Aspirin, Sodium Bicarbonate, and Citric Acid (Systemic)


VA CLASSIFICATION
Primary: CN103
Secondary: BL117; GA110

Commonly used brand name(s): Alka-Seltzer Effervescent Pain Reliever and Antacid; Flavored Alka-Seltzer Effervescent Pain Reliever and Antacid.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Analgesic-antacid—

platelet aggregation inhibitor—

Indications

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

Accepted

Pain and upset stomach (treatment)
Aspirin, sodium bicarbonate, and citric acid combination is indicated to relieve pain, especially when an upset stomach is also present {01} {02} {03} {04} {05}. However, this medication is not recommended for long-term, high-dose use because of the high sodium bicarbonate content {06}.

Platelet aggregation (prophylaxis)1
Aspirin, sodium bicarbonate, and citric acid combination is indicated to provide the platelet aggregation–inhibiting action of aspirin in the following:
Ischemic attacks, transient, in males (prophylaxis);
Thromboembolism, cerebral (prophylaxis); or
[Thromboembolism, cerebral, recurrence (prophylaxis)]—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 {07}.
—[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]{08}.
—[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]{09}.
—[Aspirin is also indicated to prevent initial or recurrent cerebrovascular embolism, TIAs, and stroke following carotid endarterectomy]{10}.
—[Aspirin is indicated in the treatment of patients who have had a completed thrombotic stroke, to prevent a recurrence]{11}.

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} {02} {07} {12}.
—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. {13} {14}
—[One study has shown that aspirin may also prevent myocardial infarction in individuals who have no history of unstable angina pectoris or myocardial infarction. However, an increased incidence of hemorrhagic stroke was reported 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, use of aspirin for this purpose remains controversial; whether aspirin's benefit outweighs its risk 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.] {12}

[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 {08}.
—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. 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. {13}
—Aspirin is also indicated, alone or in combination with dipyridamole, to reduce the risk of thrombosis and/or reocclusion of saphenous vein aortocoronary bypass grafts following coronary bypass surgery {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. {10}
—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 {10}.
—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 {10}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Aspirin: 180.16 {15}
    Sodium bicarbonate: 84.01 {15}
    Citric acid: 192.13 {15}

pKa—
    Aspirin: 3.5

Mechanism of action/Effect:


Analgesic:

Aspirin inhibits the enzyme cyclo-oxygenase to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Aspirin probably produces analgesia by inhibiting prostaglandin synthesis in the central nervous system (CNS), as well as through a peripheral action by blocking pain-impulse generation. The peripheral action may predominate and may also be due to inhibition of the synthesis of prostaglandins or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation. {16}



Antacid:

The antacid effect is produced by sodium citrate, {01} {02} which is formed, along with carbon dioxide, when the effervescent tablets are dissolved in water. The antacid reacts chemically to neutralize or buffer existing quantities of stomach acid but has no direct effect on acid output. This action results in increased pH of stomach contents, thus providing relief of hyperacidity symptoms. {17} Also, by reducing acid concentration within the lumen of the esophagus, thereby increasing intraesophageal pH and decreasing pepsin activity, the antacid action aids in the control of gastroesophageal reflux.



Platelet aggregation inhibitor:

Aspirin affects platelet function by inhibiting the enzyme prostaglandin cyclo-oxygenase 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, the optimal dosage that will suppress thromboxane A 2 formation without suppressing prostacyclin generation has not been determined. {18}



Other actions/effects:

Aspirin also has antipyretic, anti-inflammatory, and antirheumatic actions. {16}

Distribution:

In breast milk—Peak salicylate concentrations of 173 to 483 mcg per mL (17.3 to 48.3 mg per 100 mL; 1.25 to 3.5 mmol/L) have been measured 5 to 8 hours after maternal ingestion of a single 650-mg dose of aspirin {18}.

Protein binding:

Salicylate (from aspirin)—High (to albumin); decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration or renal dysfunction, and during pregnancy {18}.

Biotransformation:

Aspirin—Largely hydrolyzed in the gastrointestinal tract, liver, and blood to salicylate, an active metabolite that is further metabolized primarily in the liver {16}.

Half-life:

Aspirin—15 to 20 minutes for the intact molecule; rapidly hydrolyzed to salicylate {18}.

In breast milk (as salicylate): 3.8 to 12.5 hours (average 7.1 hours) following a single 650-mg dose of aspirin {18}.

Therapeutic plasma concentration:

Salicylate (from aspirin)—Analgesic: 25 to 50 mcg per mL; (2.5 to 5 mg per 100 mL; 0.18 to 0.36 mmol/L) {18}.

Elimination:


Aspirin—
        Renal; primarily as free salicylic acid and conjugated metabolites {16}.
        
