Version July 2025
Take care when prescribing, preparing, and administering ibuprofen/acetaminophen injection to avoid dosing errors which could result in accidental overdose and death.
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4 g/day, and often involve more than 1 acetaminophen-containing product.
Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
Ibuprofen/acetaminophen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft surgery.
Injection: NSAIDs cause an increased risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious GI events.
Oral (Rx): NSAIDs cause an increased risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.
Analgesic: Children ≥12 years and Adolescents: Acetaminophen 250 mg/ibuprofen 125 mg per tablet: Oral: Two tablets every 8 hours as needed; maximum daily dose: 6 tablets/24 hours.
There are no dosage adjustments provided in the manufacturer's labeling; however, clearance may be reduced; active metabolites may accumulate. Use with caution; initiate at lower doses or longer dosing intervals followed by careful titration. See individual monographs for specific adjustments.
KDIGO 2012 guidelines provide the following recommendations for nonsteroidal anti-inflammatory drugs (Ref):
eGFR 30 to <60 mL/minute/1.73 m2: Avoid use in patients with intercurrent disease that increases risk of acute kidney injury.
eGFR <30 mL/minute/1.73 m2: Avoid use.
There are no dosage adjustments provided in the manufacturer's labeling; however, product contains acetaminophen; use with caution. Cases of hepatotoxicity at daily acetaminophen dosages <4,000 mg/day have been reported. See individual monographs.
(For additional information see "Ibuprofen and acetaminophen: Drug information")
Pain:
IV:
Note: Combogesic IV (acetaminophen and ibuprofen) is a combination product; each 100 mL vial contains 1 g acetaminophen and 300 mg ibuprofen.
<50 kg : Acetaminophen 15 mg/kg (in combination with ibuprofen 4.5 mg/kg) every 6 hours as needed (maximum: acetaminophen 750 mg/ibuprofen 225 mg as single dose or acetaminophen 3 g/ibuprofen 900 mg per 24 hours).
≥50 kg: Acetaminophen 1 g (in combination with ibuprofen 300 mg) every 6 hours as needed (maximum: acetaminophen 4 g/ibuprofen 1.2 g per 24 hours).
Oral:
Rx: Acetaminophen 325 mg/ibuprofen 97.5 mg per tablet: Three tablets every 6 hours as needed (maximum: 12 tablets [acetaminophen 3.9 g/ibuprofen 1.17 g] per 24 hours).
OTC: Acetaminophen 250 mg/ibuprofen 125 mg per tablet: Two tablets every 8 hours as needed (maximum: 6 tablets [acetaminophen 1.5 g/ibuprofen 750 mg] per 24 hours).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution. Use of Rx products are not recommended. Also refer to individual agents.
KDIGO 2012 guidelines provide the following recommendations for nonsteroidal anti-inflammatory drugs:
eGFR 30 to <60 mL/minute/1.73 m2: Avoid use in patients with intercurrent disease that increases risk of acute kidney injury.
eGFR <30 mL/minute/1.73 m2: Avoid use.
IV:
Hepatic impairment prior to treatment:
Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use not recommended. Also refer to individual agents.
Severe impairment or severe active liver disease: Use is contraindicated.
Hepatic impairment during treatment: If signs and symptoms consistent with liver disease or systemic manifestations (eg, eosinophilia, rash) occur, discontinue treatment immediately and clinically evaluate the patient.
Oral:
Rx:
Hepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use not recommended. Also refer to individual agents.
Hepatic impairment during treatment: If signs and symptoms consistent with liver disease or systemic manifestations (eg, eosinophilia, rash) occur, discontinue treatment immediately and clinically evaluate the patient.
OTC: There are no dosage adjustments provided in the manufacturer's labeling; use with caution to avoid adverse effects and discontinue if hepatic function worsens. Also refer to individual agents.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for injectable formulation in adults, unless otherwise noted. Also see individual agents.
