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Excedrin Migraine
Classes
Analgesics with Antipyretic Activity Combinations
Administration
Tablets, caplets, or geltabs: Administer with a full glass of water. Food or milk may minimize GI upset.
Powder: Place one powder on tongue and follow with plenty of liquid, or stir powder into a glass of water or other liquid.
Adverse Reactions
odynophagia / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
Reye's syndrome / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
renal papillary necrosis / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
renal tubular necrosis / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
methemoglobinemia / Early / Incidence not known
hemolytic anemia / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
erythema nodosum / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
laryngeal edema / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
encephalopathy / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hypoprothrombinemia / Delayed / Incidence not known
bleeding / Early / Incidence not known
proteinuria / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
thrombocytosis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
prolonged bleeding time / Delayed / Incidence not known
platelet dysfunction / Delayed / Incidence not known
hemolysis / Early / Incidence not known
edema / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
hyperuricemia / Delayed / Incidence not known
sinus tachycardia / Rapid / Incidence not known
palpitations / Early / Incidence not known
withdrawal / Early / Incidence not known
medication overuse headache / Delayed / Incidence not known
pyrosis (heartburn) / Early / 2.0-10.0
dyspepsia / Early / 2.0-10.0
abdominal pain / Early / 2.0-10.0
vomiting / Early / 2.0-10.0
nausea / Early / 2.0-10.0
fever / Early / Incidence not known
anorexia / Delayed / Incidence not known
leukocytosis / Delayed / Incidence not known
purpura / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
rash / Early / Incidence not known
urticaria / Rapid / Incidence not known
dizziness / Early / Incidence not known
tinnitus / Delayed / Incidence not known
rhinitis / Early / Incidence not known
tremor / Early / Incidence not known
anxiety / Delayed / Incidence not known
insomnia / Early / Incidence not known
diarrhea / Early / Incidence not known
polyuria / Early / Incidence not known
Common Brand Names
Bayer Migraine Formula, BC MAX STRENGTH Fast Pain Relief, Excedrin Extra Strength, Excedrin Extra Strength Express, Excedrin Menstrual Complete, Excedrin Migraine, Genaced, Goody's Extra Strength, Goody's Extra Strength (Cool Orange), Goody's Extra Strength Headache, Goody's Extra Strength Headache Powder (Mixed Fruit Blast ), Pain Reliever Plus, Pamprin, Pamprin Maximum Strength, Vanquish
Dea Class
OTC
Description
Combinations product used for HA (including migraine), sinus congestion pain, myalgia, dysmenorrhea, dental pain, and minor arthritis pain. Acetaminophen is a non-narcotic analgesic; aspirin is a salicylate analgesic. Caffeine may increase the bioavailability of certain analgesics but does not have intrinsic analgesic properties.
Dosage And Indications
NOTE: Each powder contains approximately 60 mg of potassium.
Oral dosage (powder formulations) Adults, Adolescents, and Children 12 years and older
Place powder of 1 packet on tongue and follow with full glass of water, or may stir powder into a glass of water or other liquid. May repeat every 6 hours. Do not exceed 4 powders per 24 hours.
For self-medication, take 2 tablets, caplets, or geltabs PO every 6 hours as needed. Maximum of 8 tablets, caplets, or geltabs per 24 hours. For pain, do not take for more than 10 days unless directed by a physician.
500 mg acetaminophen/500 mg aspirin/130 mg caffeine PO as a single dose. Max: 500 mg/day acetaminophen/500 mg/day aspirin/130 mg/day caffeine. Guidelines classify acetaminophen; aspirin; caffeine as having established efficacy for the treatment of acute migraine.
Dosing Considerations
Acetaminophen; aspirin, ASA; caffeine should be used with extreme caution in patients with impaired hepatic function, with a prior history of acetaminophen overdose, or with a history of alcoholism.
Renal ImpairmentDosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Acetaminophen is the analgesic of choice for episodic pain in patients with underlying renal disease but, chronic use of this acetaminophen; aspirin, ASA; caffeine combination product in these patients should be discouraged (see Precautions).
Drug Interactions
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Abciximab: (Moderate) Unless contraindicated, aspirin is used in combination with abciximab. However, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Abrocitinib: (Contraindicated) Concurrent use with daily aspirin doses higher than 81 mg is contraindicated during the first 3 months of abrocitinib therapy due to an increased risk of bleeding with thrombocytopenia.
Acetaminophen; Caffeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Acetaminophen; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetaminophen; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acetazolamide: (Major) Avoid the coadministration of high-dose salicylates and carbonic anhydrase inhibitors whenever possible. There were reports of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death with high-dose aspirin and acetazolamide. Two mechanisms could cause increased acetazolamide concentrations, resulting in CNS depression and metabolic acidosis: first, competition with aspirin for renal tubular secretion and, second, displacement by salicylates from plasma protein binding sites. Additionally, carbonic anhydrase inhibitors alkalinize urine and increase the excretion of normal doses of salicylates; decreased plasma salicylate concentrations may or may not be clinically significant.
Acidifying Agents: (Moderate) Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.
Aclidinium; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Acrivastine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Acyclovir: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of acyclovir is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and acyclovir is a CYP1A2 inhibitor.
Adenosine: (Major) Larger doses of adenosine may be required or adenosine may not be effective in the presence of methylxanthines. The effects of adenosine are antagonized by methylxanthines. When used for diagnostic purposes, instruct patients to avoid consumption of methylxanthine-containing products, including caffeinated beverages, for at least 5 half-lives prior to the imaging study.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of aspirin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Albuterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Albuterol; Budesonide: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Alendronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Alendronate; Cholecalciferol: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Alkalinizing Agents: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Alogliptin: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alogliptin; Pioglitazone: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood glucose concentrations. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Alpha-glucosidase Inhibitors: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents.
Amantadine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Amiloride: (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. (Moderate) Salicylates can increase the risk of renal insufficiency in patients receiving diuretics, secondary to effects on renal blood flow. Salicylates inhibit renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Coadministration may cause hyperkalemia.
Aminoglycosides: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like the aminoglycosides may lead to additive nephrotoxicity.
Amiodarone: (Minor) Amiodarone is an inhibitor of CYP1A2 isoenzymes, and could theoretically reduce CYP1A2-mediated caffeine metabolism. The clinical significance of this potential interaction is not known.
Amlodipine; Benazepril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Amlodipine; Celecoxib: (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Amobarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Amoxicillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amoxicillin; Clarithromycin; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amoxicillin; Clavulanic Acid: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Amphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphetamine; Dextroamphetamine Salts: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphetamine; Dextroamphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Amphotericin B lipid complex (ABLC): (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Amphotericin B liposomal (LAmB): (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Amphotericin B: (Minor) Concurrent use of amphotericin B and other potentially nephrotoxic medications, like the salicylates, may enhance the potential for drug-induced renal toxicity.
Ampicillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Ampicillin; Sulbactam: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including caffeine, could lead to increases in the serum concentrations of caffeine and, thus, adverse effects. (Moderate) Use caution with the coadministration of aspirin and anagrelide. The coadministration of single or repeated doses of anagrelide and aspirin resulted in greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. In an observational study, the concomitant use of anagrelide and aspirin increased the rate of major hemorrhagic events compared to patients receiving other cytoreductive therapy. Assess the risks and benefits of concomitant aspirin and anagrelide use, particularly in patients at high risk for hemorrhage. Monitor for bleeding during concomitant therapy.
Angiotensin-converting enzyme inhibitors: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Antithrombin III: (Moderate) Large doses of salicylates (more than 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and antithrombin III should be monitored closely for bleeding.
Apixaban: (Major) Large doses of salicylates (3 to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
Aprepitant, Fosaprepitant: (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Arformoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Armodafinil: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with armodafinil. Caffeine should be used cautiously with armodafinil. Intake of caffeine should be limited. Excessive intake may cause nervousness, irritability, insomnia, or other side effects.
Articaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Ascorbic Acid, Vitamin C: (Minor) Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can decrease salicylate excretion. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Aspirin, ASA; Caffeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Aspirin, ASA; Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Atenolol; Chlorthalidone: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Azilsartan; Chlorthalidone: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Bacitracin: (Minor) Additive nephrotoxicity may occur with concurrent use of systemic bacitracin and other nephrotoxic agents, including salicylates. Topical administration of any preparation containing bacitracin, especially when applied to large surface areas, also should not be given with other drugs that have a nephrotoxic potential.
Barbiturates: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Moderate) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as barbiturates. An enhanced effect of the displaced drug may occur. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Benazepril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Benzodiazepines: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Benzphetamine: (Moderate) Avoid excessive caffeine intake during use of benzphetamine. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Beta-agonists: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Beta-blockers: (Moderate) Concurrent use of beta-blockers with aspirin and other salicylates may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.
Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and aspirin are used concomitantly. Coadministration of betrixaban and aspirin may increase the risk of bleeding.
Bismuth Subsalicylate: (Moderate) Monitor for salicylate-related adverse effects, including salicylate toxicity, if concomitant use of aspirin and bismuth subsalicylate is necessary. Adverse reactions, such as bleeding, renal impairment, and tinnitus, may occur.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Monitor for salicylate-related adverse effects, including salicylate toxicity, if concomitant use of aspirin and bismuth subsalicylate is necessary. Adverse reactions, such as bleeding, renal impairment, and tinnitus, may occur.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Bromocriptine: (Minor) Bromocriptine is highly bound (more than 90%) to serum proteins. Therefore, it may increase the unbound fraction of other highly protein-bound medications (e.g., aspirin and other salicylates), which may alter their effectiveness and risk for side effects.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Budesonide; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Bumetanide: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupivacaine; Meloxicam: (Major) Concomitant use of low dose aspirin or analgesic doses of aspirin and meloxicam is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Bupropion: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
Bupropion; Naltrexone: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
Buspirone: (Minor) In vitro studies showed that therapeutic levels of aspirin, ASA increased the plasma concentrations of free buspirone by 23% through plasma protein binding displacement. In vivo interaction studies with these drugs have not been performed.
Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butabarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Caffeine has been reported to increase the metabolism of aspirin. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Caffeine: (Moderate) Certain foods that contain high amounts of caffeine or theobromine should be limited during the therapeutic use of caffeine in order to limit additive methylxanthine effects. While taking Caffeine-containing medicines, limit the use of foods, beverages (examples: coffee, tea, colas), herbs (examples: guarana, green tea) and other products that contain additional caffeine, such as chocolate and some non-prescription medications or dietary supplements for headache, insomnia, or weight loss. Too much Caffeine can cause effects like nausea, nervousness, or sleeplessness. Some drug products for adults that contain caffeine have about as much caffeine as a cup of coffee. (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Caffeine; Sodium Benzoate: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant canagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant canagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Cannabidiol: (Moderate) Consider a dose reduction of caffeine as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased caffeine exposure is possible. Caffeine is a CYP1A2 substrate and cannabidiol is a weak CYP1A2 inhibitor.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and aspirin when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Capmatinib: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of capmatinib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and capmatinib is a CYP1A2 inhibitor. Coadministration with capmatinib increased caffeine exposure by 134%.
Capreomycin: (Major) Since capreomycin is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug. Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered.
Captopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Carbamazepine: (Minor) Carbamazepine may induce caffeine metabolism via induction of the hepatic CYP1A2 isoenzyme. (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
Cefixime: (Minor) In vitro, salicylates have displaced cefixime from its protein-binding sites, resulting in a 50% increase in free cefixime levels. The clinical significance of this effect is unclear at this time.
Cefotetan: (Minor) Cefotetan has been associated with hypoprothrombinemia and may cause additive effects when given concurrently with salicylates.
Celecoxib: (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
Celecoxib; Tramadol: (Major) Concomitant use of analgesic doses of aspirin and celecoxib is generally not recommended due to the increased risk of bleeding. Concurrent use of analgesic doses of aspirin with NSAIDs does not produce a greater therapeutic effect compared to the use of NSAIDs alone. Celecoxib (200 to 400 mg/day) did not interfere with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg) in 2 studies in healthy volunteers and in patients with osteoarthritis and established heart disease. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
Cetirizine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Chlorothiazide: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activ
Chlorpheniramine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpheniramine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Chlorpropamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Chlorthalidone: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Chlorthalidone; Clonidine: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
Cidofovir: (Contraindicated) The concomitant administration of cidofovir and NSAIDs, such as aspirin, is contraindicated due to the potential for increased nephrotoxicity. Aspirin should be discontinued 7 days prior to beginning cidofovir.
Cilostazol: (Moderate) Use caution with the coadministration of aspirin and cilostazol. Although the short-term (<= 4 days) coadministration of aspirin and cilostazol increased the inhibition of ADP-induced platelet aggregation by 22% to 37% compared to aspirin or cilostazol use alone, no clinically significant effect on PT, aPTT, or bleeding time was observed compared to aspirin alone. In clinical trials, there was no apparent increase in hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to aspirin alone. The effects of long-term coadministration are unknown. Monitor for bleeding during concomitant therapy.
Cimetidine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
Ciprofloxacin: (Moderate) Reduction or limitation of the caffeine dosage in medications and limitation of caffeine in beverages and food may be necessary during concurrent ciprofloxacin therapy. Ciprofloxacin can decrease the clearance of caffeine. Caffeine toxicity may occur and can manifest as nausea, vomiting, anxiety, tachycardia, or seizures. Ciprofloxacin is a CYP1A2 inhibitor and caffeine is a CYP1A2 substrate.
Citalopram: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Clomipramine: (Moderate) Clomipramine may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. This may increase the risk for an upper GI bleed.
Clopidogrel: (Moderate) Monitor for bleeding if aspirin and clopidogrel are used together as concomitant has an additive effect on platelet function.
Clozapine: (Major) Caffeine may inhibit clozapine metabolism via CYP1A2. Clozapine clearance has been decreased by roughly 14 percent during coadministration of caffeine, and a documented increase in clozapine serum concentrations has occurred in selected patients. In addition, a single case report associates the appearance of psychiatric symptoms with caffeine ingestion in one patient taking clozapine. Until more data are available, caffeine consumption should be minimized during clozapine treatment.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Codeine; Phenylephrine; Promethazine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Colistimethate, Colistin, Polymyxin E: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug.
Colistin: (Major) Theoretically, the chronic coadministration of these drugs may increase the risk of developing nephrotoxicity, even in patients who have normal renal function. Monitor patients for changes in renal function if these drugs are coadministered. Since colistimethate sodium is eliminated by the kidney, coadministration with other potentially nephrotoxic drugs, including salicylates, may increase serum concentrations of either drug.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking more than 150 mg/day of aspirin is advised. The efficacy and safety of administering injectable collagenase to a patient taking more than 150 mg/day of aspirin within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Corticosteroids: (Moderate) Monitor for gastrointestinal toxicity during concurrent corticosteroid and salicylate use. Concomitant use increases the risk of GI bleeding. In patients receiving concomitant corticosteroids and chronic use of salicylates, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.
Cyclosporine: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents like cyclosporine may lead to additive nephrotoxicity.
Dabigatran: (Major) Educate patients about the signs of increased bleeding and the need to report these signs to a healthcare provider immediately if coadministration of dabigatran and aspirin or another salicylate is necessary. Dabigatran can cause significant and, sometimes, fatal bleeding. This risk may be increased by concurrent use of chronic salicylate therapy.
Dalteparin: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant dapagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
Daratumumab; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Darifenacin: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urination, and counteract the effectiveness of darifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including salicylates.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like aspirin is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Desloratadine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Dexbrompheniramine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextroamphetamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Dextromethorphan; Bupropion: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dichlorphenamide: (Major) Dichlorphenamide is contraindicated with the concomitant use of high dose aspirin, ASA and should be used cautiously in patients receiving low dose aspirin. Dichlorphenamide may cause an elevation in salicylate concentrations in patients receiving aspirin. Adverse reactions including anorexia, tachypnea, lethargy, and coma have been reported with the concomitant use of dichlorphenamide and high dose aspirin.
Diclofenac: (Major) Concomitant use of analgesic doses of aspirin and diclofenac is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Diclofenac is not a substitute for low dose aspirin for cardiovascular protection.