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. {18}





In dialysis: Salicylate (from aspirin)—
        Hemodialysis: Clearances of 35 to 100 mL per minute have been reported {18}.
        Peritoneal dialysis: Removed more slowly than with hemodialysis; clearances of 45 to 90 mL per hour have been reported in infants {18}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one salicylate, including methyl salicylate (oil of wintergreen), may be sensitive to aspirin also. However, patients sensitive to aspirin may not necessarily be sensitive to salicylamide or other nonacetylated salicylates. {16}

Patients sensitive to other nonsteroidal anti-inflammatory drugs (NSAIDs) also may be sensitive to aspirin. However, cross-sensitivity between aspirin and other NSAIDs that results in bronchospastic or cutaneous reactions may be eliminated if the patient undergoes a desensitization procedure designed to restore tolerance of aspirin (See General Dosing Information ). {19}

Pregnancy/Reproduction

Pregnancy—

Aspirin

First trimester: Salicylate readily crosses the placenta. It has been reported that aspirin use during pregnancy may increase the risk of birth defects in humans; however, controlled studies using usual therapeutic doses of aspirin have not shown proof of teratogenicity. {16}

Studies in animals have shown that aspirin causes increased fetal resorptions and 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) {18}.

Third trimester: Pregnant women should not take aspirin during the last trimester of pregnancy unless aspirin therapy is prescribed and monitored by a physician {20}. Chronic, high-dose aspirin therapy may result in prolonged gestation, increased risk of postmaturity syndrome (fetal damage or death due to decreased placental function when pregnancy is greatly prolonged), and increased risk of maternal prepartum hemorrhage {18}.

Ingestion of aspirin during the last 2 weeks of pregnancy may increase the risk of fetal or neonatal hemorrhage. Also, the possibility must be considered that regular use of aspirin during late 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. {21}

Overuse or abuse of aspirin late in pregnancy has been reported to reduce birthweight and to increase the risk of stillbirth or neonatal death, possibly because of prepartum maternal or fetal hemorrhage or premature ductus arteriosus closure; however, studies using therapeutic doses of aspirin have not shown these adverse effects {21}.

Labor and delivery: Chronic, high-dose aspirin therapy late in pregnancy may result in prolonged labor, complicated deliveries, and increased risk of maternal or fetal hemorrhage {16}.



Sodium bicarbonate

Problems in humans have not been documented. However, caution is recommended because chronic use may lead to systemic alkalosis. Also, ingestion of substantial quantities of sodium may cause edema and weight gain. {17}


Breast-feeding


Aspirin:

Problems in humans with usual analgesic doses of aspirin have not been documented. However, salicylate is distributed into breast milk. In one study, peak salicylate concentrations of 173 to 483 mcg per mL (17.3 to 48.3 mg per 100 mL; 1.25 to 3.5 mmol/L) were measured in breast milk 5 to 8 hours after maternal ingestion of a single 650-mg dose of aspirin. The half-life in breast milk was 3.8 to 12.5 hours (average 7.1 hours). {18}



Sodium bicarbonate:

Problems in humans have not been documented {17}.


Pediatrics


Aspirin:

Aspirin usage may be associated with the development of Reye"s syndrome in children with acute febrile illnesses, especially influenza and varicella. It is recommended that aspirin not be administered to febrile pediatric patients until after the presence of such an illness has been ruled out {20}.

Pediatric patients, especially those with fever and dehydration, may be more susceptible to the toxic effects of salicylates {18}.



Sodium bicarbonate:

Antacids should not be given to young children (up to 6 years of age) who complain of stomach upset unless prescribed by a physician. Because young children usually are not able to describe their symptoms precisely, proper diagnosis is necessary to rule out the presence of a medical problem (e.g., appendicitis) that requires other treatment. {17}




Adolescents


Aspirin

Aspirin usage may be associated with the development of Reye"s syndrome in adolescents with acute febrile illnesses, especially influenza and varicella. It is recommended that aspirin not be administered to febrile adolescent patients until after the presence of such an illness has been ruled out. {20}



Geriatrics



Aspirin:

Patients 60 years of age or older may be more susceptible to the toxic effects of aspirin {18}.



Sodium bicarbonate:

Geriatric patients are more likely to have age-related renal function impairment; ingestion of significant quantities of sodium may be hazardous to these patients {06}. Because of the high sodium bicarbonate content, use of this combination medication should preferably be limited to 5 days at a time, unless more prolonged therapy is prescribed and monitored by a physician {06}.


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: 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 aspirin is used concurrently with any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.
Not all interactions between sodium bicarbonate and other oral medications have been identified in this monograph. Because the antacid may increase or reduce the rate and/or extent of absorption of other oral medications, patients should be advised not to take any other oral medication within 1 to 2 hours of sodium bicarbonate.

