Drug Information

Acetaminophen, aspirin, and caffeine

Acetaminophen, aspirin, and caffeine
Copyright 1978-2011 Lexicomp, Inc. All rights reserved.

(For additional information see “Acetaminophen, aspirin, and caffeine: Patient drug information”)

Brand Names: U.S.

  • Anacin® Advanced Headache Formula [OTC];
  • Excedrin® Extra Strength [OTC];
  • Excedrin® Migraine [OTC];
  • Fem-Prin® [OTC];
  • Goody’s® Extra Strength Headache Powder [OTC];
  • Goody’s® Extra Strength Pain Relief [OTC];
  • Pain-Off [OTC];
  • Vanquish® Extra Strength Pain Reliever [OTC]
Pharmacologic Category

  • Analgesic, Miscellaneous
Dosing: AdultPain management:

Based on acetaminophen component:

Mild-to-moderate pain: Oral: 325-650 mg every 4-6 hours as needed; do not exceed 4 g/day

Mild-to-moderate pain associated with migraine headache: Oral: 500 mg/dose (in combination with 500 mg aspirin and 130 mg caffeine) every 6 hours while symptoms persist; do not use for longer than 48 hours

Based on aspirin component:

Mild-to-moderate pain: Oral: 325-650 mg every 4-6 hours as needed; do not exceed 4 g/day

Mild-to-moderate pain associated with migraine headache: Oral: 500 mg/dose (in combination with 500 mg acetaminophen and 130 mg caffeine) every 6 hours; do not use for longer than 48 hours

Product labeling:

Excedrin® Extra Strength, Excedrin® Migraine: Oral: 2 doses every 6 hours (maximum: 8 doses/24 hours)

Note: When used for migraine, do not use for longer than 48 hours

Goody’s® Extra Strength Headache Powder: Oral: 1 powder, placed on tongue or dissolved in water, every 4-6 hours (maximum: 4 powders/24 hours)

Goody’s® Extra Strength Pain Relief Tablets: Oral: 2 tablets every 4-6 hours (maximum: 8 tablets/24 hours)

Vanquish® Extra Strength Pain Reliever: Oral: 2 tablets every 4 hours (maximum: 12 tablets/24 hours)

Dosing: PediatricProduct labeling:

Excedrin® Extra Strength, Excedrin® Migraine: Oral: Children >12 years: Refer to adult dosing

Goody’s® Extra Strength Headache Powder: Oral: Children >12 years: Refer to adult dosing

Goody’s® Extra Strength Pain Relief Tablets: Oral: Children >12 years: Refer to adult dosing

Vanquish® Extra Strength Pain Reliever: Oral: Children >12 years: Refer to adult dosing

Dosing: GeriatricRefer to adult dosing.

Dosing: Hepatic ImpairmentUse with caution. Limited, low-dose therapy usually well tolerated in hepatic disease/cirrhosis. However, cases of hepatotoxicity at daily acetaminophen dosages <4 g/day have been reported. Avoid chronic use in hepatic impairment.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Caplet:

Excedrin® Extra Strength, Excedrin® Migraine: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Vanquish® Extra Strength Pain Reliever: Acetaminophen 194 mg, aspirin 227 mg, and caffeine 33 mg

Geltab (Excedrin® Extra Strength, Excedrin® Migraine): Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Powder (Goody’s® Extra Strength Headache Powder): Acetaminophen 260 mg, aspirin 520 mg, and caffeine 32.5 mg [contains lactose]

Tablet:

Anacin® Advanced Headache Formula: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Excedrin® Extra Strength, Excedrin® Migraine, Pain-Off: Acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg

Fem-Prin®: Acetaminophen 194.4 mg, aspirin 226.8 mg, and caffeine 32.4 mg

Goody’s® Extra Strength Pain Relief: Acetaminophen 130 mg, aspirin 260 mg, and caffeine 16.25 mg

Generic Equivalent Available: U.S.Yes

UseRelief of mild-to-moderate pain; mild-to-moderate pain associated with migraine headache

Medication Safety Issues

Sound-alike/look-alike issues:

Excedrin® may be confused with Dexedrine®

Other safety concerns:

Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.