Diclofenac; Misoprostol: (Major) Concomitant use of analgesic doses of aspirin and diclofenac is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Diclofenac is not a substitute for low dose aspirin for cardiovascular protection.
Dicloxacillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Diethylpropion: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Diflunisal: (Major) The concurrent use of diflunisal and salicylates is not recommended due to the increased risk of gastrointestinal toxicity with little or no increase in anti-inflammatory efficacy. (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
Diphenhydramine; Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Diphenhydramine; Naproxen: (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
Diphenhydramine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Dipyridamole: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Disulfiram: (Moderate) Disulfiram has been shown to inhibit caffeine elimination. Caffeine elimination decreased by 30 percent in those patients that were not recovering alcoholics and by 24 percent in those patients that were recovering alcoholics. During disulfiram therapy, patients may need to limit their caffeine intake if nausea, nervousness, tremor, restlessness, palpitations, or insomnia complaints occur. Adverse events were not noted during this pharmacokinetic study, however, the decrease in caffeine clearance could be significant in some patients, including some patients with cardiovascular disease.
Dobutamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Dopamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Doxapram: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants, like doxapram. CNS stimulants and sympathomimetics are associated with adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias, and the concomitant use of these drugs increases the risk of developing such adverse reactions. Coadminsitration should be avoided or used cautiously.
Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Echinacea: (Moderate) Echinacea may inhibit the metabolism of caffeine. Echinacea reduces the oral clearance of caffeine by 27 percent and increases the mean AUC by 129 percent. Monitor patients for signs of increased caffeine serum concentrations if these drugs are coadministered until more data are available.
Edoxaban: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Efavirenz: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Efgartigimod Alfa; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant empagliflozin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Enalapril, Enalaprilat: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Enoxaparin: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
Ephedrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants like ephedrine. Adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with ephedrine. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
Ephedrine; Guaifenesin: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants like ephedrine. Adverse effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with ephedrine. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, guarana, colas, or chocolate) to avoid caffeine-like side effects.
Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Epoprostenol: (Moderate) When used concurrently with platelet inhibitors, epoprostenol may increase the risk of bleeding.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Eptifibatide: (Moderate) Unless contraindicated, aspirin is used in combination with eptifibatide. However, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Ergotamine; Caffeine: (Minor) Caffeine has been reported to increase the metabolism of aspirin.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant sitagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Erythromycin: (Moderate) Inhibitors of the hepatic CYP4501A2, such as erythromycin, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine related side effects. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced.
Escitalopram: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and caffeine. Coadministration of psychostimulants, such as caffeine, with esketamine may increase blood pressure.
Eszopiclone: (Minor) Patients taking eszopiclone for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime, as well as excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep. Limit use of caffeine-containing products including medications, dietary supplements (e.g., guarana), and beverages (e.g., coffee, green tea, other teas, or colas).
Ethacrynic Acid: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Ethanol: (Major) Concomitant ingestion of alcohol with salicylates, especially aspirin, ASA, increases the risk of developing gastric irritation and GI mucosal bleeding. Alcohol and salicylates are mucosal irritants and aspirin decreases platelet aggregation. Routine ingestion of alcohol and aspirin can cause significant GI bleeding, which may or may not be overt. Even occasional concomitant use of salicylates and alcohol should be avoided. Chronic ingestion of alcohol is often associated with hypoprothrombinemia and this condition increases the risk of salicylate-induced bleeding. Patients should be warned regarding the potential for increased risk of GI bleeding if alcohol-containing beverages are taken concurrently with salicylates. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.
Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Ethotoin: (Minor) Large doses of salicylates can displace hydantoins from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Etidronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of etidronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Etodolac: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Exenatide: (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
Fenoprofen: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Fesoterodine: (Minor) Beverages containing caffeine or ethanol may aggravate bladder symptoms and counteract the effectiveness of fesoterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas) and alcoholic beverages.
Fexofenadine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
Flavocoxid, Flavocoxid; Citrated Zinc Bisglycinate: (Major) Because flavocoxid has been associated with isolated cases of occult GI bleeding, additive pharmacodynamic effects may be seen in patients receiving salicylates. Avoid the concurrent use of flavocoxid with salicylates until further data are available.
Fluconazole: (Moderate) Fluconazole has been shown to inhibit the clearance of caffeine by 25 percent. The clinical significance of these interactions has not been determined.
Fluoxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Flurbiprofen: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Fluticasone; Salmeterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Fluticasone; Vilanterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Fluvoxamine: (Moderate) Strong inhibitors of CYP1A2, such as fluvoxamine, may inhibit the metabolism of caffeine. No specific management is recommended except in patients with caffeine-related side effects after initiating fluvoxamine. In such patients, the dosage of caffeine containing medications or the ingestion of caffeine containing products may need to be reduced. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Fondaparinux: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA) in combination with fondaparinux. Data on the concomitant use of fondaparinux with aspirin are lacking; however, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Formoterol; Mometasone: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Foscarnet: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents, such as foscarnet, may lead to additive nephrotoxicity.
Fosinopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Fosphenytoin: (Minor) Large doses of salicylates can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug. Fosphenytoin is converted to phenytoin in vivo, so this interaction may also occur with fosphenytoin.
Furosemide: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Garlic, Allium sativum: (Moderate) Garlic, Allium sativum may produce clinically-significant antiplatelet effects; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as aspirin, ASA.
Ginger, Zingiber officinale: (Moderate) There may be an increased risk of bleeding in patients on aspirin therapy who take ginger as a supplement (i.e., usual dietary intake is not expected to pose a risk). Several pungent constituents of ginger, Zingiber officinale are reported to inhibit arachidonic acid induced platelet activation in human whole blood. Ginger-associated platelet inhibition may be related to a decrease in COX-1/Thromboxane synthase enzymatic activity. The increased risk of bleeding is theoretical; clinical data of an interaction are not available.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and aspirin as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Givosiran: (Major) Avoid concomitant use of givosiran and caffeine due to the risk of increased caffeine-related adverse reactions. If use is necessary, consider decreasing the caffeine dose. Caffeine is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glipizide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glycopyrrolate; Formoterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Grapefruit juice: (Minor) Data are limited and conflicting as to whether grapefruit juice significantly alters the serum concentrations and/or AUC of caffeine. Caffeine is primarily a CYP1A2 substrate, and grapefruit juice appears to have but a small effect on this enzyme in vivo. One report suggests that grapefruit juice decreases caffeine elimination by inhibition of flavin-containing monooxygenase, a P450 independent system. This interaction might increase caffeine levels and mildly potentiate the clinical effects and common side effects of caffeine. If side effects appear, patients may need to limit either caffeine or grapefruit juice intake.
Green Tea: (Moderate) Green tea should be used cautiously in patients taking aspirin; there may be an increased risk of bleeding. Monitoring clinical and/or laboratory parameters is warranted. Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. (Moderate) Many green tea products contain caffeine. Due to the risk for adverse effects, avoid the concurrent administration of caffeine and green tea products that contain caffeine when possible. Concurrent administration can produce excessive caffeine-related adverse events such as nausea, irritability, nervousness, and insomnia.
Griseofulvin: (Moderate) Concurrent administration of griseofulvin with salicylates may result in decreased salicylate serum concentrations. Caution and close monitoring for changes in the effectiveness of the salicylate are recommended.
Guaifenesin; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Guaifenesin; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Heparin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Hyaluronidase, Recombinant; Immune Globulin: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function. (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hydantoins: (Moderate) Higher caffeine doses may be needed after hydantoin administration; hydantoins increase caffeine elimination. (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Hydrocodone; Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Hydrocodone; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Ibandronate: (Moderate) Monitor renal function and for gastrointestinal adverse events during concurrent use of intravenous or oral ibandronate use, respectively, and aspirin. Acute renal failure has been observed with intravenous ibandronate and concomitant use of other nephrotoxic agents may increase this risk. Additionally, the oral formulations of both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as aspirin; the risk of bleeding may be increased. If coadministration with asprin is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia. (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels. (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as aspirin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood. Also, aspirin may mask signs of infection such as fever and in patients following treatment with antineoplastic agents or immunosuppressives.