Acetaminophen    (prolonged concurrent use of acetaminophen with aspirin 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 aspirin not exceed that recommended for acetaminophen or aspirin given individually)


Acidifiers, urinary, such as:
Ammonium chloride
Ascorbic acid
Potassium or sodium phosphates    (the aspirin and antacid combination medication contains sufficient sodium bicarbonate to alkalinize the urine and counteract the effect of urinary acidifiers; frequent use of sodium bicarbonate, especially in high doses, is best avoided by patients receiving therapy to acidify the urine {16} {22})


Alcohol or
» Anti-inflammatory drugs, nonsteroidal (NSAIDs), other or
Corticosteroids or
Corticotropin (ACTH), chronic therapeutic use of    (concurrent use of any of these medications with aspirin may increase the risk of gastrointestinal side effects, including ulceration and gastrointestinal blood loss {16} {18} [although less likely with this highly buffered formulation than with other aspirin products that are not enteric-coated]; {06} also, concurrent use of aspirin and other NSAIDs may not provide additional symptomatic relief and is therefore not recommended)

    (aspirin may decrease the bioavailability of many NSAIDs, including diflunisal, fenoprofen, indomethacin, ketoprofen, meclofenamate, piroxicam, and the active sulfide metabolite of sulindac)


Alkalizers, urinary, other, such as:
Antacids, calcium and/or magnesium-containing
Carbonic anhydrase inhibitors
Citrates
Sodium bicarbonate    (frequent use of the sodium bicarbonate in this combination medication by patients receiving other urinary alkalizers may increase the risk of additive effects, including an unacceptably high degree of urinary alkalinization and, except with the carbonic anhydrase inhibitors, systemic alkalosis {23})

    (concurrent use of sodium citrate with sodium bicarbonate may promote the development of calcium stones in patients with uric acid stones, due to sodium ion opposition to the hypocalciuric effect of the alkaline load; may also cause hypernatremia {23})

    (concurrent use of other urinary alkalizers may also significantly reduce or shorten the analgesic effect of aspirin because alkalinization of the urine increases excretion of the active salicylate metabolite of aspirin {23})


Amphetamines or{17}
» Mecamylamine or
Quinidine{17}    (antacid-induced alkalinization of the urine may inhibit urinary excretion of these medications, possibly causing increases in half-life, duration of action, and/or toxicity; although the clinical significance of this effect is probably minimal with occasional low-dose use of the aspirin and antacid combination, concurrent use with mecamylamine is not recommended and dosage adjustment of the other medications may be needed when long-term therapy with the aspirin and antacid combination is initiated or discontinued)


Anticholinergics or other medications with anticholinergic activity (See Appendix II ){17}    (antacids may decrease absorption of anticholinergics, thereby reducing their effectiveness; it is recommended that the aspirin and antacid combination and an anticholinergic be taken at least 1 hour apart)

    (antacid-induced alkalinization of the urine may also delay excretion, and thereby potentiate the side effects, of the anticholinergic; however, the clinical significance of this effect is probably minimal with occasional low-dose use of the aspirin and antacid combination)


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

    (concurrent use with aspirin is not recommended [except in a prescribed antithrombotic regimen] because aspirin-induced inhibition of platelet function may lead to prolonged bleeding time and hemorrhage in patients receiving anticoagulant or thrombolytic therapy)

    (the potential occurrence of gastrointestinal ulceration or hemorrhage during aspirin therapy [although less likely with this highly buffered formulation than with other aspirin products that are not enteric-coated] may cause increased risk to patients receiving anticoagulant or thrombolytic therapy)


Anticonvulsants, hydantoin{29}{30}{31}{32}{33}    (aspirin may decrease metabolism of hydantoin anticonvulsants, leading to increased serum concentrations and to increased therapeutic and/or toxic effects of the anticonvulsant; adjustment of hydantoin dosage may be necessary)


» Antidiabetic agents, oral or
Insulin    (effects of these medications may be increased by large doses of aspirin; 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 symptoms of aspirin-induced ototoxicity, {16} such as dizziness, vertigo, and tinnitus)


Bismuth subsalicylate    (ingestion of large repeated doses, e.g., 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 {18})


Calcium-containing preparations or
Milk or milk products    (concurrent and prolonged use with sodium bicarbonate may result in the milk-alkali syndrome {17})


» Cefamandole or
» Cefoperazone or
» Cefotetan or
» Plicamycin    (these medications may cause hypoprothrombinemia; in addition, plicamycin may inhibit platelet aggregation; concurrent use with aspirin may increase the risk of bleeding because of additive interferences with blood clotting and/or the potential occurrence of gastrointestinal ulceration or hemorrhage during aspirin therapy)