>10%: Local: Infusion-site pain (18%)
1% to 10%:
Dermatologic: Hyperhidrosis (2% to 3%), pruritus (2% to 3%)
Gastrointestinal: Vomiting (6%)
Nervous system: Drowsiness (tablet: 2%)
Frequency not defined (any formulation):
Cardiovascular: Thrombosis (including acute myocardial infarction, cerebrovascular accident)
Gastrointestinal: Gastrointestinal signs and symptoms (including gastrointestinal hemorrhage, gastrointestinal perforation [intestinal perforation, stomach], gastrointestinal ulcer)
Hepatic: Acute hepatic failure
Postmarketing: Dermatologic: Exfoliative dermatitis, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis
Hypersensitivity (eg, anaphylactic reactions, serious skin reactions) to acetaminophen, ibuprofen, other nonsteroidal anti-inflammatory drug (NSAIDs), or any component of the formulation; history of asthma, urticaria, or allergic-type reaction to aspirin or other NSAIDs; use in the setting of coronary artery bypass graft surgery; severe hepatic impairment or severe active liver disease (IV only).
OTC labeling: When used for self-medication, do not use if previous allergic reaction to any other pain reliever/fever reducer; do not use with other drug products containing acetaminophen; prior to or following cardiac surgery.
Concerns related to adverse effects:
• Anaphylactoid reactions/hypersensitivity: Even in patients without prior exposure to ibuprofen, anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Hypersensitivity and anaphylactic reactions have also been reported with acetaminophen.
• Cardiovascular events: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including fatal myocardial infarction (MI) and stroke. Risk may occur early during treatment and may increase with dose and duration of use. Avoid use in patients with a recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk (ACC/AHA [Amsterdam 2014]). Avoid use in patients undergoing revascularization procedures. New-onset hypertension or exacerbation of hypertension may occur. NSAIDs may also impair response to antihypertensive agents; monitor BP; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in heart failure (FDA 2015).
• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects that may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• GI events: Use with caution in patients on concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids), advanced hepatic disease, coagulopathy, use of alcohol, or in elderly patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events. In patients with a history of GI ulcer bleeding requiring NSAID therapy, a COX-2 inhibitor in combination with a proton pump inhibitor is recommended to reduce the risk of recurrent bleeding (Barkun 2019). Discontinue use if GI bleeding occurs.
• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Rarely, NSAID use has been associated with potentially severe blood dyscrasias.
• Hepatotoxicity: Acetaminophen has been associated with acute liver failure, at times resulting in liver transplant and death. Hepatotoxicity is usually associated with excessive acetaminophen intake and often involves >1 product that contains acetaminophen. Do not exceed the maximum recommended daily dose (>4 g daily in adults) (Lancaster 2015). Hepatotoxicity has been reported with therapeutic doses of acetaminophen in patients with alcohol use disorder. In addition, chronic daily dosing may also result in liver damage in some patients (Bolesta 2002). Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, liver necrosis, hepatic failure) have occurred with NSAID use.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, angiotensin-converting enzyme [ACE]-inhibitors). Monitor potassium closely.
• Infection: May mask signs and symptoms of infection (eg, pain, fever, inflammation) resulting in delayed diagnosis.
• Ophthalmic events: Ophthalmologic adverse effects have been reported with NSAID use. Discontinue therapy and refer for ophthalmologic evaluation if symptoms occur.
• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors or angiotensin II receptor blockers, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.
• Skin reactions: May cause serious skin adverse events (sometimes fatal), including acute generalized exanthematous pustulosis, exfoliative dermatitis, fixed drug eruption (including generalized bullous fixed drug eruption), Stevens-Johnson syndrome, and toxic epidermal necrolysis; may occur without warning. Discontinue use at first sign of skin rash (or any other hypersensitivity).
Disease-related concerns:
• Aseptic meningitis: NSAIDs may increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus and mixed connective tissue disorders.
• Asthma: Use with caution in patients with asthma. Use of ibuprofen is contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur.
• Coronary artery bypass graft surgery: Avoid ibuprofen use in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.