Ibuprofen: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Ibuprofen; Famotidine: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Ibuprofen; Oxycodone: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection.
Ibuprofen; Pseudoephedrine: (Major) Concomitant use of analgesic doses of aspirin and ibuprofen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardioprotection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, as appropriate. Administer single doses of ibuprofen at least 2 to 4 hours or more after aspirin and wait 8 hours after ibuprofen administration before administering aspirin to avoid significant interference. Monitor for signs and symptoms of renal impairment. Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg 3 times daily is administered with enteric-coated low-dose aspirin. The interaction exists even after ibuprofen 400 mg once daily, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin. A decrease in antiplatelet activity (53%) was observed when ibuprofen 400 mg once daily was administered 2 hours before low-dose immediate-release aspirin 81 mg/day for 6 days. An interaction was still observed, but minimized, when ibuprofen 400 mg once daily was administered as early as 8 hours before immediate-release aspirin (90.7%). There was no interaction with the antiplatelet activity of aspirin when ibuprofen 400 mg once daily was administered 2 hours after immediate-release aspirin (99.2%). In another study of low-dose immediate-release aspirin 81 mg/day and ibuprofen 400 mg 3 times daily (1, 7, and 13 hours post-aspirin dose) for 10 consecutive days, there was no interaction with the antiplatelet activity of aspirin (98.3%); however, there were individuals with aspirin antiplatelet activity below 95%, with the lowest being 90.2%. When a similarly designed study was conducted with enteric-coated aspirin 81 mg/day for 6 days and ibuprofen 400 mg 3 times daily (2, 7 and 12 h post-aspirin dose) for 6 days, there was an interaction with the antiplatelet activity at 24 hours after the day 6 aspirin dose (67%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Ibuprofen is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
Imatinib: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
Immune Globulin IV, IVIG, IGIV: (Moderate) Immune Globulin (IG) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients receiving known nephrotoxic drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates. Coadminister IG products at the minimum concentration available and the minimum rate of infusion practicable. Also, closely monitor renal function.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant incretin mimetic and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Indacaterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Indacaterol; Glycopyrrolate: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Indapamide: (Moderate) Salicylates can increase the risk of renal toxicity in patients receiving diuretics because salicylates inhibit renal prostaglandin synthesis, which can lead to fluid retention and increased peripheral vascular resistance.
Indomethacin: (Major) The concurrent use of salicylates and indomethacin is not recommended. Combined use does not produce any greater therapeutic effect than indomethacin monotherapy. Also, a significantly greater incidence of gastrointestinal adverse effects with concurrent use has been observed. Because NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, additive effects may be seen in patients receiving platelet inhibitors (e.g., aspirin), anticoagulants, or thrombolytic agents.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and salicylates due to the risk of glomerulonephritis and nephrotoxicity as well as the potential risk of bleeding from thrombocytopenia. Consider discontinuation of salicylates in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Insulin Glargine; Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Insulins: (Moderate) Monitor blood glucose during concomitant insulin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
Ipratropium; Albuterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Iron Sucrose, Sucroferric Oxyhydroxide: (Moderate) Administer aspirin at least 1 hour before oral iron sucrose, sucroferric oxyhydroxide. Oral iron salts may reduce the bioavailability of aspirin, leading to decreased absorption.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. The use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.
Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Minor) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of caffeine, including caffeine found in green tea products.
Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs. Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of any MAOI. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Minor) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of caffeine, including caffeine found in green tea products.
Isoproterenol: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Ketoconazole: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
Ketoprofen: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity. (Minor) Caffeine administered concurrently with ketoprofen reduced the urine volume in 4 healthy volunteers. The clinical significance of the interaction in preterm neonates is not known.
Ketorolac: (Contraindicated) Ketorolac is contraindicated in patients currently receiving salicylates due to increased risk of serious NSAID-related adverse events, including gastrointestinal bleeding, ulceration, and perforation.
Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Lamotrigine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Lansoprazole; Amoxicillin; Clarithromycin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Leniolisib: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of leniolisib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and leniolisib is a CYP1A2 inhibitor.
Lesinurad: (Moderate) Aspirin, ASA at doses higher than 325 mg per day may decrease the efficacy of lesinurad in combination with allopurinol. Aspirin at doses of 325 mg or less per day (i.e., for cardiovascular protection) does not decrease the efficacy of lesinurad and can be coadministered with lesinurad.
Lesinurad; Allopurinol: (Moderate) Aspirin, ASA at doses higher than 325 mg per day may decrease the efficacy of lesinurad in combination with allopurinol. Aspirin at doses of 325 mg or less per day (i.e., for cardiovascular protection) does not decrease the efficacy of lesinurad and can be coadministered with lesinurad.
Levalbuterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Levoketoconazole: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Linagliptin: (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant linagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Linezolid: (Moderate) Caffeine use should be minimized or avoided during and for 1 to 2 weeks after discontinuation of linezolid. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Dangerous cardiac arrhythmias or severe hypertension can occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs.
Lisdexamfetamine: (Moderate) Avoid excessive caffeine intake during use of lisdexamfetamine. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Lisinopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Lithium: (Major) Caffeine appears to reduce serum lithium concentrations. Adverse reactions to lithium have also been noted to increase simultaneously with a reduction in caffeine intake. Patients taking lithium should be counseled regarding their intake of caffeine.
Lixisenatide: (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Loop diuretics: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Lopinavir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Loratadine; Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Low Molecular Weight Heparins: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
Macimorelin: (Major) Avoid use of macimorelin with drugs that directly affect pituitary growth hormone secretion, such as salicylates. Healthcare providers are advised to discontinue salicylate therapy and observe a sufficient washout period before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
Mannitol: (Major) In general, avoid use of mannitol and salicylates. Concomitant administration of nephrotoxic drugs, such as the salicylates, increases the risk of renal failure after administration of mannitol. However, mannitol promotes the urinary excretion of salicylates, and may be used as an adjunct in salicylate intoxication.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the manufacturer of varicella virus vaccine live recommends the avoidance of salicylates or aspirin, ASA use for 6 weeks after vaccination. Reye's syndrome, which exclusively affects children under 15 years old, has been associated with aspirin use following active varicella infection. Vaccination with close clinical monitoring is recommended for children who require therapeutic aspirin, ASA therapy; according to the CDC the use of attenuated, live varicella virus vaccine is thought to present less risk than natural varicella disease to such children.
Meclofenamate Sodium: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Mefenamic Acid: (Major) Increased adverse gastrointestinal (GI) effects are possible if mefenamic acid is used with salicylates. In addition, concomitant administration of salicylates and mefenamic acid may result in an increase in unbound plasma concentrations of either drug, which could result in greater adverse effects. In general, concomitant use of aspirin and mefenamic acid is not recommended.
Meglitinides: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of antidiabetic agents. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.
Melatonin: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime, as well as excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
Meloxicam: (Major) Concomitant use of low dose aspirin or analgesic doses of aspirin and meloxicam is generally not recommended due to the increased risk of bleeding and renal impairment. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Metaproterenol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Repaglinide: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of antidiabetic agents. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.
Metformin; Rosiglitazone: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sitagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Methamphetamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methamphetamine. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Methazolamide: (Major) Avoid the coadministration of high-dose salicylates and carbonic anhydrase inhibitors, like methazolamide, whenever possible. The combination yielded reports of anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death. The mechanism appears to be accumulation of the carbonic anhydrase inhibitor, resulting in increased CNS depression and metabolic acidosis. The acidosis may allow greater CNS penetration of the salicylate.
Methohexital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Methotrexate: (Major) Do not administer salicylates before or concomitantly with high doses of methotrexate, such as used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate concentrations, resulting in deaths from severe hematologic and gastrointestinal toxicity. Use caution when salicylates are administered concomitantly with lower doses of methotrexate. Salicylates have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity. Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by salicylates.
Methyclothiazide: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Methylphenidate Derivatives: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate or its derivatives. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
Methylsulfonylmethane, MSM: (Moderate) It would be prudent for patients who take aspirin to avoid methylsulfonylmethane, MSM. Monitor patients who choose to take MSM while on aspirin therapy for bleeding. Patients taking MSM and anticoagulant drugs have reported increased anticoagulant effects such as increased bruising or blood in the stool.