Ciprofloxacin or
Norfloxacin    (antacid-induced alkalinization of the urine may reduce the solubility of these medications in urine, leading to a risk of crystalluria and nephrotoxicity; however, the clinical significance of this effect is probably minimal with occasional low-dose use of the aspirin and antacid combination)


Diuretics, loop or
Diuretics, thiazide    (concurrent use with sodium bicarbonate may increase the possibility of hypochloremic alkalosis)


Enteric-coated medications    (sodium bicarbonate increases intragastric pH, which may cause early dissolution, and loss of the protective effect, of enteric coatings; gastric or duodenal irritation may result; the medications should be taken several hours apart)


Furosemide    (concurrent use of furosemide with high doses of aspirin increases the risk of ototoxicity; also, furosemide may competitively inhibit renal excretion of salicylate, thereby increasing the risk of salicylate toxicity)


Histamine H 2-receptor antagonists, such as:
Cimetidine{17}
Famotidine
Nizatidine
Ranitidine    (antacids may decrease absorption of these medications when ingested simultaneously; the medications should be taken at least 30 to 60 minutes apart)


Iron supplements, oral    (antacids decrease absorption of orally administered iron; administration of the medications should be separated by the largest possible interval {17})


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


» Methenamine    (antacid-induced alkalinization of the urine reduces the effectiveness of methenamine in the treatment of urinary tract infections by inhibiting its conversion to the active substance, formaldehyde {17}; although clinical significance with occasional low-dose administration of the aspirin and antacid combination has not been determined, concurrent use is best avoided {06})


» Methotrexate    (aspirin may displace methotrexate from its binding sites and decrease its renal clearance, leading to toxic plasma concentrations of methotrexate; if aspirin is 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 aspirin therapy be withheld for 24 to 48 hours prior to, and for at least 12 hours [or until plasma methotrexate concentrations have decreased to a nontoxic level] following, a high-dose methotrexate infusion)


Mexiletine    (marked antacid-induced alkalinization of the urine may retard renal excretion of mexiletine)


Other medications, oral, especially:
» Ciprofloxacin{34}
» Enoxacin{35}
» Itraconazole{36}
» Ketoconazole{17}
» Lomefloxacin{37}
» Norfloxacin{38}
» Ofloxacin{39}
» Tetracyclines{17}    (antacids present as buffering agents in analgesic products may interfere with the absorption of many other orally administered medications; if used concurrently, a buffered analgesic product 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, 3 to 4 hours before or after tetracycline, and at least 1 to 2 hours before or after other orally administered medications)


Ototoxic medications, other (See Appendix II ), especially
» Vancomycin    (concurrent or sequential administration of these medications with aspirin 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, other (See Appendix II )    (aspirin should be administered concurrently with other platelet aggregation inhibitors only if such therapy is prescribed and monitored by a physician, because additive inhibition of platelet aggregation, the potential occurrence of gastrointestinal ulceration or hemorrhage during aspirin therapy [although less likely with this highly buffered formulation than with other aspirin products that are not enteric-coated], and the hypoprothrombinemic effect of large doses of aspirin increase the risk of serious bleeding)


» Probenecid or
» Sulfinpyrazone    (uricosuric effects of probenecid or sulfinpyrazone may be decreased by doses of aspirin that produce serum salicylate concentrations above 50 mcg per mL [5 mg per 100 mL; 0.36 mmol/L]; also, probenecid may decrease renal clearance and increase plasma concentrations of salicylate, thereby increasing the risk of toxicity)

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

    (concurrent use of sulfinpyrazone with aspirin may increase the risk of gastrointestinal ulceration or hemorrhage, although such effects are less likely with this highly buffered formulation than with other aspirin products that are not enteric-coated; also, concurrent use of sulfinpyrazone with aspirin may increase the risk of bleeding at sites other than the gastrointestinal tract because of additive inhibition of platelet aggregation)


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


Sucralfate    (antacids may interfere with binding of sucralfate to the mucosa when ingested simultaneously; the 2 medications should be taken at least one-half hour apart)


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



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
Copper sulfate urine sugar tests    (false-positive test results may occur with chronic use of 2.4 grams or more of aspirin a day {16})


» Gastric acid secretion test    (sodium bicarbonate may antagonize the effect of pentagastrin or histamine in the evaluation of gastric acid secretory function; administration of sodium bicarbonate is not recommended on the morning of the test)


Gerhardt test for urine aceto-acetic acid    (aspirin may interfere with this test by reacting with ferric chloride to produce a reddish color that persists after boiling {16})


Glucose enzymatic urine sugar tests    (false-negative test results may occur with chronic use of 2.4 grams or more of aspirin a day {16})