Adverse Reactions SignificantSee individual agents.

ContraindicationsHypersensitivity to acetaminophen, aspirin, salicylates, caffeine, or any component of the formulation; pregnancy

Metabolism/Transport EffectsAcetaminophen: Substrate (minor) of CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A4; Inhibits CYP3A4 (weak)

Aspirin: Substrate (minor) of CYP2C9

Caffeine: Substrate of CYP1A2 (major), 2C9 (minor), 2D6 (minor), 2E1 (minor), 3A4 (minor); Inhibits CYP1A2 (weak), 3A4 (moderate)

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

ACE Inhibitors: Salicylates may diminish the antihypertensive effect of ACE Inhibitors. They may also diminish other beneficial pharmacodynamic effects desired for the treatment of CHF. The effects are likely dose-related. 100 mg doses aspirin appear to cause no problems, whereas 300 mg doses appear to significantly affect ACE Inhibitor efficacy. Risk C: Monitor therapy

Adenosine: Caffeine may diminish the therapeutic effect of Adenosine. Risk D: Consider therapy modification

Alendronate: Aspirin may enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy

SEE MORE:  Acetaminophen (paracetamol)

Ammonium Chloride: May increase the serum concentration of Salicylates. Risk C: Monitor therapy

Anticoagulants: Salicylates may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Anticonvulsants (Hydantoin): May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the anticoagulant effect of Salicylates. Exceptions: Bepridil [Off Market]. Risk C: Monitor therapy

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: Salicylates may enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Exceptions: Brinzolamide; Dorzolamide. Risk D: Consider therapy modification

Cholestyramine Resin: May decrease the absorption of Acetaminophen. Effect is minimal if cholestyramine is administered 1 hour after acetaminophen. Risk D: Consider therapy modification

Collagenase (Systemic): Antiplatelet Agents may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

Corticosteroids (Systemic): Salicylates may enhance the adverse/toxic effect of Corticosteroids (Systemic). These specifically include gastrointestinal ulceration and bleeding. Corticosteroids (Systemic) may decrease the serum concentration of Salicylates. Withdrawal of corticosteroids may result in salicylate toxicity. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Cyproterone: May decrease the serum concentration of CYP2E1 Substrates. Risk C: Monitor therapy

Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

Divalproex: Salicylates may increase the serum concentration of Divalproex. Risk C: Monitor therapy

Drotrecogin Alfa: Salicylates may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Management: Weigh potential benefits of drotrecogin against increased bleeding risk in patients who have received platelet inhibitors including aspirin (over 650 mg daily within 1 week). Monitor for bleeding and stop infusion if clinically important bleeding occurs. Risk D: Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Aspirin. Risk X: Avoid combination

Formoterol: Caffeine may enhance the adverse/toxic effect of Formoterol. Caffeine may enhance the hypokalemic effect of Formoterol. Risk C: Monitor therapy

Ginkgo Biloba: May enhance the anticoagulant effect of Salicylates. Management: Consider alternatives to this combination of agents. Monitor for signs and symptoms of bleeding (especially intracranial bleeding) if salicylates are used in combination with ginkgo biloba. Risk D: Consider therapy modification

Glucosamine: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Heparin: Aspirin may enhance the anticoagulant effect of Heparin. Risk C: Monitor therapy

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk D: Consider therapy modification

Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Imatinib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Influenza Virus Vaccine (Live/Attenuated): May enhance the adverse/toxic effect of Salicylates. Specifically, Reye’s syndrome may develop. Risk X: Avoid combination

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

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Isoniazid: May enhance the adverse/toxic effect of Acetaminophen. Risk C: Monitor therapy

Ketorolac: May enhance the adverse/toxic effect of Aspirin. Risk X: Avoid combination

Ketorolac (Nasal): May enhance the adverse/toxic effect of Aspirin. Risk X: Avoid combination

Ketorolac (Systemic): May enhance the adverse/toxic effect of Aspirin. Risk X: Avoid combination

Loop Diuretics: Salicylates may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may increase the serum concentration of Salicylates. Risk C: Monitor therapy