• Coronavirus disease 2019 (COVID-19): Clinical or population-based data regarding the risks of NSAIDs in the setting of COVID-19 are limited (FDA Safety Communication 2020; Kim 2020). Some experts recommend the use of acetaminophen as the preferred antipyretic agent, when possible, and if NSAIDs are needed, to use the lowest effective dose and shortest duration (EMA 2020; Kim 2020). In general, for patients already taking an NSAID for a comorbid condition, it is recommended to continue the NSAID as directed by their health care provider (EMA 2020; NIH 2020; WHO 2020).
• Ethanol use: Use acetaminophen with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage. Patients should avoid ethanol or limit to <3 drinks/day.
• Hepatic impairment: Use with caution in patients with hepatic impairment; reduced doses may be required due to extensive hepatic metabolism. Patients with advanced hepatic disease are at an increased risk of GI bleeding and kidney failure with NSAIDs (AASLD [Biggins 2021]; AASLD [Runyon 2013]).
Special populations:
• Older adult: Older adult patients are at increased risk for adverse effects (especially peptic ulceration, CNS effects, renal toxicity) from NSAIDs even at low doses; use with caution.
Other warnings/precautions:
• Self-medication (OTC use): Should not be used with other products containing acetaminophen. Patients should be instructed to contact health care provider if new symptoms occur, if redness or swelling occurs in the painful area, or for pain lasting >10 days. Consuming ≥3 alcoholic beverages/day or taking longer than recommended may increase the risk of GI bleeding. Also see individual agents.
Hepatoxicity has been reported in patients using acetaminophen. In pediatric patients, this is most commonly associated with supratherapeutic dosing, more frequent administration than recommended, and use of multiple acetaminophen-containing products; however, hepatotoxicity has been rarely reported with recommended dosages (AAP [Sullivan 2011]; Heard 2014). All sources of acetaminophen (eg, prescription, OTC, combination) should be considered when evaluating a patient's maximum daily dose. To lower the risk for hepatotoxicity, the maximum daily acetaminophen dose should be limited to ≤75 mg/kg/day (maximum of 5 daily doses), not to exceed 4,000 mg/day (AAP [Sullivan 2011]; Heard 2014; Krenzelok 2012; Lavonas 2010). Acetaminophen avoidance or a lower total daily dose (2,000 to 3,000 mg/day) has been suggested for adults with increased risk for acetaminophen hepatotoxicity (eg, malnutrition, certain liver diseases, use of drugs that interact with acetaminophen metabolism); similar data are unavailable in pediatric patients (Hayward 2016; Larson 2007; Worriax 2007).
A single-center, 10-year, retrospective review of pediatric patients diagnosed with acute kidney injury (AKI) (n=1,015; ages ≤18 years) reported nonsteroidal anti-inflammatory drugs (NSAIDs) as a potential cause of AKI in 2.7% of patients (n=27); a higher incidence (6.6%) was reported when additional exclusion factors were included in the data analysis. Dosing information was available for 74% of the NSAID-associated AKI cases (n=20); dosing was within the recommended range in 75% (n=15) of these cases. The median age of children with NSAID-associated AKI was 14.7 years (range: 0.5 to 17.7 years) and 15% of patients were <5 years and more likely to require dialysis than the older patients. Some experts suggest the incidence of NSAID-associated AKI found in this study is conservative due to aggressive exclusion criteria (eg, concurrent aminoglycoside or other nephrotoxic therapy) and the actual incidence may be higher (Brophy 2013; Misurac 2013).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Combogesic: Acetaminophen 1,000 mg and ibuprofen 300 mg/100 mL (100 mL)
Tablet, Oral:
Acetaminophen-Ibuprofen: Acetaminophen 250 mg and ibuprofen 125 mg
Advil Dual Action: Acetaminophen 250 mg and ibuprofen 125 mg
Combogesic: Acetaminophen 325 mg and ibuprofen 97.5 mg
FT Dual Action: Acetaminophen 250 mg and ibuprofen 125 mg [contains corn starch]
Motrin Dual Action: Acetaminophen 250 mg and ibuprofen 125 mg [contains corn starch]
May be product dependent
Solution (Combogesic Intravenous)
1000-300 mg/100 mL (per mL): $0.28
Tablets (Advil Dual Action Oral)
125-250 mg (per each): $0.36
Tablets (Combogesic Oral)
325-97.5 mg (per each): $3.59
Tablets (Motrin Dual Action Oral)
125-250 mg (per each): $0.17
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer without regard to meals. May be administered with food or milk if GI upset occurs.