Metoclopramide: (Minor) Metoclopramide can increase the rate or extent of absorption of aspirin because of accelerated gastric emptying, which increases the contact time with the small bowel where this drug is absorbed.
Metolazone: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone.
Mexiletine: (Moderate) Mexiletine is an inhibitor of CYP1A2 isoenzymes, and may reduce CYP1A2-mediated caffeine metabolism. Mexiletine has been shown to increase caffeine concentrations by as much as 23 percent after a single 200 mg dose of mexiletine (nonsignificant increase, p<0.1). Another study has reported that the elimination of caffeine is decreased by 50 percent. While the clinical significance of this interaction is not known, elevated plasma caffeine levels may be of concern in patients with arrhythmias. Patients with cardiac arrhythmias on mexiletine should be cautioned to limit their intake of caffeine.
Midodrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Migalastat: (Moderate) Separate the administration of oral caffeine and migalastat by at least 2 hours if concomitant use is necessary. Simultaneous coadministration may decrease migalastat exposure and efficacy. Coadministration of 190 mg caffeine reduced the mean migalastat AUC by 55%.
Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
Mitotane: (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
Modafinil: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Caffeine should be used cautiously with modafinil. Excessive intake should be limited. Excessive intake may cause nervousness, irritability, insomnia or other side effects.
Moexipril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Monoamine oxidase inhibitors: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. The use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.
Mycophenolate: (Moderate) Mycophenolic acid is more than 98% bound to albumin. Concurrent use of mycophenolate with salicylates can decrease the protein binding of mycophenolic acid resulting in an increase in the free fraction of MPA. Patients should be observed for increased clinical effects from mycophenolate as well as additive adverse effects.
Nabumetone: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Nafcillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Naproxen: (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
Naproxen; Esomeprazole: (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
Naproxen; Pseudoephedrine: (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Nateglinide: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of antidiabetic agents. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.
Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Nitazoxanide: (Moderate) The active metabolite of nitazoxanide, tizoxanide, is highly bound to plasma proteins. Caution should be exercised when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices because competition for binding sites may occur.
Nitroglycerin: (Moderate) When coadministered with aspirin, ASA (doses between 500 mg and 1000 mg), the maximum plasma concentration (Cmax) and exposure (AUC) of a single nitroglycerin dose is increased by 67% and 73%, respectively. Additionally, limited data suggest that patients receiving aspirin, ASA in high doses can exhibit an exaggerated response to sublingual nitroglycerin. Although hypotension and tachycardia were more significant during concomitant therapy, no special precautions appear necessary. The pharmacologic effects of 0.4% nitroglycerin rectal ointment may also be enhanced when administered concomitantly with aspirin, ASA; therefore, close clinical monitoring is advised.
Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Caffeine and caffeine containing products should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours post-procedure.
Norepinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Obeticholic Acid: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of obeticholic acid is necessary; lower caffeine doses may be necessary. Concomitant use has been observed to increase caffeine overall exposure by 42%; caffeine is a CYP1A2 substrate and obeticholic acid is a CYP1A2 inhibitor.
Olanzapine; Fluoxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Olodaterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and aspirin, ASA when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding. Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives. Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Special consideration should be given to myelosuppressed patients prior to receiving aspirin.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Omeprazole; Sodium Bicarbonate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Oxacillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Oxaprozin: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Oxybutynin: (Minor) Consuming greater than 400 mg/day caffeine has been associated with the development of urinary incontinence. Caffeine may aggravate bladder symptoms, increase urine output, and counteract the effectiveness of drugs used to treat overactive bladder such as oxybutynin. Patients may wish to limit their intake of caffeinated drugs, dietary supplements (e.g., guarana), or beverages (e.g., green tea, other teas, coffee, colas).
Pacritinib: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of pacritinib is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and pacritinib is a CYP1A2 inhibitor.
Pamidronate: (Moderate) Monitor renal function during concomitant pamidronate and aspirin use due to risk for additive nephrotoxicity.
Paroxetine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Peginterferon Alfa-2b: (Moderate) The effects of peginterferon alfa-2b on CYP1A2 were evaluated in drug interaction studies. Administration of peginterferon alfa-2b with caffeine, a CYP1A2 substrate, resulted in an 18% to 39% increase in the geographic mean exposure for caffeine, suggesting inhibition of CYP1A2. Monitor for adverse effects associated with increased exposure to caffeine if peginterferon alfa-2b is coadministered with caffeine.
Penicillin G Benzathine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Penicillin G: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Penicillin V: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Penicillins: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Pentobarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Pentosan: (Moderate) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other platelet inhibitors (e.g., aspirin, ASA) in combination with pentosan. Also, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Pentoxifylline: (Moderate) The concomitant administration of platelet inhibitor with pentoxifylline in the treatment of intermittent claudication has not been evaluated and should be approached with caution, due to the potential for synergistic effects.
Perindopril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Perindopril; Amlodipine: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Pertuzumab; Trastuzumab; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Phendimetrazine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Phenelzine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. The use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.
Phenobarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Phentermine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Phentermine; Topiramate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Phenytoin: (Minor) Large doses of salicylates can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug. Displacement of phenytoin from binding sites can lead to a decrease in the total phenytoin serum concentration. Close monitoring for excessive phenytoin toxicity or decreased phenytoin efficacy is recommended.
Phosphorated Carbohydrate Solution: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
Phosphorus: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
Photosensitizing agents (topical): (Minor) Preclinical data suggest that agents that affect platelet function and inhibit prostaglandin synthesis could decrease the efficacy of photosensitizing agents used during photodynamic therapy.
Pioglitazone: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Pioglitazone; Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Pioglitazone; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Piperacillin; Tazobactam: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Piroxicam: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen. (Moderate) Concomitant administration of antipyretics, such as aspirin, ASA, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
Posaconazole: (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events.
Potassium Bicarbonate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Potassium Chloride: (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Potassium Citrate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Potassium Citrate; Citric Acid: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Moderate) Urinary alkalinizing agents, like potassium citrate, increase the excretion of salicylates by increasing renal clearance.
Potassium Phosphate: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
Potassium Phosphate; Sodium Phosphate: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
Pramlintide: (Moderate) Salicylates can indirectly increase insulin secretion, and thus decrease blood glucose concentrations. In large doses, salicylates may cause hyperglycemia and glycosuria. After acute overdose, aspirin can cause either hypo- or hyperglycemia. Large doses of aspirin should be used cautiously in patients receiving antidiabetic agents. (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone, dehydroepiandrosterone, DHEA appears to have antiplatelet effects, which may prolong bleeding times. Because of these potential, varied effects on coagulation, patients receiving DHEA concurrently with aspirin, should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone, dehydroepiandrosterone, DHEA appears to have antiplatelet effects, which may prolong bleeding times. Because of these potential, varied effects on coagulation, patients receiving DHEA concurrently with aspirin, should be monitored for side effects or the need for dosage adjustments.
Prasugrel: (Moderate) Although indicated for concomitant use, both prasugrel and aspirin are associated with bleeding. Aspirin 150 mg did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared to either drug alone. Monitor for bleeding during concomitant therapy.
Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Prilocaine; Epinephrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Primidone: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Probenecid: (Contraindicated) Concurrent use of probenecid and salicylates is contraindicated. The uricosuric actions of probenecid are inhibited by salicylates. When probenecid is used to treat hyperuricemia or gout, do not administer with salicylates.
Probenecid; Colchicine: (Contraindicated) Concurrent use of probenecid and salicylates is contraindicated. The uricosuric actions of probenecid are inhibited by salicylates. When probenecid is used to treat hyperuricemia or gout, do not administer with salicylates.
Procarbazine: (Major) Ingestion of certain products should be minimized while receiving procarbazine therapy, as the drug has some MAO inhibiting actions. Caffeine may produce hypertension or hypertensive crisis or induce cardiac arrhythmias if administered to patients taking drugs with strong MAOI properties. All preparations containing caffeine should be used sparingly such as teas, coffee, chocolate, cola, guarana, or 'stay awake' products. Some non-prescription medicines also contain caffeine and should not be taken without health care professional advice. Following discontinuation of procarbazine, dietary restrictions should continue for at least 2 weeks due to the slow recovery from the enzyme-inhibiting effects.
