and older: Oral, 325 mg every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.



Strength(s) usually available
U.S.—
Not commercially available.

Canada—


325 mg of ASA and 55 mg of caffeine (OTC) [Astone{67}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Take with food and a full glass of water.


ASPIRIN AND CAFFEINE TABLETS

Usual adult and adolescent dose
See Aspirin Tablets USP. Dosage is based only on the aspirin component.

Usual pediatric dose
Analgesic/Antipyretic
Children up to 9 years of age: Product of suitable strength not available.

Children 9 years of age and older: Oral, 325 to 400 mg every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.



Strength(s) usually available
U.S.—


400 mg of aspirin and 32 mg of caffeine (OTC) [Anacin Caplets{84}] [Anacin Tablets{84}] [Gensan{62}] [P-A-C Revised Formula{62}]


500 mg of aspirin and 32 mg of caffeine (OTC) [Anacin Maximum Strength{84}]

Canada—


325 mg of ASA and 4 mg of caffeine [Kalmex{67}]


325 mg of ASA and 15 mg of caffeine (OTC) [C2 (double-scored )]{67}


325 mg of ASA and 30 mg of caffeine citrate equivalent to 15 mg of caffeine base (OTC) [Herbopyrine{67}] [217 (scored)]{67}{85}


325 mg of ASA and 30 mg of caffeine (OTC) [Nervine]{67}


325 mg of ASA and 32 mg of caffeine (OTC) [Anacin{67}{86}]


325 mg of ASA and 32.4 mg of caffeine (OTC) [Antidol{67}]


325 mg of ASA and 33 mg of caffeine (OTC) [Calmine] [{67}Dolomine{67}]


325 mg of ASA and 65 mg of caffeine (OTC) [Instantine{67}]


375 mg of ASA and 30 mg of caffeine citrate equivalent to 15 mg of caffeine base [Arco Pain Tablet{67}]


500 mg of ASA and 30 mg of caffeine citrate equivalent to 15 mg of caffeine base (OTC) [217 Strong{67}{85}]


500 mg of ASA and 32 mg of caffeine (OTC) [Anacin Extra Strength{67}{86}] [Pain Aid{67}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Take with food and a full glass of water.



Rectal Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ASPIRIN SUPPOSITORIES USP

Usual adult and adolescent dose
Analgesic/antipyretic
Rectal, 325 to 650 mg every four hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 4 grams, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Rectal, 3.6 to 5.4 grams a day in divided doses.

Note: In acute rheumatic fever, up to 7.8 grams a day in divided doses may be given.


Platelet aggregation inhibitor
The suppositories have not been recommended by FDA for use as a platelet aggregation inhibitor.


Usual pediatric dose
Analgesic/antipyretic
Rectal, 1.5 grams per square meter of body surface a day in four to six divided doses; or for

Children up to 2 years of age—Dosage must be individualized by physician.

Children 2 to 4 years of age—Rectal, 160 mg every four hours as needed, while symptoms persist.

Children 4 to 6 years of age—Rectal, 240 mg every four hours as needed, while symptoms persist.

Children 6 to 9 years of age—Rectal, 325 mg every four hours as needed, while symptoms persist.

Children 9 to 11 years of age—Rectal, 325 to 400 mg every four hours as needed, while symptoms persist.

Children 11 to 12 years of age—Rectal, 325 to 480 mg every four hours as needed, while symptoms persist.

Note: Do not exceed 2.5 grams per square meter of body surface per day. It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Rectal, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.


[Kawasaki disease]1
During the early febrile stage: Rectal, 80 to 120 mg (average 100 mg) per kg of body weight a day in four divided doses for fourteen days {10} {11} {12} or until inflammation has subsided. {57} However, absorption may be impaired or erratic during this stage of the illness, and considerably higher doses may be required. {28} It is recommended that dosage be adjusted to achieve and maintain a plasma salicylate concentration of 20 to 30 mg per 100 mL.

During the convalescent stage: Rectal, 3 to 5 mg per kg of body weight a day as a single dose. If no coronary artery abnormalities occur, treatment is usually continued for a minimum of eight weeks. If coronary artery abnormalities occur, it is recommended that treatment be continued for at least one year, even if the abnormalities regress, and longer if abnormalities persist. {11}


Strength(s) usually available
U.S.—


60 mg (OTC)[Generic]{62}


120 mg (OTC)[Generic]{62}


125 mg (OTC)[Generic]{62}


200 mg (OTC)[Generic]{62}


300 mg (OTC)[Generic]{62}


325 mg (OTC)[Generic]{62}


600 mg (OTC)[Generic]{62}


650 mg (OTC)[Generic]{62}


1.2 grams (OTC)[Generic]{62}

Canada—


150 mg of ASA (OTC) [PMS-ASA{70}][Generic]{67}


650 mg of ASA (OTC) [PMS-ASA{70}][Generic]{67}

Note: The strengths of the specific products may not conform to the recommended pediatric doses. Also, the strengths of some products labeled in grains may vary, depending on the manufacturer.