5-Hydroxyindoleacetic acid (5-HIAA), urine, determinations    (aspirin may alter results when fluorescent method is used {16})


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)


Renal function test using phenolsulfonphthalein (PSP)    (salicylate [from aspirin] may competitively inhibit renal tubular secretion of PSP, thereby decreasing urinary PSP concentration and invalidating test results {16})


Vanillylmandelic acid (VMA), urine, determinations    (aspirin may cause values to be falsely increased or decreased, depending on method used {16})

With physiology/laboratory test values
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] {16})


Cholesterol, serum    (concentrations may be decreased by chronic use of 5 grams or more of aspirin per day {16})


pH, systemic and urinary    (may be increased by sodium bicarbonate)


Potassium, serum    (concentrations may be decreased because of increased potassium excretion caused by direct effect of aspirin on renal tubules {16})


Uric acid, serum    (concentrations may be increased with doses of aspirin that produce plasma salicylate concentrations below 100 to 150 mcg per mL [10 to 15 mg per 100 mL; 0.724 to 1.09 mmol/L] or decreased with doses that produce plasma salicylate concentrations above 100 to 150 mcg per mL [10 to 15 mg per 100 mL; 0.724 to 1.09 mmol/L] {16})


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:
» Angioedema, anaphylaxis, or other severe allergic reaction induced by aspirin or other NSAIDs, history of    (high risk of recurrence)


» Asthma and nasal polyps, aspirin sensitivity–induced    (high risk of severe allergic reactions)


» Bleeding ulcers or
» Hemorrhagic states, other active    (may be exacerbated {18} because aspirin inhibits platelet aggregation and, in high doses, may decrease procoagulant factor synthesis)


» Hemophilia or other bleeding problems, including coagulation or platelet function disorders    (increased risk of hemorrhage {18})


Risk-benefit should be considered when the following medical problems exist
Anemia    (may be exacerbated because aspirin may increase gastrointestinal blood loss; also, pseudoanemia may result from aspirin-induced peripheral vasodilation {18})


» Any condition in which administration of substantial quantities of sodium would be detrimental, such as:
Congestive heart failure{17}
Edema
Hepatic cirrhosis{17}
Hypertension{17}
Toxemia of pregnancy{17}
» Appendicitis, or symptoms of    (antacids may complicate existing condition {17})


» Gastritis, erosive or
» Peptic ulcer    (may be exacerbated because of aspirin's ulcerogenic effects; risk of gastrointestinal bleeding is increased {18})


Gout    (aspirin may increase serum uric acid concentrations and interfere with efficacy of uricosuric agents {18})


Hepatic function impairment    (salicylates metabolized in liver; also, in severe hepatic impairment, inhibition of platelet function by aspirin may increase risk of hemorrhage)


Hypoprothrombinemia or
Vitamin K deficiency{18}    (increased risk of bleeding because of antiplatelet action of aspirin and decreased procoagulant factor synthesis with high doses)


Mild sensitivity reaction to aspirin, history of    (increased risk of severe allergic reactions)


» Renal function impairment, especially if resulting in anuria or oliguria    (increased risk of sodium retention, which may lead to hypernatremia, edema, and increased blood pressure)

    (increased risk of salicylate toxicity because of reduced excretion {18})



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):

Renal function determinations    (may be required during long-term, high-dose use of sodium bicarbonate, especially in patients with renal function impairment {17})




Side/Adverse Effects

Note: Aspirin may decrease renal function, especially when serum salicylate concentrations reach 250 mcg per mL (25 mg per 100 mL; 1.8 mmol/L). However, the risk of complications due to this action appears minimal in patients with normal renal function. {18}
Aspirin-induced bronchospasm is most likely to occur in patients with the triad of asthma, allergies, and nasal polyps induced by aspirin {18}.
Aspirin-induced angioedema or urticaria may be more likely to occur in patients with a history of recurrent idiopathic angioedema or urticaria {18}.
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 {18}. Although use of this highly buffered formulation may decrease the risk of adverse gastrointestinal effects, this potential benefit must be weighed against the risk of administering large quantities of sodium bicarbonate {06}.
Adverse effects are more likely to occur at serum salicylate concentrations of 300 mcg per mL (30 mg per 100 mL; 2.17 mmol/L) 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: {18}



Salicylate Concentration
Effect
mcg/mL
mg/100
mL
mmol/L
±200
±20
1.45
Mild toxicity (tinnitus, decreased hearing)
250
25
1.8
Hepatotoxicity (abnormal liver function tests);
Decreased renal function
300
30
2.17
Decreased prothrombin time
310
31
2.24
Deafness
350
35
2.53
Hyperventilation
>400
>40
2.9
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 unknown—dependent on dosage and on frequency and duration of sodium bicarbonate administration {17}
    