Methotrexate: Salicylates may increase the serum concentration of Methotrexate. Salicylate doses used for prophylaxis of cardiovascular events are not likely to be of concern. Risk D: Consider therapy modification

Metyrapone: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy

NSAID (Nonselective): May enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (Nonselective). Exceptions: Diclofenac. Risk D: Consider therapy modification

Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Potassium Acid Phosphate: May increase the serum concentration of Salicylates. Risk C: Monitor therapy

PRALAtrexate: Salicylates may increase the serum concentration of PRALAtrexate. Salicylate doses used for prophylaxis of cardiovascular events are unlikely to be of concern. Risk D: Consider therapy modification

Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Risk D: Consider therapy modification

Probenecid: Salicylates may diminish the therapeutic effect of Probenecid. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Quinolone Antibiotics: May decrease the metabolism of Caffeine. Exceptions: Gemifloxacin; Levofloxacin; Levofloxacin (Systemic); Lomefloxacin; Moxifloxacin; Moxifloxacin (Systemic); Nalidixic Acid; Ofloxacin; Ofloxacin (Systemic); Sparfloxacin. Risk C: Monitor therapy

Regadenoson: Caffeine may diminish the vasodilatory effect of Regadenoson. Risk D: Consider therapy modification

Rivaroxaban: Antiplatelet Agents may enhance the anticoagulant effect of Rivaroxaban. Management: Avoid concurrent use of clopidogrel with rivaroxaban unless the anticipated benefits outweigh the risks of bleeding. Avoid concurrent use of rivaroxaban with other antiplatelet agents whenever possible. Risk D: Consider therapy modification

Salicylates: May enhance the anticoagulant effect of other Salicylates. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Risk D: Consider therapy modification

Sulfonylureas: Salicylates may enhance the hypoglycemic effect of Sulfonylureas. Of concern with regular, higher doses of salicylates, not sporadic, low doses. Risk C: Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Thrombolytic Agents: Salicylates may enhance the adverse/toxic effect of Thrombolytic Agents. An increased risk of bleeding may occur. Risk C: Monitor therapy

Ticagrelor: Aspirin may enhance the antiplatelet effect of Ticagrelor. Aspirin may diminish the therapeutic effect of Ticagrelor. More specifically, the benefits of ticagrelor relative to clopidogrel may be diminished in patients receiving daily aspirin doses greater than 100-150 mg daily. Management: Avoid daily aspirin doses greater than 100 mg in patients receiving ticagrelor. Canadian recommendations are to avoid daily aspirin doses greater than 150 mg. Daily low-dose aspirin (U.S.: 75-100 mg; Canada: 75-150 mg) is recommended. Risk D: Consider therapy modification

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Tiludronate: Aspirin may decrease the serum concentration of Tiludronate. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Salicylates. Bleeding may occur. Risk C: Monitor therapy

Valproic Acid: Salicylates may increase the serum concentration of Valproic Acid. Risk C: Monitor therapy

Varicella Virus-Containing Vaccines: Salicylates may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. Reye’s Syndrome may develop. Risk D: Consider therapy modification

Vitamin E: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Salicylates may enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Ethanol/Nutrition/Herb InteractionsEthanol: Excessive intake of ethanol may increase the risk of acetaminophen-induced hepatotoxicity. Avoid ethanol or limit to <3 drinks/day.

Pregnancy Risk FactorD (show table)

International Brand Names

  • Bufferin Advance (TW);
  • Excedrin (CO);
  • Exidol (IL);
  • Nogren (ID)
Pharmacodynamics/KineticsSee individual agents.