Packaging and storage:
Store between 8 and 15 °C (46 and 59 °F), unless otherwise specified by manufacturer. Store in a well-closed container, in a cool place.

Auxiliary labeling:
   • Store in a cool place. May be refrigerated.
   • For rectal use only.


ASPIRIN, BUFFERED

Summary of Differences


Category/indications:
Aspirin, buffered, also indicated as a platelet aggregation inhibitor.



Pharmacology/pharmacokinetics:
Aspirin irreversibly inhibits platelet aggregation.



Precautions:


Cross-sensitivity and/or related problems—
Risk of cross-sensitivity with other nonsteroidal anti-inflammatory drugs (NSAIDs) significantly greater with aspirin than with other salicylates.



Drug interactions and/or related problems—
Aspirin may increase ascorbic acid requirement (prolonged high-dose use).

Theoretically, aspirin may decrease zidovudine clearance.

Higher risk of bleeding (compared with other salicylates) when aspirin is used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.

Antacids present as buffering agents may decrease absorption of fluoroquinolone antibiotics, itraconazole, ketoconazole, and oral tetracyclines.



Laboratory value alterations—
Aspirin interferes with urine 5-hydroxyindoleacetic acid determinations.

Aspirin interferes with protirelin-induced thyroid stimulating hormone release determinations.

Aspirin prolongs bleeding time.



Medical considerations/contraindications—
Aspirin should not be used in patients with a history of severe sensitivity reactions to aspirin, other NSAIDs, nasal polyps and asthma, or thrombocytopenia.

Aspirin should be used with caution in patients with asthma or glucose-6-phosphate dehydrogenase (G6PD) deficiency.




Side/adverse effects:
Aspirin is more ulcerogenic than other salicylates.

Rarely, aspirin causes hemolytic anemia (in patients with G6PD deficiency).



Additional Dosing Information
See also General Dosing Information.

The doses for buffered aspirin formulations are based on the FDA's dosing recommendations for aspirin. The dosage unit of 325 mg (5 grains) is used. The conversion factor of 1 grain equal to 65 mg is used. Strengths of specific products may vary, depending on the manufacturer.

The amount and type of buffering may vary among products.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ASPIRIN, ALUMINA, AND MAGNESIA TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic
Oral, 500 mg every three or four hours or 1000 mg every six hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 4 grams, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 3.6 to 5.4 grams a day in divided doses.

Note: In acute rheumatic fever, up to 7.8 grams a day in divided doses may be given.


Platelet aggregation inhibitor
Oral, 325 mg a day, with the following exceptions:
Ischemic attacks, transient, in males or

[Thromboembolism, cerebral, recurrence]1
Oral, 1 gram a day. Dosage may be reduced to 325 mg a day if the patient is unable to tolerate the higher dose.

[Ischemic attacks, transient, occurring in association with mitral valve prolapse]1
Oral, 325 mg to 1 gram a day.

[Prevention of thrombosis or occlusion of coronary bypass graft]
Oral, 325 mg seven hours postoperatively (via a nasogastric tube), then 325 mg three times daily, concurrently with 75 mg of dipyridamole. Dipyridamole may be discontinued one week postoperatively, but aspirin should be continued indefinitely.

Platelet aggregation inhibitor therapy is most effective when it is initiated two days prior to scheduled surgery. However, preoperative administration of aspirin has been shown to increase perisurgical bleeding and is not recommended. Therapy is therefore initiated with dipyridamole (recommended dosage 100 mg four times a day for two days prior to surgery and 100 mg one hour postoperatively [via a nasogastric tube]). Dipyridamole therapy is continued postoperatively (recommended dosage 75 mg seven hours postoperatively, via a nasogastric tube, then 75 mg three times a day, concurrently with aspirin) for at least one week.

Note: Although the doses recommended above for use of aspirin as a platelet aggregation inhibitor have been found effective in clinical studies, optimum dosage has not been established. For indications other than prevention of transient ischemic attacks or recurrence of cerebral thromboembolism, lower doses are often used. A few studies have shown that 160 mg of aspirin every twenty-four hours, or 325 mg every forty-eight hours, may effectively inhibit platelet aggregation while minimizing the risk of aspirin-induced side effects.
For most antithrombotic indications, lower doses than can be achieved with the aspirin, alumina, and magnesia formulation are used. However, this formulation may be used when 500-mg or 1-gram doses are appropriate.




Usual pediatric dose
Analgesic/antipyretic
Product of suitable strength not available.

Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.


[Kawasaki disease]1
During the early febrile stage: Oral, 80 to 120 mg (average 100 mg) per kg of body weight a day in four divided doses for fourteen days {10} {11} {12} or until inflammation has subsided. {57} However, absorption may be impaired or erratic during this stage of the illness, and considerably higher doses may be required. {28} It is recommended that dosage be adjusted to achieve and maintain a plasma salicylate concentration of 20 to 30 mg per 100 mL.