Promethazine; Phenylephrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Pseudoephedrine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Pseudoephedrine; Triprolidine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
Psyllium: (Moderate) Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber can adsorb salicylates. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.
Quinapril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Racepinephrine: (Moderate) Patients who are using racepinephrine inhalation are advised to avoid foods and beverages that contain caffeine. They should also avoid dietary supplements containing ingredients, such as caffeine, that are reported or claimed to have a stimulant effect. If a patient is taking prescribed medications containing caffeine, then they should seek health care professional advice prior to the use of racepinephrine. Additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate may be additive. Consider alternatives to racepinephrine for the treatment of asthma.
Ramelteon: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
Ramipril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Rasagiline: (Moderate) Although sympathomimetics and psychostimulants are contraindicated for use with other monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses.
Regadenoson: (Major) Caffeine is a non-specific adenosine receptor antagonist and can interfere with the efficacy of regadenoson. Patients should avoid consumption of any products containing caffeine (including caffeine from foods and beverages such as coffee, green tea, other teas, colas, and chocolate) for at least 12 hours before regadenoson administration.
Repaglinide: (Moderate) Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of antidiabetic agents. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.
Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Rifampin: (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents. (Minor) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of caffeine, including caffeine found in green tea products.
Risedronate: (Minor) Monitor for gastrointestinal adverse events during concurrent use of risedronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Ritlecitinib: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of ritlecitinib is necessary; lower caffeine doses may be necessary. Concomitant use has been observed to increase caffeine overall exposure by 2.65-fold; caffeine is a CYP1A2 substrate and ritlecitinib is a CYP1A2 inhibitor.
Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Rituximab; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Rivaroxaban: (Major) Salicylates such as aspirin are known to increase bleeding, and bleeding risk may be increased when these drugs are used concomitantly with rivaroxaban. The safety of long-term concomitant use of these drugs has not been studied. Promptly evaluate any signs or symptoms of bleeding or blood loss if patients are treated concomitantly with salicylates. In a single-dose drug interaction study, no pharmacokinetic interactions were observed after concomitant administration of acetylsalicylic acid (aspirin, ASA) with rivaroxaban.
Ropivacaine: (Moderate) Coadministration of ropivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue ropivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Rosiglitazone: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Rucaparib: (Moderate) Monitor for an increase in caffeine-related adverse reactions if coadministration with rucaparib is necessary. Some patients may need to reduce or limit their caffeine intake. Caffeine is a sensitive CYP1A2 substrate and rucaparib is a weak CYP1A2 inhibitor. Concomitant use increased the AUC of caffeine by 2.6-fold.
Salicylic Acid: (Moderate) Concomitant use of salicylic acid with other drugs which may contribute to elevated serum salicylate levels (e.g., oral aspirin or other oral salicylates and other salicylate containing medications, such as sports injury creams) should be avoided. Concurrent use may result in excessive exposure to salicylic acid. Consider replacing aspirin therapy with an alternative non-steroidal anti-inflammatory agent that is not salicylate based where appropriate.
Salmeterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Saxagliptin: (Moderate) Monitor blood glucose during concomitant saxagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Secobarbital: (Moderate) Caffeine has been reported to increase the metabolism of barbiturates, and barbiturates increase caffeine elimination. Higher caffeine doses may be needed after barbiturate administration. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Monitor for estrogen-related adverse effects during concomitant acetaminophen and ethinyl estradiol use. Acetaminophen may increase plasma ethinyl estradiol concentrations, possibly by inhibition of conjugation. (Minor) Serum concentrations of caffeine may be increased during concurrent administration with ethinyl estradiol. Patients may desire to limit products that contain high amounts of caffeine to minimize caffeine-related side effects such as nausea or tremors.
Selective serotonin reuptake inhibitors: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Selegiline: (Moderate) Although psychostimulants are contraindicated for use with other monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with selegiline because of the selective monoamine oxidase-B (MAO-B) inhibition of selegiline at manufacturer recommended doses. However, cardiac arrhythmias or severe hypertension is possible if doses are exceeded or caffeine intake is excessive.
Serotonin norepinephrine reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Sertraline: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Sitagliptin: (Moderate) Monitor blood glucose during concomitant sitagliptin and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sodium Acetate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Sodium Bicarbonate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
Sodium Citrate; Citric Acid: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Sodium Lactate: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Sodium Oxybate: (Moderate) Caffeine should be avoided or used cautiously with oxybates. Monitor for potential side effects such as nervousness, irritability, insomnia, and/or cardiac arrhythmias.
Sodium Thiosulfate; Salicylic Acid: (Moderate) Concomitant use of salicylic acid with other drugs which may contribute to elevated serum salicylate levels (e.g., oral aspirin or other oral salicylates and other salicylate containing medications, such as sports injury creams) should be avoided. Concurrent use may result in excessive exposure to salicylic acid. Consider replacing aspirin therapy with an alternative non-steroidal anti-inflammatory agent that is not salicylate based where appropriate.
Solifenacin: (Minor) Consuming > 400 mg/day caffeine has been associated with the development of urinary incontinence. Beverages containing caffeine may aggravate bladder symptoms, increase urine output, and counteract the effectiveness of solifenacin to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and caffeine. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
Spironolactone: (Moderate) Monitor renal function and for decreased efficacy of spironolactone if coadministration with aspirin is necessary. The spironolactone dose may need to be titrated to higher maintenance dose. In persons who are elderly, volume-depleted (including those receiving diuretic therapy), or with compromised renal function, coadministration of spironolactone and aspirin may result in deterioration of renal function, including possible acute renal failure; these effects are usually reversible. Aspirin may reduce the efficacy of spironolactone. A single aspirin 600 mg dose inhibited the natriuretic effect of spironolactone, which was hypothesized be due to inhibition of tubular secretion of canrenone, causing decreased effectiveness of spironolactone.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. (Moderate) Monitor renal function and for decreased efficacy of spironolactone if coadministration with aspirin is necessary. The spironolactone dose may need to be titrated to higher maintenance dose. In persons who are elderly, volume-depleted (including those receiving diuretic therapy), or with compromised renal function, coadministration of spironolactone and aspirin may result in deterioration of renal function, including possible acute renal failure; these effects are usually reversible. Aspirin may reduce the efficacy of spironolactone. A single aspirin 600 mg dose inhibited the natriuretic effect of spironolactone, which was hypothesized be due to inhibition of tubular secretion of canrenone, causing decreased effectiveness of spironolactone.
St. John's Wort, Hypericum perforatum: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Stiripentol: (Moderate) Consider a dose adjustment of caffeine when coadministered with stiripentol. Coadministration may alter plasma concentrations of caffeine resulting in an increased risk of adverse reactions and/or decreased efficacy. Caffeine is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by stiripentol potentially resulting in clinically significant interactions.
Sulfonamides: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as sulfonamides. An enhanced effect of the displaced drug may occur.
Sulfonylureas: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sulindac: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Sumatriptan; Naproxen: (Major) Concomitant use of analgesic doses of aspirin and naproxen is generally not recommended due to the increased risk of bleeding and renal impairment. Because there may be an increased risk of cardiovascular events after discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics as appropriate. A pharmacodynamic study demonstrated that lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the study due to the longer washout period. A decrease in antiplatelet activity was observed at 24 hours after 10 days of naproxen 220 mg/day with low-dose immediate-release aspirin 81 mg/day (93.1%) vs. aspirin alone (98.7%). The interaction was observed even after discontinuation of naproxen on day 11 while aspirin therapy continued but normalized by day 13. The interaction was greater when naproxen was given 30 minutes before aspirin (87.7% vs. 98.7%) and minimal when aspirin was administered 30 minutes before naproxen (95.4% vs. 98.7%). The interaction was minimal at 24 hours after day 10 when naproxen 220 mg twice daily was given 30 minutes before low-dose immediate-release aspirin (95.7% vs. 98.7%); however, the interaction was greater on day 11 after naproxen discontinuation (84.3% vs. 98.7%) and did not normalize by day 13 (90.7% vs. 98.5%). Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone. Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
Suvorexant: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as suvorexant, eszopiclone, zaleplon, or zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
Tacrolimus: (Moderate) Tacrolimus, in the absence of overt renal impairment, may adversely affect renal function. Care should be taken in using tacrolimus with other nephrotoxic drugs, such as salicylates.