IV: For IV infusion only. Administer undiluted over 15 minutes. Attach an administration set in accordance with the manufacturer's recommendations. If dose to be administered is less than acetaminophen 1g/ibuprofen 300 mg, withdraw appropriate dose and place into separate empty, sterile container (eg, glass bottle, plastic IV container, syringe) for administration. Do not mix with other diluents or other medications.
Oral: May be administered with food or milk if stomach upset occurs.
IV: Store in original container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze. Protect from heat and light.
Oral:
Rx: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.
OTC: Store at 20°C to 25°C (68°F to 77°F); avoid excessive heat (40°C [104°F]).
An FDA-approved patient medication guide, which is available with the product information and at the following website, must be dispensed with this medication:
Combogesic: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/209471s001lbl.pdf#page=28
Oral: Temporary relief of minor aches and pains due to headache, backache, toothache, menstrual cramps, muscular aches, and minor pain of arthritis (OTC product: FDA approved in ages ≥12 years and adults).
Parenteral: Temporary relief of mild to moderate pain; management of moderate to severe pain as an adjunct to opioid analgesics (FDA approved in adults). Only indicated for short-term use of ≤5 days.
Beers Criteria: Ibuprofen is identified in the Beers Criteria as a potentially inappropriate medication to be avoided for chronic use in patients 65 years and older (unless alternative agents are ineffective and patient can receive concomitant gastroprotective agent) due to increased risk of GI bleeding and peptic ulcer disease in older adults in a high-risk category (eg, older than 75 years of age or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents). In addition, avoid for short-term scheduled use in combination with oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents unless alternatives are ineffective and patient can receive concomitant gastroprotective agent (Beers Criteria [AGS 2023]).
Maxigesic brand name for ibuprofen/acetaminophen [Australia, New Zealand, Singapore] but also brand name for diclofenac sodium/paracetamol [India].
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.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program
5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of 5-Aminosalicylic Acid Derivatives. Risk C: Monitor
Abciximab: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Abrocitinib: Agents with Antiplatelet Effects may increase antiplatelet effects of Abrocitinib. Risk X: Avoid
Acalabrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Acemetacin: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid
Alcohol (Ethyl): May increase hepatotoxic effects of Acetaminophen. Risk C: Monitor
Aliskiren: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Aliskiren. Risk C: Monitor
Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease excretion of Aminoglycosides. Data only in premature infants. Risk C: Monitor
Aminolevulinic Acid (Systemic): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Systemic). Risk X: Avoid
Aminolevulinic Acid (Topical): Photosensitizing Agents may increase photosensitizing effects of Aminolevulinic Acid (Topical). Risk C: Monitor
Anagrelide: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Angiotensin II Receptor Blockers: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Angiotensin II Receptor Blockers may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Risk C: Monitor
Angiotensin-Converting Enzyme Inhibitors: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Angiotensin-Converting Enzyme Inhibitors. Angiotensin-Converting Enzyme Inhibitors may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Risk C: Monitor
Anticoagulants (Miscellaneous Agents): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Anticoagulants (Miscellaneous Agents). Risk C: Monitor
Antiplatelet Agents (P2Y12 Inhibitors): Agents with Antiplatelet Effects may increase antiplatelet effects of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor
Aspirin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may decrease therapeutic effects of Aspirin. Aspirin may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Specifically, the risk for bleeding may be increased. Aspirin may decrease serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Management: In general, avoid regular, frequent use of NSAIDs with aspirin whenever possible. If combined, monitor for increased bleeding and a reduced cardioprotective effect of aspirin. Risk D: Consider Therapy Modification
Atazanavir: May increase serum concentration of UGT1A1 Substrates. Management: Do not use UGT1A1 substrates for which small increases in exposure can cause serious adverse effects together with atazanavir, and use caution with any UGT1A1 substrate, even when small changes in exposure are less likely to cause serious adverse effects. Risk D: Consider Therapy Modification
Belumosudil: May increase serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider Therapy Modification