During the convalescent stage: Oral, 3 to 5 mg per kg of body weight a day as a single dose. If no coronary artery abnormalities occur, treatment is usually continued for a minimum of eight weeks. If coronary artery abnormalities occur, it is recommended that treatment be continued for at least one year, even if the abnormalities regress, and longer if abnormalities persist. {11}


Strength(s) usually available
U.S.—


500 mg of aspirin, with 27 {71} mg of aluminum hydroxide and 100 mg of magnesium hydroxide (OTC) [Arthritis Pain Formula{87}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


ASPIRIN, ALUMINA, AND MAGNESIUM OXIDE TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic or
Antirheumatic (nonsteroidal anti-inflammatory)
See Aspirin, Alumina, and Magnesia Tablets USP. Dosage is based only on the aspirin component.

Platelet aggregation inhibitor
See Aspirin, Alumina, and Magnesia Tablets USP. Dosage is based only on the aspirin component. For most antithrombotic indications, lower doses than can be achieved with the aspirin, alumina, and magnesium oxide formulation are used. However, this formulation may be used when 500-mg or 1-gram doses are appropriate.


Usual pediatric dose
See Aspirin, Alumina, and Magnesia Tablets USP . Dosage is based only on the aspirin component.

Strength(s) usually available
U.S.—


500 mg of aspirin, with dried aluminum hydroxide gel equivalent to 125 mg of aluminum hydroxide and 150 mg of magnesium oxide (OTC) [Cama Arthritis Pain Reliever{88}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


BUFFERED ASPIRIN TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic
Oral, 325 to 500 mg every three hours, 325 to 650 mg every four hours, or 650 mg to 1000 mg every six hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 4 grams, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Platelet aggregation inhibitor
See Aspirin, Alumina, and Magnesia Tablets USP .


Usual pediatric dose
Analgesic/antipyretic
Oral, 1.5 grams of aspirin per square meter of body surface a day in four to six divided doses; or for

Children up to 2 years of age: Dosage must be individualized by physician.

Children 2 to 4 years of age: Oral, 1/2 of a 325-mg tablet every four hours as needed, while symptoms persist.

Children 4 to 6 years of age: Oral, 3/4 of a 325-mg tablet every four hours as needed, while symptoms persist.

Children 6 to 9 years of age: Oral, 1 tablet (325 mg) every four hours as needed, while symptoms persist.

Children 9 to 11 years of age: Oral, 1 to 11/4 tablets (325 mg each) every four hours as needed, while symptoms persist.

Children 11 to 12 years of age: Oral, 1 to 11/2 tablets (325 mg each) every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg of aspirin per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight of aspirin per day may be required in some patients.


[Kawasaki disease]1
During the early febrile stage: Oral, 80 to 120 mg (average 100 mg) per kg of body weight a day in four divided doses for fourteen days {10} {11} {12} or until inflammation has subsided. {57} However, absorption may be impaired or erratic during this stage of the illness, and considerably higher doses may be required. {28} It is recommended that dosage be adjusted to achieve and maintain a plasma salicylate concentration of 20 to 30 mg per 100 mL.

During the convalescent stage: Oral, 3 to 5 mg per kg of body weight a day as a single dose. If no coronary artery abnormalities occur, treatment is usually continued for a minimum of eight weeks. If coronary artery abnormalities occur, it is recommended that treatment be continued for at least one year, even if the abnormalities regress, and longer if abnormalities persist. {11}


Strength(s) usually available
U.S.—


325 mg of aspirin (OTC) [Arthritis Pain Ascriptin{89}] [Bufferin Caplets{90}] [Bufferin Tablets{90}] [Buffex{62}] [Buffinol{62}] [Magnaprin{62}] [Regular Strength Ascriptin{89}][Generic]{62}


500 mg of aspirin (OTC) [Arthritis Strength Bufferin{93}] [Buffinol Extra{62}] [Extra Strength Bayer Plus Caplets{91}] [Maximum Strength Ascriptin{62}]

Canada—


325 mg of ASA (OTC) [Aspirin Plus Stomach Guard Regular Strength{94}] [Bufferin Caplets{67}] [Tri-Buffered ASA{67}][Generic]{67}


500 mg of ASA (OTC) [Aspirin Plus Stomach Guard Extra Strength{94}] [Bufferin Extra Strength Caplets][Generic]{67}

Note: See individual product label for buffering agent(s).
The strengths of the specific products may not conform to the recommended pediatric doses.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


BUFFERED ASPIRIN AND CAFFEINE TABLETS

Usual adult and adolescent dose
See Buffered Aspirin Tablets USP. Dosage is based only on the aspirin component.

Usual pediatric dose
Analgesic/antipyretic
Oral, 1.5 grams of aspirin per square meter of body surface a day in four to six divided doses; or for

Children up to 2 years of age: Dosage must be individualized by physician.

Children 2 to 4 years of age: Oral, 1/2 of a 325-mg tablet every four hours as needed, while symptoms persist.

Children 4 to 6 years of age: Oral, 3/4 of a 325-mg tablet every four hours as needed, while symptoms persist.