Edema (swelling of face, fingers, ankles, feet, or lower legs; unusual weight gain)
    
hypercalcemia associated with milk-alkali syndrome (frequent urge to urinate; continuing headache; continuing loss of appetite; nausea or vomiting; unusual tiredness or weakness)
    
increased blood pressure
    
metabolic alkalosis (mood or mental changes; muscle pain or twitching; nervousness or restlessness; slow breathing; unpleasant taste; unusual tiredness or weakness)—more likely in patients with renal function impairment

Incidence less frequent or rare
    
Anaphylaxis (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)—may occur secondary to gastrointestinal microbleeding
    
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 )



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal irritation (heartburn, indigestion, mild stomach pain and/or nausea with or without vomiting)
    
increased thirst
    
stomach cramps





Overdose
For specific information on the agents used in the management of aspirin, sodium bicarbonate, and citric acid overdose, see Charcoal, Activated (Oral-Local) 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 syptoms 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)
    
severe overdose (bloody urine; convulsions; hallucinations; severe nervousness, excitement, or confusion; shortness of breath or troubled breathing; unexplained fever){18}
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 {18}.
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 {18}.




Treatment of overdose
{20}{24}{25}{26}To decrease absorption—Emptying the stomach via induction of emesis 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. 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.

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

Specific treatment—For treatment of hemorrhaging caused by overdose: Vitamin K 1 or blood may be administered. See the package insert or Vitamin K (Systemic) monograph for specific dosing guidelines for use of this product.

Monitoring—May include monitoring for pulmonary edema and instituting appropriate therapy if required.

Monitoring serum salicylate concentration until it is apparent that the concentration is decreasing to the nontoxic range. Salicylate 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. Salicylate concentrations indicative of varying degrees of toxicity are as follows:



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—May include 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 referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Aspirin, Sodium Bicarbonate, and Citric Acid (Systemic).

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

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or sodium bicarbonate

Pregnancy—Not taking aspirin in third trimester unless prescribed by physician; high-dose, chronic use or abuse of aspirin in 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 may also prolong and complicate labor and delivery; sodium may cause edema and weight gain





Use in children—Checking with physician before giving to children with symptoms of acute febrile illness, especially influenza or varicella, because of the risk of Reye"s syndrome; also, increased susceptibility to aspirin toxicity in children, especially with fever and dehydration



Use in teenagers— Checking with physician before giving to teenagers with symptoms of acute febrile illness, especially influenza or varicella, because of the risk of Reye's syndrome





Use in the elderly— Increased risk of aspirin toxicity; also, because of the very high sodium content, use should preferably be limited to 5 days at a time, unless more prolonged therapy is prescribed and monitored by a physician
Other medications, especially anticoagulants, oral antidiabetic agents, oral imidazole antifungals, mecamylamine, methenamine, methotrexate, NSAIDs, platelet aggregation inhibitors, those cephalosporins that may cause hypoprothrombinemia, probenecid, sulfinpyrazone, oral tetracyclines, and vancomycin
Other medical problems, especially symptoms of appendicitis, coagulation or platelet function disorders, conditions in which sodium may be detrimental, gastrointestinal problems such as ulceration or erosive gastritis (especially a bleeding ulcer) or gastrointestinal obstruction, and renal function impairment

Proper use of this medication
» Importance of not taking more medication than recommended on package label, unless otherwise directed by physician, because of risk of aspirin- or sodium bicarbonate-induced adverse effects

Proper administration:

Taking in liquid form only; not ingesting tablets or tablet fragments

Preparing liquid: Placing 1 or 2 tablets in glass, then adding 1/2 glass (120 mL) cool water

Checking for complete tablet dissolution before drinking; drinking while solution is still effervescing, or after it has settled

Drinking entire amount, then rinsing glass with a little more water and drinking that, to ensure receiving full dosage

» Proper dosing
Missed dose (if on scheduled dosing): Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress if long-term or high-dose therapy is prescribed

Checking with physician if symptoms persist for longer than 10 days for adults or 5 days for children, condition becomes worse, new symptoms occur, or the painful area is red or swollen

» Not taking this medication within:

   —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
   —3 to 4 hours before or after an oral tetracycline
   —1 or 2 hours before or after any other oral medication


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

» Possibility of overdose if other medications containing aspirin or other salicylates (including diflunisal) or significant quantities of sodium are used

Not taking aspirin for 5 days prior to any kind of surgery, unless otherwise directed by physician

» If taking aspirin as a platelet aggregation inhibitor:

Taking only the amount prescribed; checking with physician to determine whether an alternative medication, rather than additional aspirin, should be used to relieve pain, fever, arthritis