Bemiparin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Bemiparin. Management: Avoid this combination if possible, due to an increased risk of bleeding. If coadministration cannot be avoided, monitor patients closely for clinical and laboratory evidence of bleeding. Risk D: Consider Therapy Modification
Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Beta-Blockers. Risk C: Monitor
Bile Acid Sequestrants: May decrease absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Risk C: Monitor
Busulfan: Acetaminophen may increase serum concentration of Busulfan. Risk C: Monitor
Caplacizumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Caplacizumab. Specifically, the risk of bleeding may be increased. Risk C: Monitor
CarBAMazepine: May increase metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor
Cardiac Glycosides: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Cardiac Glycosides. Risk C: Monitor
Clofarabine: OAT1/3 Inhibitors may increase serum concentration of Clofarabine. Risk C: Monitor
Collagenase (Systemic): Agents with Antiplatelet Effects may increase adverse/toxic effects of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor
Corticosteroids (Systemic): May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor
CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Risk D: Consider Therapy Modification
Dapsone (Topical): May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Risk C: Monitor
Dasatinib: Acetaminophen may increase hepatotoxic effects of Dasatinib. Dasatinib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and dasatinib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
Deferasirox: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor
Deoxycholic Acid: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Desirudin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Desirudin. Risk C: Monitor
Desmopressin: Nonsteroidal Anti-Inflammatory Agents may increase hyponatremic effects of Desmopressin. Risk C: Monitor
Dichlorphenamide: OAT1/3 Inhibitors may increase serum concentration of Dichlorphenamide. Risk C: Monitor
Direct Oral Anticoagulants (DOACs): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Direct Oral Anticoagulants (DOACs). Risk C: Monitor
Drospirenone-Containing Products: May increase hyperkalemic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
Enoxaparin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Enoxaparin. Management: Discontinue nonselective NSAIDs prior to initiation of enoxaparin whenever possible. If coadministration cannot be avoided, monitor patients closely for clinical and laboratory evidence of bleeding. Risk D: Consider Therapy Modification
Eplerenone: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Eplerenone. Risk C: Monitor
Flucloxacillin: May increase adverse/toxic effects of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. Risk C: Monitor
Fluconazole: May increase serum concentration of Ibuprofen. Risk C: Monitor
Fondaparinux: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Fondaparinux. Management: Discontinue nonselective nonsteroidal anti-inflammatory agents prior to the initiation of fondaparinux, if possible. If coadministration is required, monitor patients closely for signs and symptoms of bleeding. Risk D: Consider Therapy Modification
Fosphenytoin-Phenytoin: May decrease serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor
Glycoprotein IIb/IIIa Inhibitors: Agents with Antiplatelet Effects may increase antiplatelet effects of Glycoprotein IIb/IIIa Inhibitors. Risk C: Monitor
Heparin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Heparin. Risk C: Monitor
Heparins (Low Molecular Weight): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Heparins (Low Molecular Weight). Risk C: Monitor
Herbal Products with Anticoagulant/Antiplatelet Effects: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of HydrALAZINE. Risk C: Monitor
Ibritumomab Tiuxetan: Agents with Antiplatelet Effects may increase antiplatelet effects of Ibritumomab Tiuxetan. Risk C: Monitor
Ibrutinib: Agents with Antiplatelet Effects may increase adverse/toxic effects of Ibrutinib. Specifically, the risk of bleeding and hemorrhage may be increased. Risk C: Monitor
Imatinib: Ibuprofen may decrease serum concentration of Imatinib. Specifically, ibuprofen may decrease intracellular concentrations of imatinib, leading to decreased clinical response. Management: Consider using an alternative to ibuprofen in patients who are being treated with imatinib. Available evidence suggests other NSAIDs do not interact in a similar manner. Risk D: Consider Therapy Modification
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Acetaminophen may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Inotersen: Agents with Antiplatelet Effects may increase adverse/toxic effects of Inotersen. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Isoniazid: May increase hepatotoxic effects of Acetaminophen. Isoniazid may increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Ketorolac (Nasal): May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid
Ketorolac (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Ketorolac (Systemic). Risk X: Avoid
LamoTRIgine: Acetaminophen may decrease serum concentration of LamoTRIgine. Risk C: Monitor
Limaprost: May increase adverse/toxic effects of Agents with Antiplatelet Effects. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Lithium: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: Consider Therapy Modification
Local Anesthetics: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor
Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may decrease diuretic effects of Loop Diuretics. Loop Diuretics may increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Risk D: Consider Therapy Modification
Lorlatinib: May decrease serum concentration of Acetaminophen. Risk C: Monitor
Lumacaftor and Ivacaftor: May decrease serum concentration of Ibuprofen. Risk C: Monitor
Macimorelin: Coadministration of Nonsteroidal Anti-Inflammatory Agents and Macimorelin may alter diagnostic results. Risk X: Avoid
MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of MetFORMIN. Risk C: Monitor
Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider Therapy Modification
Methoxsalen (Systemic): Photosensitizing Agents may increase photosensitizing effects of Methoxsalen (Systemic). Risk C: Monitor
Methoxyflurane: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Methoxyflurane. Risk X: Avoid
MetyraPONE: May increase 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 X: Avoid
Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Mifamurtide. Risk X: Avoid
Miscellaneous Antiplatelets: Agents with Antiplatelet Effects may increase antiplatelet effects of Miscellaneous Antiplatelets. Risk C: Monitor
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. Risk C: Monitor
Nadroparin: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Nadroparin. Management: Coadministration of NSAIDs and nadroparin is not recommended due to an increased risk of bleeding. If coadministration is required, monitor patients closely for clinical and laboratory signs of bleeding. Risk D: Consider Therapy Modification
Naftazone: May increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
Nitric Oxide: May increase adverse/toxic effects of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (Topical): Nonsteroidal Anti-Inflammatory Agents (Topical) may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider Therapy Modification
Nonsteroidal Anti-Inflammatory Agents: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk for gastrointestinal toxicity is increased. Risk X: Avoid
Obinutuzumab: Agents with Antiplatelet Effects may increase adverse/toxic effects of Obinutuzumab. Specifically, the risk of bleeding may be increased. Management: Consider avoiding coadministration of obinutuzumab and agents with antiplatelet effects, especially during the first cycle of obinutuzumab therapy. Risk D: Consider Therapy Modification
Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Risk C: Monitor
PEMEtrexed: Ibuprofen may increase serum concentration of PEMEtrexed. Management: In patients with an estimated creatinine clearance of 45 to 79 mL/min, avoid ibuprofen for 2 days before, the day of, and 2 days following the administration of pemetrexed. Monitor for increased pemetrexed toxicities if combined. Risk D: Consider Therapy Modification
Pentosan Polysulfate Sodium: Agents with Antiplatelet Effects may increase adverse/toxic effects of Pentosan Polysulfate Sodium. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor
PHENobarbital: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Phenylbutazone: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid
Phenylephrine (Systemic): Acetaminophen may increase serum concentration of Phenylephrine (Systemic). Risk C: Monitor
Pirtobrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor
Porfimer: Photosensitizing Agents may increase photosensitizing effects of Porfimer. Risk X: Avoid
Potassium Salts: Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Potassium Salts. Risk C: Monitor
Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may increase hyperkalemic effects of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may decrease antihypertensive effects of Potassium-Sparing Diuretics. Risk C: Monitor
PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider Therapy Modification
Prilocaine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor for signs of methemoglobinemia when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid use of these agents with prilocaine/lidocaine cream in infants less than 12 months of age. Risk C: Monitor
Primaquine: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Primaquine. Specifically, the risk for methemoglobinemia may be increased. Management: Avoid concomitant use of primaquine and other drugs that are associated with methemoglobinemia when possible. If combined, monitor methemoglobin levels closely. Risk D: Consider Therapy Modification
Primidone: May increase metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor
Probenecid: May increase 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. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. Risk D: Consider Therapy Modification
Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor
Quinolones: Nonsteroidal Anti-Inflammatory Agents may increase neuroexcitatory and/or seizure-potentiating effects of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Quinolones. Risk C: Monitor
RifAMPin: May increase hepatotoxic effects of Acetaminophen. RifAMPin may decrease serum concentration of Acetaminophen. Risk C: Monitor
Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase adverse/toxic effects of Salicylates. An increased risk of bleeding may be associated with use of this combination. Risk X: Avoid
Seladelpar: OAT1/3 Inhibitors may increase serum concentration of Seladelpar. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: May increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may decrease therapeutic effects of Selective Serotonin Reuptake Inhibitor. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider Therapy Modification
Selumetinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Serotonin/Norepinephrine Reuptake Inhibitor: May increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor
Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider Therapy Modification
Sodium Nitrite: Methemoglobinemia Associated Agents may increase adverse/toxic effects of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor
Sodium Phosphates: May increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor
SORAfenib: Acetaminophen may increase hepatotoxic effects of SORAfenib. SORAfenib may increase serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and sorafenib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider Therapy Modification
Sulopenem Etzadroxil: OAT1/3 Inhibitors may increase serum concentration of Sulopenem Etzadroxil. Risk C: Monitor
Sulprostone: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Sulprostone. Risk X: Avoid
Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Tacrolimus (Systemic). Risk C: Monitor
Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may increase nephrotoxic effects of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider Therapy Modification
Tenoxicam: May increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk X: Avoid
Thiazide and Thiazide-Like Diuretics: Nonsteroidal Anti-Inflammatory Agents may decrease therapeutic effects of Thiazide and Thiazide-Like Diuretics. Thiazide and Thiazide-Like Diuretics may increase nephrotoxic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
Thrombolytic Agents: Agents with Antiplatelet Effects may increase adverse/toxic effects of Thrombolytic Agents. Specifically, the risk of bleeding may be increased. Risk C: Monitor
Tipranavir: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Tolperisone: Nonsteroidal Anti-Inflammatory Agents may increase adverse/toxic effects of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may increase therapeutic effects of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor
Tricyclic Antidepressants: May increase antiplatelet effects of Nonsteroidal Anti-Inflammatory Agents. Tricyclic Antidepressants may increase adverse/toxic effects of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Risk C: Monitor
Vaccines: Acetaminophen may decrease therapeutic effects of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider Therapy Modification
Vadadustat: OAT1/3 Inhibitors may increase serum concentration of Vadadustat. Risk C: Monitor
Valproic Acid and Derivatives: Ibuprofen may decrease serum concentration of Valproic Acid and Derivatives. Risk C: Monitor
Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase serum concentration of Vancomycin. Risk C: Monitor
Verteporfin: Photosensitizing Agents may increase photosensitizing effects of Verteporfin. Risk C: Monitor
Vitamin E (Systemic): May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Vitamin K Antagonists: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may increase anticoagulant effects of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Risk D: Consider Therapy Modification
Volanesorsen: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Voriconazole: May increase serum concentration of Ibuprofen. Specifically, concentrations of the S-(+)-ibuprofen enantiomer may be increased. Risk C: Monitor
Zanubrutinib: May increase antiplatelet effects of Agents with Antiplatelet Effects. Risk C: Monitor
Refer to individual monographs.
Acetaminophen crosses the placenta (Naga Rani 1989).
Refer to individual monographs for additional information.
Short-term use: Relief of pain.
Long-term use: Relief of pain, occult blood loss, liver enzymes; urine output, BUN, and creatinine (in patients at risk for kidney impairment), acetaminophen concentrations (in patients with hepatic disease).
Suspected overdose: Serum acetaminophen concentrations, hepatic function, kidney function.
Acetaminophen: The mechanism of acetaminophen is not fully elucidated; it produces analgesia by increasing the pain threshold.
Ibuprofen: Ibuprofen reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties.
Refer to individual agents.