Children 6 to 9 years of age: Oral, 1 tablet (325 mg) every four hours as needed, while symptoms persist.

Children 9 to 11 years of age: Oral, 1 to 11/4 tablets (325 mg each) every four hours as needed, while symptoms persist.

Children 11 to 12 years of age: Oral, 1 to 11/2 tablets (325 mg each) or 1 tablet (421 mg) every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg of aspirin per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight of aspirin per day may be required in some patients.



Strength(s) usually available
U.S.—


421 mg of aspirin and 32 mg of caffeine (OTC) [Cope{95}]

Canada—


325 mg of ASA and 15 mg of caffeine (OTC) [C2 Buffered{67} (scored)]

Note: See individual product label for buffering agent(s).
The strengths of the specific products may not conform to the recommended pediatric doses.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


CHOLINE SALICYLATE

Summary of Differences


Pharmacology/pharmacokinetics:
Choline salicylate does not have a clinically significant effect on platelet aggregation.



Precautions:
Cross-sensitivity and/or related problems—Lower risk than with aspirin of cross-sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).

Drug interactions and/or related problems—Lower risk of bleeding (compared with aspirin) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.

Medical considerations/contraindications—May be used in patients with a history of severe sensitivity reactions to aspirin or other NSAIDs, although caution is advised.



Side/adverse effects:
Less ulcerogenic than aspirin.



Additional Dosing Information
See also General Dosing Information.

The nonarthritic doses are based on the FDA's dosing recommendations for aspirin.

A 435-mg dose of choline salicylate is equivalent in salicylate content to 325 mg of aspirin.


Oral Dosage Forms

CHOLINE SALICYLATE ORAL SOLUTION

Usual adult and adolescent dose
Analgesic/antipyretic
Oral, 435 to 669 mg (equivalent in salicylate content to 325 to 500 mg of aspirin) every three hours, 435 to 870 mg (equivalent in salicylate content to 325 to 650 mg of aspirin) every four hours, or 870 to 1338 mg (equivalent in salicylate content to 650 to 1000 mg of aspirin) every six hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 5352 mg, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 4.8 to 7.2 grams (equivalent in salicylate content to 3.6 to 5.4 grams of aspirin) a day in divided doses.


Usual pediatric dose
Analgesic/antipyretic
Oral, 2 grams (equivalent in salicylate content to 1.5 grams of aspirin) per square meter of body surface a day in four to six divided doses; or for

Children up to 2 years of age: Dosage must be individualized by physician.

Children 2 to 4 years of age: Oral, 217.5 mg (equivalent in salicylate content to 162.5 mg of aspirin) every four hours as needed, while symptoms persist.

Children 4 to 6 years of age: Oral, 326.5 mg (equivalent in salicylate content to 243.8 mg of aspirin) every four hours as needed, while symptoms persist.

Children 6 to 9 years of age: Oral, 435 mg (equivalent in salicylate content to 325 mg of aspirin) every four hours as needed, while symptoms persist.

Children 9 to 11 years of age: Oral, 435 to 543.8 mg (equivalent in salicylate content to 325 to 406.3 mg of aspirin) every four hours as needed, while symptoms persist.

Children 11 to 12 years of age: Oral, 435 to 652.5 mg (equivalent in salicylate content to 325 to 487.5 mg of aspirin) every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 107 to 133 mg (equivalent in salicylate content to 80 to 100 mg of aspirin) per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 174 mg (equivalent in salicylate content to 130 mg of aspirin) per kg of body weight per day may be required in some patients.



Strength(s) usually available
U.S.—


870 mg (equivalent in salicylate content to 650 mg of aspirin) per 5 mL (OTC) [Arthropan{62}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Take with food or a full glass of water.


CHOLINE AND MAGNESIUM SALICYLATES

Summary of Differences


Pharmacology/pharmacokinetics:
This medication does not have a clinically significant effect on platelet aggregation.



Precautions:


Cross-sensitivity and/or related problems—
Lower risk than with aspirin of cross-sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).



Drug interactions and/or related problems—
Lower risk of bleeding (compared with aspirin) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.

Magnesium may decrease absorption of fluoroquinolone antibiotics, itraconazole, ketoconazole, and oral tetracyclines.



Medical considerations/contraindications—
Should not be used in patients with chronic advanced renal impairment because of risk of hypermagnesemic toxicity.

May be used in patients with a history of severe sensitivity reactions to aspirin or other NSAIDs, although caution is advised.



Patient monitoring—
Monitoring of serum magnesium concentration recommended if large doses administered to patients with renal insufficiency.




Side/adverse effects:
Less ulcerogenic than aspirin.



Additional Dosing Information
See also General Dosing Information.

Choline and magnesium salicylates oral solution may be mixed with fruit juices just prior to administration.


Oral Dosage Forms

CHOLINE AND MAGNESIUM SALICYLATES ORAL SOLUTION

Usual adult and adolescent dose
Analgesic or
Antipyretic
Oral, 2 to 3 grams of salicylate a day in two or three divided doses.