Not discontinuing therapy without first checking with the prescriber

Not using an NSAID together with this medication for more than a few days, unless otherwise directed by physician

If taking more than an occasional 1 or 2 doses of this medication:

» Avoiding alcoholic beverages, because of the increased risk of aspirin-induced gastrointestinal toxicity

» Avoiding large amounts of milk or milk products

Possible need for sodium restriction

Caution if any laboratory tests required; possible interference with test results

Diabetics: Aspirin may cause false urine sugar test results with prolonged use of 8 or more 325-mg (5-grain) doses per day

» Suspected overdose: Getting emergency help at once


Side/adverse effects
Signs of potential side effects, especially edema, hypercalcemia associated with milk-alkali syndrome, increased blood pressure, metabolic alkalosis, anaphylaxis, anemia, bronchospastic allergic reaction, allergic dermatitis, and gastrointestinal ulceration or bleeding


General Dosing Information
The dosage of aspirin should be reduced if fever or illness causes fluid depletion, especially in children {18}.

In general, it is recommended that aspirin therapy be discontinued 5 days before surgery to reduce the risk of bleeding problems {18}.

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). Desensitized patients will also be able to tolerate nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin. However, unless aspirin or another NSAID is then administered on a daily basis, intolerance of these medications redevelops within a few days. {19}

For treatment of adverse effects
Recommended treatment of metabolic alkalosis consists of the following:

   • Rebreathing of expired air from a paper bag or mask.
   • Parenteral administration of calcium gluconate, for severe alkalosis.


Oral Dosage Forms

ASPIRIN EFFERVESCENT TABLETS FOR ORAL SOLUTION USP

Usual adult and adolescent dose {01} {02} {03}
Analgesic/antacid
Oral, 325 to 500 mg of aspirin every three hours, 325 to 650 mg of aspirin every four hours, or 650 mg to 1 gram of aspirin every six hours as needed, while symptoms persist.

Note: It is recommended that the total daily dose of aspirin not exceed 4 grams, and that a physician be consulted if symptoms are not relieved within ten days.


Platelet aggregation inhibitor1
Oral, 325 mg of aspirin a day.

Note: Optimal dosage has not been established. Doses lower than 325 mg of aspirin a day are often utilized, since there is evidence that 160 mg of aspirin every twenty-four hours may effectively inhibit platelet aggregation while minimizing the risk of aspirin-induced side effects. Doses higher than 325 mg of aspirin a day are also recommended for specific indications responsive to platelet aggregation inhibition. However, because of its high sodium bicarbonate content, this formulation is not recommended for long-term therapy with doses higher than 325 mg of aspirin a day.



Usual adult prescribing limits
Geriatric patients—Oral, up to 4 regular-strength or extra-strength tablets a day {01} {02} {03}. Limiting the duration of treatment to five days may be advisable, unless longer treatment is prescribed and monitored by a physician {06}.

Nongeriatric adults—Oral, up to 8 regular-strength unflavored tablets {01}, 6 regular-strength flavored tablets {02}, or 7 extra-strength {03} tablets a day. A physician should be consulted if symptoms are not relieved within ten days.

Note: The lower maximum daily dosage recommended for the flavored regular-strength formulation, which contains more citric acid per tablet than the unflavored regular-strength formulation, is dictated by the FDA-mandated twenty-four-hour dosing limit for citric acid in OTC products {27}.


Usual pediatric dose
Analgesic/antacid {06}
Children up to 3 years of age: Dosage must be individualized by physician.

Children 3 to 5 years of age: Oral, 167 mg of aspirin (one-half of a regular-strength tablet) every four to six hours as needed, while symptoms persist.

Children 6 to 12 years of age: Oral, 325 mg (one regular-strength tablet) every four to six 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 symptoms are not relieved within five days.



Strength(s) usually available

Note: When dissolved in water, aspirin effervescent tablets for oral solution provide aspirin in the form of sodium acetylsalicylate.

U.S.—



{01} {02} {03}Regular-strength


325 mg of aspirin, with 1.916 grams of sodium bicarbonate and 1 gram of citric acid (OTC) [Alka-Seltzer Effervescent Pain Reliever and Antacid (sodium 567 mg [24.65 mmol] per tablet)]


325 mg of aspirin, with 1.71 grams of sodium bicarbonate and 1.22 grams of citric acid (OTC) [Flavored Alka-Seltzer Effervescent Pain Reliever and Antacid (sodium 506 mg [22 mmol] per tablet)]



Extra-strength


500 mg of aspirin, with 1.985 grams of sodium bicarbonate and 1 gram of citric acid (OTC) [Alka-Seltzer Effervescent Pain Reliever and Antacid (sodium 588 mg [25.56 mmol] per tablet)]

Canada—



{04}Regular strength


325 mg of ASA, with 1.916 grams of sodium bicarbonate and 1 gram of citric acid (OTC) [Alka-Seltzer Effervescent Pain Reliever and Antacid (sodium 567 mg [24.65 mmol] per tablet)]


325 mg of ASA, with 1.71 grams of sodium bicarbonate and 1.22 grams of citric acid (OTC) [Flavored Alka-Seltzer Effervescent Pain Reliever and Antacid (sodium 506 mg [22 mmol] per tablet)]

Note: 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.