REFERENCES

  1. Antlitz AM, Mead JA Jr, and Tolentino MA, “Potentiation of Oral Anticoagulant Therapy by Acetaminophen,” Curr Ther Res Clin Exp, 1968, 10(10):501-7. [PubMed 4971464]
  2. Bagheri H, Bernhard NB, and Montastruc JL, “Potentiation of the Acenocoumarol Anticoagulant Effect by Acetaminophen,” Ann Pharmacother, 1999, 33(4):506. [PubMed 10332548]
  3. Bartle WR and Blakely JA, “Potentiation of Warfarin Anticoagulation by Acetaminophen,” JAMA, 1991, 265(10):1260. [PubMed 1995971]
  4. Boeijinga JJ, Boerstra EE, Ris P, et al, “Interaction Between Paracetamol and Coumarin Anticoagulants,” Lancet, 1982, 1(8270):506. [PubMed 6121161]
  5. Capone ML, Sciulli MG, Tacconelli S, et al, “Pharmacodynamic Interaction of Naproxen With Low-Dose Aspirin in Healthy Subjects,” J Am Coll Cardiol, 2005, 45(8):1295-1301. [PubMed 15837265]
  6. Catella-Lawson F, Reilly MP, Kapoor SC, et al, “Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin,” N Engl J Med, 2001, 345(25):1809-17. [PubMed 11752357]
  7. Cryer B, Verlin RG, Cooper SA, et al, “Double-Blind, Randomized, Parallel, Placebo-Controlled Study of Ibuprofen Effects on Thromboxane B2 Concentrations in Aspirin-Treated Healthy Adult Volunteers,” Clin Ther, 2005, 27(2):185-191. [PubMed 15811481]
  8. Desjardins PJ, Cooper SA, Gallegos TL, et al, “The Relative Analgesic Efficacy of Propiram Fumarate, Codeine Aspirin, and Placebo in Postimpaction Dental Pain,” J Clin Pharmacol, 1984, 24(1):35-42. [PubMed 6368614]
  9. Dionne RA, Campbell RA, Cooper SA, et al, “Suppression of Postoperative Pain by Preoperative Administration of Ibuprofen in Comparison to Placebo, Acetaminophen, and Acetaminophen Plus Codeine,” J Clin Pharmacol, 1983, 23(1):37-43. [PubMed 6341415]
  10. Forbes JA, Butterworth GA, Burchfield WH, et al, “Evaluation of Ketorolac, Aspirin, and an Acetaminophen-Codeine Combination in Postoperative Oral Surgery Pain,” Pharmacotherapy, 1990, 10(6 Pt 2):77S-93S. [PubMed 2082317]
  11. Forbes JA, Keller CK, Smith JW, et al, “Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen-Codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery,” Pharmacotherapy, 1986, 6(5):211-8. [PubMed 3540871]
  12. Gadisseur AP, Van Der Meer FJ, and Rosendaal FR, “Sustained Intake of Paracetamol (Acetaminophen) During Oral Anticoagulant Therapy With Coumarins Does Not Cause Clinically Important INR Changes: A Randomized Double-Blind Clinical Trial,” J Thromb Haemost, 2003, 1(4):714-7. [PubMed 12871405]
  13. Gebauer MG, Nyfort-Hansen K, Henschke PJ, et al, “Warfarin and Acetaminophen Interaction,” Pharmacotherapy, 2003, 23(1):109-12. [PubMed 12523469]
  14. Hylek EM, Heiman H, Skates SJ, et al, “Acetaminophen and Other Risk Factors for Excessive Warfarin Anticoagulation,” JAMA, 1998, 279(9):657-62. [PubMed 9496982]
  15. Kwan D, Bartle WR, and Walker SE, “The Effects of Acute and Chronic Acetaminophen Dosing on the Pharmacodynamics and Pharmacokinetics of (R)- and (S)-Warfarin,” Clin Pharmacol Ther, 1995, 57:212.
  16. Licht H, Seeff LB, and Zimmerman HJ, “Apparent Potentiation of Acetaminophen Hepatotoxicity by Alcohol,” Ann Intern Med, 1980, 92(4):511.
  17. Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922. [PubMed 12628894]
  18. Rubin RN, Mentzer RL, and Budzynski AZ, “Potentiation of Anticoagulant Effect of Warfarin by Acetaminophen (Tylenol®),” Clin Res, 1984, 32:698a.
  19. van den Bemt PM, Geven LM, Kuitert NA, et al, “The Potential Interaction Between Oral Anticoagulants and Acetaminophen in Everyday Practice,” Pharm World Sci, 2002, 24(5):201-4. [PubMed 12426965]