Anti-inflammatory (nonsteroidal) or
Antirheumatic
Oral, 3 grams of salicylate a day in a single dose at bedtime, or in two or three divided doses, initially. Dosage must then be adjusted according to the requirements and response of the individual patient {36} {59}.


Usual pediatric dose
Analgesic
Antipyretic or
Anti-inflammatory (nonsteroidal)
Children weighing up to 37 kg: Oral, 50 mg of salicylate per kg of body weight per day in two divided doses.

Children weighing more than 37 kg: Oral, 2.2 grams of salicylate a day in two divided doses {36} {59}.


Strength(s) usually available
U.S.—


500 mg of salicylate (contains 293 mg of choline salicylate and 362 mg of magnesium salicylate) per 5 mL. (Rx) [Trilisate{96}]

Note: Each 5-mL dose of this medication is equivalent in salicylate content to 650 mg of aspirin.


Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Take with food or a full glass of water.


CHOLINE AND MAGNESIUM SALICYLATES TABLETS

Usual adult and adolescent dose
See Choline and Magnesium Salicylates Oral Solution.

Usual pediatric dose
See Choline and Magnesium Salicylates Oral Solution.

Strength(s) usually available
U.S.—


500 mg of salicylate (contains 293 mg of choline salicylate and 362 mg of magnesium salicylate) (Rx) [CMT{62}] [Tricosal{97}] [Trilisate{94} (scored )][Generic]{62}


750 mg of salicylate (contains 440 mg of choline salicylate and 544 mg of magnesium salicylate) (Rx) [CMT{62}] [Tricosal{97}] [Trilisate{94} (scored )][Generic]{62}


1000 mg of salicylate (contains 587 mg of choline salicylate and 725 mg of magnesium salicylate) (Rx) [CMT{62}] [Tricosal{62}] [Trilisate{96} ( scored)][Generic]{62}

Canada—


500 mg of salicylate (contains 293 mg of choline salicylate and 362 mg of magnesium salicylate) (Rx) [Trilisate{98} (scored )]

Note: Each 500-mg tablet is equivalent in salicylate content to 650 mg of aspirin. Each 750-mg tablet is equivalent in salicylate content to 975 mg of aspirin. Each 1000-mg tablet is equivalent in salicylate content to 1.3 grams of aspirin.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Take with food and a full glass of water.


MAGNESIUM SALICYLATE

Summary of Differences


Pharmacology/pharmacokinetics:
Magnesium salicylate does not have a clinically significant effect on platelet aggregation.



Precautions:


Cross-sensitivity and/or related problems—
Lower risk than with aspirin of cross-sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).



Drug interactions and/or related problems—
Lower risk of bleeding (compared with aspirin) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.

Magnesium may decrease absorption of fluoroquinolone antibiotics, itraconazole, ketoconazole, and oral tetracyclines.



Medical considerations/contraindications—
Should not be used in patients with chronic advanced renal impairment.

May be used in patients with a history of severe sensitivity reactions to aspirin or other NSAIDs, although caution is advised.



Patient monitoring—
Monitoring of serum magnesium concentration recommended if large doses are administered to patients with renal insufficiency.




Side/adverse effects:
Less ulcerogenic than aspirin.



Additional Dosing Information
See also General Dosing Information.

A 545-mg dose of magnesium salicylate is equivalent in salicylate content to 650 mg of aspirin.


Oral Dosage Forms

MAGNESIUM SALICYLATE TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic
Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 2 regular-strength tablets (containing the equivalent of 303.7 mg of anhydrous magnesium salicylate per tablet) every four hours as needed, up to a maximum of 12 tablets a day, {99} or

Oral, 2 extra-strength tablets (containing the equivalent of 467 mg of anhydrous magnesium salicylate, or more, per tablet) every six hours as needed, up to a maximum of 8 tablets a day {100} {101} {102}.


Note: For patient self-medication, it is recommended that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Usual pediatric dose
Dosage has not been established {99} {100} {101} {102}.

Strength(s) usually available
U.S.—


377 mg of magnesium salicylate tetrahydrate equivalent to 303.7 mg of anhydrous magnesium salicylate (OTC) [Doan's Regular Strength Tablets{99}]


545 mg (Rx) [Magan{62}]


580 mg of magnesium salicylate tetrahydrate equivalent to 467 mg of anhydrous magnesium salicylate (OTC) [Backache Caplets{100}] [Bayer Select Maximum Strength Backache Pain Relief Formula{101}] [Maximum Strength Doan's Analgesic Caplets{102}]


600 mg (Rx) [Mobidin{62} (scored)]

Canada—


325 mg (OTC) [Doan's Backache Pills{67}]


650 mg (OTC) [Sero-Gesic{67}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


SALSALATE

Summary of Differences


Pharmacology/pharmacokinetics:
Salsalate does not have a clinically significant effect on platelet aggregation.