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:
   • Keep container tightly closed.

Note: Explain preparation of solution and administration.

1 Not included in Canadian product labeling.



Revised: 08/29/1994



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. Alka-Seltzer Effervescent Antacid & Pain Reliever (Miles Consumer Healthcare). In: PDR Physicians' desk reference for nonprescription drugs. 14th ed. 1992. Montvale, NJ: Medical Economics Data, 1993: 609-10.
  1. Flavored Alka-Seltzer Effervescent Antacid & Pain Reliever (Miles Consumer Healthcare). In: PDR Physicians' desk reference for nonprescription drugs. 14th ed. 1992. Montvale, NJ: Medical Economics Data, 1993: 610-1.
  1. Extra Strength Alka-Seltzer Antacid & Pain Reliever (Miles Consumer Healthcare). In: PDR Physicians' desk reference for nonprescription drugs. 14th ed. 1992. Montvale, NJ: Medical Economics Data, 1993: 612.
  1. Alka-Seltzer formulations (Miles Consumer Healthcare). In: Krogh CME, editor. Self-Medication Product Information. 4th ed. Ottawa: Canadian Pharmaceutical Association, 1992: M10, T83.
  1. US Food and Drug Administration. Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; amendment to tentative final monograph. Federal Register 1994 February 2; 59(22): 5068-70.
  1. Panel response to monograph revision 1/90.
  1. Tentative final monograph. Notice of proposed rulemaking for internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use. Washington, DC: Federal Food and Drug Administration. Federal Register 53 (221), 1988 Wednesday Nov 16: 46204-46258.
  1. Panel response to Salicylates monograph ballot 8/89.
  1. Chest 1989 Feb; 95 (suppl): 98S-106S.
  1. Chest 1989 Feb; 95 (suppl): 128S-139S.
  1. Chest 1989 Feb; 95 (suppl): 140S-155S.
  1. Chest 1989 Feb; 95 (suppl): 52S-72S.
  1. Chest 1989 Feb; 95 (suppl): 107S-117S.
  1. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988 Aug 13; 2: 349-60.
  1. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc, 1993: 59, 155, 607.
  1. Panel response to Salicylates monograph revision 1980.
  1. Panel response to Sodium bicarbonate monograph revision 1982.
  1. Panel response to Salicylates monograph revision 1982.
  1. Seminar at American Academy of Allergy and Immunology Annual Meeting. Washington, DC, 2/87.
  1. Panel response to Salicylates ballot 6/90.
  1. Panel response to Salicylates monograph revision 1983.
  1. Panel response to monograph revision 1/90.
  1. Panel response to monograph revision 1/90.
  1. Committee on accident and poison prevention. American Academy of Pediatrics. Salicylates. In: Aronow R, editor. 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, Dolan MC, McKnight DR. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989 Nov; 18: 1186-90.
  1. Personal communication
  1. Panel response to Itraconazole monograph revision 1993.
  1. Larsen JR, Larsen LS. Clinical features and management of poisoning due to phenytoin. Med Toxicol Adverse Drug Exp 1989; 4(4): 229-45.
  1. Hansten PD, Horn JR. Drug interactions. Philadelphia: Lea & Febiger, 5th ed., 1985: 121-38.
  1. Shinn AF, Shrewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St Louis: Mosby, 1985: 229-70.
  1. Nation RL, Evans AM, Milne RW. Pharmacokinetic drug interactions with phenytoin (Part I). Clin Pharmacokinet 1990 Jan; 18(1): 37-60.
  1. Dilantin/Phenytoin ``Right Dose'' Program. Advances in the management of acute seizures in hospitalized patients. Resource Manual. Health Sciences Institute, 1990.
  1. Hoffken G, et al. Pharmacokinetics and bioavailability of ciprofloxacin and ofloxacin: effects of food and antacid intake. Rev Infect Dis 1988; 19(suppl 1): S138-S139.
  1. Penetrex (Rhone-Poulenc Rorer). In: PDR Physicians' desk reference. 48th ed. 1994. Montvale, NJ: Medical Economics Data Production Company, 1994: 1861-3.
  1. Panel response to Itraconazole monograph revision 1993.
  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 Agent 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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