Tasimelteon: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking melatonin or the melatonin analogs (ramelteon, tasimelteon) for sleep should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
Telavancin: (Minor) Concurrent or sequential use of telavancin with drugs that inhibit renal prostaglandins such as salicylates may lead to additive nephrotoxicity. Closely monitor renal function and adjust telavancin doses based on calculated creatinine clearance.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Tenofovir Alafenamide: (Moderate) Monitor for changes in renal function if tenofovir alafenamide is administered in combination with nephrotoxic agents, such as salicylates. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir alafenamide with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, thus, increasing the risk of adverse reactions.
Tenofovir Disoproxil Fumarate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of t enofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
Terbinafine: (Minor) Terbinafine has been shown to inhibit the clearance of caffeine. The clinical significance of this interaction has not been determined.
Terbutaline: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Teriflunomide: (Minor) Monitor for decreased efficacy of caffeine during coadministration of teriflunomide. Teriflunomide may be a weak inducer of CYP1A2. When teriflunomide was given concurrently with caffeine in vivo, a CYP1A2 substrate, the Cmax and AUC of caffeine decreased by 18% and 55%, respectively.
Tetracaine: (Moderate) Coadministration of tetracaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue tetracaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Theophylline, Aminophylline: (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking aminophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently. Patients should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. (Major) Caffeine is a CNS stimulant. The concurrent administration of caffeine to patients taking theophylline may produce excessive caffeine-like side effects, such as nausea, irritability or nervousness. Adverse effects such as tremors, insomnia, seizures, or cardiac arrhythmias are also possible when excessive dosages of caffeine are taken concurrently with theophylline. Patients taking theophylline should avoid medications containing caffeine when possible. Patients may also need to limit their intake of caffeine-containing beverages or foods (e.g., coffee, green tea, other teas, colas, or chocolate) to avoid caffeine-like side effects. In neonates, theophylline is metabolized to caffeine; initiating caffeine after theophylline therapy is halted may result in caffeine toxicity in neonates if serum caffeine levels are not monitored prior to the initiation of caffeine therapy. Concurrent use of theophylline with caffeine in neonates is not recommended due to the potential for additive toxicity.
Thiazide diuretics: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Thiazolidinediones: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and salicylate use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Thrombin Inhibitors: (Moderate) An additive risk of bleeding may be seen in patients receiving salicylates (e.g., aspirin, ASA) in combination with thrombin inhibitors. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Nonsteroidal antiinflammatory drugs (NSAIDs) may also increase bleeding risk when given with argatroban because of their potential to cause GI bleeding or inhibit platelet aggregation.
Thrombolytic Agents: (Moderate) Concurrent administration of thrombolytic agents and salicylates may further increase the serious risk of bleeding.
Ticagrelor: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
Ticlopidine: (Moderate) Use caution with coadministration of ticlopidine and aspirin. Ticlopidine potentiates the effect of aspirin on platelet aggregation. Safety of concomitant use of ticlopidine and aspirin has not been established beyond 30 days. Monitor for bleeding during concomitant therapy.
Tiotropium; Olodaterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Tirofiban: (Moderate) Unless contraindicated, aspirin is used in combination with tirofiban. However, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Tizanidine: (Minor) Tizanidine delays the time to attain peak concentrations of acetaminophen by about 16 minutes. The clinical significance of this interaction is unknown.
Tobacco: (Major) Advise patients who are taking caffeine to avoid smoking tobacco. Smoking tobacco has been observed to increase caffeine clearance by 50% to 70%. Caffeine is a CYP1A2 substrate and smoking tobacco induces CYP1A2.
Tolazamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Tolbutamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and aspirin use. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Tolmetin: (Major) The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. The use of salicylates together with NSAIDs can also lead to additive GI toxicity.
Tolterodine: (Minor) Beverages containing caffeine may aggravate bladder symptoms and counteract the effectiveness of tolterodine to some degree. Patients may wish to limit their intake of caffeinated drugs, dietary supplements, or beverages.
Torsemide: (Moderate) Salicylates may decrease the diuretic, natriuretic, and antihypertensive actions of diuretics, possibly through inhibition of renal prostaglandin synthesis. Patients receiving loop diuretics and salicylates should be monitored for changes in the effectiveness of their diuretic therapy.
Trandolapril: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.
Trandolapril; Verapamil: (Moderate) Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation. (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Tranylcypromine: (Major) Excessive use of caffeine in any form should be avoided in patients receiving Monoamine oxidase inhibitors (MAOIs). Limit caffeine intake during MAOI use and for 1 to 2 weeks after discontinuation of any MAOI. The use of non-prescription medicines or dietary supplements containing caffeine should be avoided. Patients should try to avoid or limit the intake of all items containing caffeine such as tea, coffee, chocolate, and cola. Cardiac arrhythmias or severe hypertension may occur because of the potentiation of caffeine's sympathomimetic effects by MAOIs if caffeine intake is excessive.
Trastuzumab; Hyaluronidase: (Minor) Salicylates, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Trazodone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant trazodone and salicylate use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when serotonin norepinephrine reuptake inhibitors are coadministered with another anticoagulant.
Treprostinil: (Moderate) When used concurrently with anticoagulants or platelet inhibitors, treprostinil may increase the risk of bleeding.
Triamterene: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant triamterene and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant triamterene and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Tromethamine: (Moderate) Concurrent administration of high doses of alkalinizing agents may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid.
Umeclidinium; Vilanterol: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Valproic Acid, Divalproex Sodium: (Moderate) Concurrent salicylate therapy can increase the free-fraction of valproic acid, causing possible valproic acid toxicity. Valproic acid levels should be monitored when these agents are used concomitantly.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure as well as for signs of worsening renal function and loss of diuretic efficacy, including antihypertensive effects, during concomitant thiazide diuretic and salicylate use. Salicylate use decreases glomerular filtration rate and renal blood flow, and concomitant diuretic use may increase the risk of this reaction. Salicylates may diminish the effectiveness of diuretics due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.
Vancomycin: (Minor) Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents, such as vancomycin, may lead to additive nephrotoxicity.
Varicella-Zoster Virus Vaccine, Live: (Major) No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the manufacturer of varicella virus vaccine live recommends the avoidance of salicylates or aspirin, ASA use for 6 weeks after vaccination. Reye's syndrome, which exclusively affects children under 15 years old, has been associated with aspirin use following active varicella infection. Vaccination with close clinical monitoring is recommended for children who require therapeutic aspirin, ASA therapy; according to the CDC the use of attenuated, live varicella virus vaccine is thought to present less risk than natural varicella disease to such children.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and acetaminophen may result in altered concentrations of acetaminophen. Vemurafenib is an inhibitor of CYP1A2 and CYP2A6, and an inducer of CYP3A4. Acetaminophen is a substrate of CYP1A2, CYP2A6, and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
Verapamil: (Minor) In a few reported cases, coadministration of verapamil with aspirin, ASA has led to increased bleeding times greater than observed with aspirin alone. The exact mechanism and clinical significance of this interaction is unknown. (Minor) Verapamil reduces the clearance of caffeine and increases serum caffeine concentrations, presumably via inhibition of hepatic metabolism. During concomitant therapy with verapamil, it may be prudent to advise patients to limit or minimize the intake of caffeinated products to minimize caffeine-related side effects.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with aspirin is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation like aspirin could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
Viloxazine: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of viloxazine is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and viloxazine is a CYP1A2 inhibitor.
Vonoprazan; Amoxicillin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Vonoprazan; Amoxicillin; Clarithromycin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
Vorapaxar: (Moderate) Although indicated for concomitant use, both vorapaxar and aspirin are associated with bleeding. Monitor for bleeding during concomitant therapy.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with aspirin products and to promptly report any bleeding events to the practitioner.