Precautions:
Cross-sensitivity and/or related problems—Lower risk than with aspirin of cross-sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).

Drug interactions and/or related problems—Lower risk of bleeding (compared with aspirin) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.

Medical considerations/contraindications—May be used in patients with a history of severe sensitivity reactions to aspirin or other NSAIDs, although caution is advised.



Side/adverse effects:
Less ulcerogenic than aspirin.



Additional Dosing Information

Bioequivalence information
Bioavailability or bioequivalence problems among different brands of Salsalate Tablets USP have not been documented {108}.


Oral Dosage Forms

SALSALATE CAPSULES USP

Usual adult and adolescent dose
Antirheumatic
Oral, 1 gram three times a day initially. Dosage may then be titrated according to patient response.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


500 mg (Rx) [Disalcid{103}][Generic]{62}


750 mg (Rx)[Generic]{62}

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a light-resistant container, unless otherwise specified by manufacturer. Store in a tight container.

Auxiliary labeling:
   • Take with food and a full glass of water.


SALSALATE TABLETS {109} USP

Note: Bioavailability or bioequivalence problems among different brands of Salsalate Tablets USP have not been documented. {108}


Usual adult and adolescent dose
Analgesic/antipyretic or
Antirheumatic
Oral, 500 mg to 1 gram two or three times a day initially. Dosage may then be titrated according to patient response.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


500 mg (Rx) [Amigesic{62}] [Disalcid{103} (scored)] [Mono-Gesic{104}] [Salflex{104}] [Salsitab{105}][Generic]{62}


750 mg (Rx) [Amigesic{62} (scored)] [Anaflex 750{62}] [Disalcid{103} (scored)] [Marthritic{62}] [Mono-Gesic{106} (scored)] [Salflex{104} (scored)] [Salsitab{105} (scored)][Generic]{112}

Canada—


500 mg (Rx) [Disalcid{107} (scored)]


750 mg (Rx) [Disalcid{107} (scored)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a light-resistant container, unless otherwise specified by manufacturer. Store in a tight container. {109}

Auxiliary labeling:
   • Take with food and a full glass of water.


SODIUM SALICYLATE

Summary of Differences


Pharmacology/pharmacokinetics:
Sodium salicylate does not have a clinically significant effect on platelet aggregation.



Precautions:


Cross-sensitivity and/or related problems—
Lower risk than with aspirin of cross-sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs).



Drug interactions and/or related problems—
Caution required when large doses administered concurrently with sodium-retaining medications.

Lower risk of bleeding (compared with aspirin) when used concurrently with other medications that may inhibit blood clotting or cause gastrointestinal ulceration or bleeding.



Medical considerations/contraindications—
Caution required in hypertensive patients or those on a sodium-restricted diet because of sodium content.

May be used in patients with a history of severe sensitivity reactions to aspirin or other NSAIDs, although caution is advised.




Side/adverse effects:
Less ulcerogenic than aspirin.



Additional Dosing Information
See also General Dosing Information.

The nonarthritic doses are based on the FDA's dosing recommendations for sodium salicylate. The dosage unit of 325 mg (5 grains) is used for adult doses. The conversion factor of 65 mg equal to 1 grain is used. Strengths of specific products may vary, depending on the manufacturer.

The uncoated tablet form of sodium salicylate should be administered with food or a full glass (240 mL) of water to lessen gastric irritation.

Each 325-mg tablet of sodium salicylate contains 2 mEq (46 mg) of sodium.


Oral Dosage Forms

SODIUM SALICYLATE TABLETS USP

Usual adult and adolescent dose
Analgesic/antipyretic
Oral, 325 to 650 mg every four hours as needed, while symptoms persist.

Note: For patient self-medication, it is recommended that the total daily dose not exceed 4 grams, and that a physician be consulted if pain is not relieved within ten days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 3.6 to 5.4 grams a day in divided doses.


Usual pediatric dose
Analgesic/antipyretic
Oral, 1.5 grams per square meter of body surface a day in four to six divided doses; or for

Children up to 6 years of age: Product of suitable strength not available.

Children 6 years of age and older: Oral, 325 mg every four hours as needed, while symptoms persist.

Note: It is recommended that children up to 12 years of age receive no more than five doses in each twenty-four-hour period, unless otherwise directed by a physician, and that a physician be consulted if pain is not relieved within five days, fever within three days, or sore throat within two days.


Antirheumatic (nonsteroidal anti-inflammatory)
Oral, 80 to 100 mg per kg of body weight a day in divided doses.

Note: If an adequate response is not achieved within one or two weeks, dosage adjustment should be based on measurement of plasma salicylate concentration. Up to 130 mg per kg of body weight per day may be required in some patients.



Strength(s) usually available
U.S.—
Not commercially available.

Canada—


325 mg (OTC) [Dodd's Pills{67}] [Gin Pain Pills{67}]


500 mg [Dodd's Extra Strength{67}]

Note: The strengths of the specific products may not conform to the recommended pediatric dose. Also, the strengths of individual products labeled in grains may vary, depending on the manufacturer.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Take with food and a full glass of water.


SODIUM SALICYLATE DELAYED-RELEASE TABLETS

Usual adult and adolescent dose
See Sodium Salicylate Tablets USP.

Usual pediatric dose
See Sodium Salicylate Tablets USP.

Strength(s) usually available
U.S.—


325 mg (OTC)[Generic]{62}


650 mg (OTC)[Generic]{62}

Canada—
Not commercially available.

Note: Strengths of individual products labeled in grains may vary, depending on the manufacturer.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Swallow tablets whole.
   • Take with a full glass of water.



Revised: 07/25/1995



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. The Federal Register 1988 Nov. 16; 53 (22146204-46260). Tentative Final Monograph and Notice of Proposed Rulemaking; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use.
  1. Chest 1989 Feb. (Suppl.); 95: 98S-106S.
  1. Chest 1989 Feb. (Suppl.); 95: 128S-139S.
  1. Chest 1989 Feb. (Suppl.); 95: 140S-155S.
  1. Chest 1989 Feb. (Suppl.); 95: 52S-72S.
  1. Chest 1989 Feb. (Suppl.); 95: 107S-117S.
  1. Aspirin (Sterling) In: CPS 23 1988.
  1. Aspirin and dipyridamole (Asasantine, Boehringer Ingelheim). In: CPS 23 1988.
  1. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17m187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988 Aug 13; 332: 349-60.
  1. Ichida F, Fatica NS, Engle MA, et al. Coronary artery involvement in Kawasaki syndrome in Manhattan, New York: Risk factors and role of aspirin. Pediatrics 1987; 80: 828-35.
  1. Bierman FZ, Gersony WM. Kawasaki disease: Clinical perspective. J Pediatrics 1987; 111: 789-93.
  1. Newburger JW, Takahashi M, Burns MC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986 Aug 7; 315: 341-7.
  1. Furusho K, Nakano H, Shinomiya K, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984 Nov 10; 2: 1055-7.
  1. Koren G, Rose V, Lavi S, Rowe R. Probable efficacy of high-dose salicylates in reducing coronary involvement in Kawasaki disease. J Amer Med Assoc 1985 Aug 9; 254: 767-9.
  1. Panel consensus, monograph revision 1989.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 61, 147, 400, 602, 620.
  1. Dukes MNG, editor. Meyler"s side effects of drugs. An encyclopedia of adverse reactions and interactions. 10th ed. Amsterdam: Elsevier, 1984.
  1. Open
  1. Open
  1. Open
  1. Panelist comment.
  1. Caffeine (Systemic) monograph, USP DI 1990.
  1. Larsen JR, Larsen LS. Clinical features and management of poisoning due to phenytoin. Med Toxicol Adverse Drug Exp 1989; 4: 229-45.
  1. Antacids (Oral-Local) monograph, USP DI 1990.
  1. Proterilin (Systemic) monograph, USP DI 1990.
  1. Panelist comments on Sodium Iodide I 123 (Systemic) and Sodium Iodide I 131 (Systemic) monographs, revision of 1/17/90.
  1. Panelist comments on Dipyridamole (Systemic) monograph revision for USP DI 1990.
  1. Koren G, MacLeod SM; Difficulty in achieving therapeutic serum concentrations of salicylate in Kawasaki disease. J Pediatr 1984; 105: 991-5.
  1. Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987; 37: 1392-4.
  1. Reviewer comment.
  1. Committee on accident and poison prevention American Academy of Pediatrics. Salicylates. In: Aronow R, ed. Handbook of common poisonings in children. Evanston, Illinois: American Academy of Pediatrics, 1983; 126-30.
  1. Anonymous. Salicylate. In: The British Columbia drug and poison information centre poison management manual. Ottawa, Canada: Canadian Pharmaceutical Association, 1984; 289-91.
  1. Dugandzic RM, Tierney MG, Dickinson GE, et al. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989 Nov; 18: 1186–90.
  1. Panel comment (old revision).
  1. Sanford-Driscoll M, Knodel LC. Induction of hemolytic anemia by nonsteroidal anti-inflammatory drugs. Drug Intell Clin Pharm 1986; 20: 925-34.
  1. Choline and magnesium salicylates package insert (Trilisate, Purdue-Frederick—U.S.), Rev 5/87, Rec 2/89.
  1. Aspirin package insert (ZORprin, Boots—U.S.), Rev 9/88, Rec 3/89.
  1. Panelist comment.
  1. Panel consensus.
  1. Panel consensus.
  1. Panel consensus.
  1. Open
  1. Panel consensus.
  1. The Federal Register 1990 July 5.
  1. Open
  1. Panel consensus.
  1. Panel consensus.
  1. Panel consensus.
  1. Open
  1. Open
  1. Panel responses to monograph revision.
  1. Panel consensus.
  1. Panel consensus.
  1. Panelist comment.
  1. Panelist comments
  1. Panel responses to proposed revision.
  1. Panel responses to monograph revision
  1. Panel consensus.
  1. Panelist responses to revision.
  1. Panel consensus.
  1. Panel responses to monograph revision.
  1. Red book 1995. Montvale, NJ: Medical Economics Company, 1995: 114, 124, 135, 313, 412, 472, 498-502, 514, 614, 622.
  1. Aspirin (Healthprin, Smart). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 810.
  1. Aspirin (Empirin, BW). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 854.
  1. Aspirin (Genuine Bayer Aspirin products, regular strength, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 713-5.
  1. Aspirin (Genuine Bayer Aspirin products, extra strength, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 712.
  1. Analgesic Products Table. In: Krogh CME, editor. Self-medication product information. Volume 2, 4th edition. Canadian Pharmaceutical Association, 1993: 205-11.