Warfarin: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Zafirlukast: (Minor) Coadministration of aspirin may increase plasma concentrations of zafirlukast. The potential clinical sequelae of increased zafirlukast concentrations are not known.
Zaleplon: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zaleplon should avoid caffeine-containing medications, dietary supplements, foods, and beverages close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep.
Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
Zileuton: (Moderate) Monitor for an increase in caffeine-related adverse reactions, including nervousness, irritability, insomnia, tachycardia, or tremor, if concomitant use of zileuton is necessary; lower caffeine doses may be necessary. Concomitant use may increase caffeine exposure; caffeine is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.
Zoledronic Acid: (Moderate) Monitor renal function during concomitant zoledronic acid and aspirin use due to risk for additive nephrotoxicity.
Zolmitriptan: (Minor) Zolmitriptan can delay the Tmax of acetaminophen by one hour. A single 1 g dose of acetaminophen does not alter the pharmacokinetics of zolmitriptan and its active metabolite. The interaction between zolmitriptan and acetaminophen is not likely to be clinically significant.
Zolpidem: (Minor) Caffeine is a central nervous system (CNS) stimulant. Patients taking medications for sleep, such as zolpidem should avoid caffeine-containing medications, dietary supplements, foods, and beverages within the hours close to bedtime. Patients should be encouraged to avoid excessive total daily caffeine intake, as part of proper sleep hygiene, since caffeine intake can interfere with proper sleep. However, in healthy subjects (without insomnia) in a pharmacokinetic study, coadministration of caffeine at a dosage of 150 to 300 mg with zolpidem did not counteract the sedative effects of a single 10 mg dose of zolpidem.
How Supplied
Acetaminophen, Aspirin, Caffeine/Bayer Migraine Formula/Excedrin Extra Strength/Excedrin Extra Strength Express/Excedrin Menstrual Complete/Excedrin Migraine/Genaced/Goody's Extra Strength/Pain Reliever Plus/Pamprin/Pamprin Maximum Strength/Vanquish Oral Tab: 194-227-33mg, 250-250-65mg
BC MAX STRENGTH Fast Pain Relief/Goody's Extra Strength (Cool Orange)/Goody's Extra Strength Headache/Goody's Extra Strength Headache Powder (Mixed Fruit Blast ) Oral Pwd: 260-520-32.5mg, 325-500-65mg, 500-500-65mg
Maximum Dosage
NOTE: Do not exceed recommended dosage limits for the specific product prescribed; the following are general guidelines:
AdultsAcetaminophen 4000 mg/day PO; aspirin 2080 mg/day PO; caffeine 520 mg/day PO.
GeriatricAcetaminophen 4000 mg/day PO; aspirin 2080 mg/day PO; caffeine 520 mg/day PO.
AdolescentsAcetaminophen 4000 mg/day PO; aspirin 2080 mg/day PO; caffeine 520 mg/day PO.
Children>= 12 years: Acetaminophen 4000 mg/day PO; aspirin 2080 mg/day PO; caffeine 520 mg/day PO.
< 12 years: Safety and efficacy have not been established.
Mechanism Of Action
Mechanism of Action:•Acetaminophen: The exact mechanism of analgesia is unknown. Acetaminophen acts primarily in the CNS and increases the pain threshold by inhibiting cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen does not inhibit PG synthesis in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects. The antipyretic activity of acetaminophen is exerted by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulating center by inhibiting PG synthesis. Heat is dissipated by vasodilatation, increased peripheral blood flow, and sweating.•Aspirin, ASA: The activity of aspirin is due to its ability to inhibit cyclooxygenase (COX). Cyclooxygenase is responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step in prostaglandin synthesis. In vivo, aspirin is hydrolyzed to salicylic acid and acetate. However, hydrolysis is not required for aspirin activity. Aspirin irreversibly inhibits COX by acetylation of a specific serine moiety. In comparison, salicylic acid has little or no ability to inhibit COX in vitro despite inhibiting prostaglandin synthesis at the site of inflammation in vivo. The exact mechanism of prostaglandin inhibition by salicylic acid is unclear. Aspirin appears to inhibit COX through two pathways and seems to have a different mechanism of action than other salicylates. The antiinflammatory action of aspirin is believed to be a result of peripheral inhibition of COX-1 and COX-2, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. Salicylates are effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, salicylates have an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.•Caffeine: Caffeine causes cerebral vasoconstriction, which decreases blood flow and oxygen tension. In combination with acetaminophen, caffeine may provide a quicker onset of action and enhance pain relief allowing for lower doses of analgesics. In some patients, caffeine relieves headaches by treating the effects of caffeine withdrawal.
Pharmacokinetics
Acetaminophen; aspirin, ASA; and caffeine combination products are administered orally. The pharmacokinetics of this drug combination have not been studied. The systemic pharmacokinetic information below is based on administration of each agent alone.
•Acetaminophen: Acetaminophen is metabolized in the liver via glucuronidation and sulfate conjugation and is excreted in the urine as glutathione and sulfate conjugates. However, about 10—15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 and 1A2 and then glucuronidation to cysteine and mercapturic acid conjugates. In cases of glucuronide depletion, such as acetaminophen overdose, a hepatotoxic metabolite is formed. The half-life of acetaminophen in patients with normal hepatic function is 2—4 hours.
•Aspirin, ASA: Aspirin is hydrolyzed to salicylic acid by the liver and is widely distributed into most body tissues. Aspirin is poorly bound to plasma proteins, but it should be used cautiously in patients already receiving other highly protein-bound drugs due to high protein binding of salicylic acid. Aspirin is 99% metabolized to salicylic acid and other metabolites. The elimination half-life of aspirin in plasma is about 15—20 minutes. Salicylic acid, but not aspirin itself, undergoes saturable kinetics. At low doses, the elimination is first-order and the half-life remains constant at 2—3 hours; however, at higher doses, the enzymes responsible for metabolism become saturated and the apparent half-life can increase to 15—30 hours. Because of this, 5—7 days may be required before a steady-state concentration is reached. Salicylic acid and its metabolites are excreted primarily by the kidneys. The excretion of salicylic acid is enhanced by alkalinization of the urine.
•Caffeine: Caffeine undergoes hepatic metabolism to paraxanthine, theobromine, and theophylline. Elimination of caffeine is renal as inactive metabolites. The elimination half-life of caffeine in adults is 3—7 hours.
Acetaminophen; aspirin, ASA; and caffeine combination products are administered orally. The pharmacokinetics of this drug combination have not been studied.
Pregnancy And Lactation
Experts usually recommend avoiding aspirin-containing products, like acetaminophen; aspirin; caffeine combination products, during breast-feeding. Salicylates are excreted into breast milk and could cause adverse effects in infants. Mean peak breast milk concentrations of salicylate in 6 nursing mothers after aspirin doses of 500, 1,000, and 1,500 mg were 5.8, 15.8, and 38.8 mg/L, respectively. Salicylate concentrations were detectable in breast milk within 1 hour of dosing and reached maximum concentration within 2 to 6 hours. Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated product; with milk:plasma ratios of 0.5 to 0.7 reported. Higher caffeine intake (more than 500 mg/day) by a nursing individual may cause irritability or poor sleeping patterns in the infant who is breast-feeding. Alternative analgesics and fever treatments considered to be compatible with breast-feeding include acetaminophen (as a single agent) and ibuprofen. Medical experts regard acetaminophen as usually compatible with breast-feeding and as a first-line choice for analgesia, headache or fever in the lactating individual, including for those patients who are immediately postpartum and planning to breastfeed. Amounts present in milk are much less than the doses usually given to infants, and adverse effects in breastfed infants appear to be rare.[27500] Limited published studies report acetaminophen passes rapidly into human milk with similar concentrations in the milk and plasma. Average and maximum neonatal doses of 1% and 2%, respectively, of the weight-adjusted maternal dose are reported after a single oral dose of 1,000 mg. There is one well-documented report of rash occurring in a breastfed infant that resolved with drug discontinuation and recurred with resumption.[42289]