  1. Aspirin (Apo-ASA, Apotex). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 83.
  1. Aspirin (Aspirin, Sterling Health). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 118-9.
  1. Aspirin (PMS-ASA, Pharmascience). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1033.
  1. Aspirin (Bayer Children"s Aspirin, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 711-2.
  1. Aspirin (St. Joseph Adult Chewable Aspirin, Schering-Plough). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 808-9.
  1. Aspirin (Acuprin 81, Richwood). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1984.
  1. Aspirin (Aspirin Regimen Bayer, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 709-11.
  1. Aspirin (Ecotrin, SmithKline Beecham). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 816-8.
  1. Aspirin (Halfprin, Kramer). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1244-5.
  1. Aspirin (Extra Strength Bayer Arthritis Pain Regimen, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 711.
  1. Aspirin (Extra Strength Arthritis Foundation Safety Coated Aspirin, McNeil Consumer). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 675.
  1. Aspirin (Easprin, PD). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1839-40.
  1. Aspirin (Aspirin, Coated, Sterling Health). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 119.
  1. Aspirin (Entrophen, Frosst). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 446-7.
  1. Aspirin (Novasen, Novasen Sp.C, Novopharm). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 892.
  1. Aspirin (Extended-release Bayer 8-hour Aspirin, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 712.
  1. Aspirin (Anacin, A.H. Robins Consumer). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 8.
  1. Aspirin (217, Frosst). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1374-5.
  1. Aspirin (Anacin, Whitehall-Robins). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 65-6.
  1. Personal communication, Whitehall Laboratories—US information representative, via telephone 6/5/95.
  1. Aspirin (CAMA, Sandoz). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 785.
  1. Aspirin, Buffered (Ascriptin, Rhone-Poulenc Rorer). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1983.
  1. Aspirin, Buffered (Bufferin, Bristol-Myers). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 613-4.
  1. Aspirin, Buffered (Extra Strength Bayer Plus, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 713.
  1. Aspirin, Buffered (Extra Strength Bufferin, Bristol-Myers). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 615.
  1. Aspirin, Buffered (Arthritis Strength Bufferin, Bristol-Myers). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 614-5.
  1. Aspirin, Buffered (Aspirin Plus Stomach Guard, Sterling Health). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 119.
  1. Personal communication, Mentholatum—US information representative, via telephone 6/5/95.
  1. Choline and Magnesium Salicylates (Trilisate, Purdue Frederick). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1940-1.
  1. Choline and Magnesium Salicylates (Tricosal, Duramed). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 971.
  1. Choline and Magnesium Salicylates (Trilisate, Purdue Frederick). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1360-1.
  1. Magnesium Salicylate (Doan"s Regular Strength, Ciba Consumer). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 634.
  1. Magnesium Salicylate (Backache Caplets, Bristol-Myers). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 613.
  1. Magnesium Salicylate (Bayer Select Maximum Strength Backache Pain Relief Formula, Miles). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 715-6.
  1. Magnesium Salicylate (Maximum Strength Doan"s Analgesic Caplets, Ciba Consumer). In: PDR Physicians" desk reference for nonprescription drugs. 16th ed. 1995. Montvale, NJ: Medical Economics Data Production Co, 1995: 633.
  1. Salsalate (Disalcid, 3M). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 1381-2.
  1. Salsalate (Salflex, Carnrick). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 846-7.
  1. Salsalate (Salsitab, Upsher-Smith). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 2598.
  1. Salsalate (Mono-Gesic, Central). In: PDR Physicians" desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data Production Company, 1995: 853.
  1. Salsalate (Disalcid, 3M). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 396-7.
  1. Reviewers" responses to ballot of 5/9/95.
  1. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: Ninth supplement, 1993: 3502.
  1. Shimada J, et al. Effect of antacid on absorption of the quinolone lomefloxacin. Antimicrob Agents Chemother 1992; 36(6): 1219-24.
  1. Nix DE, et al. Inhibition of norfloxacin absorption by antacids. Antimicrob Agents Chemother 1990; 34(3): 432-5.
  1. Flor S, et al. Effects of magnesium-aluminum hydroxide and calcium carbonate antacids on bioavailability of ofloxacin. Antimicrob Agents Chemother 1990; 34(12): 2436-8.
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