Brand names: Advil, Caldolor, IBU, Motrin, NeoProfen
Drug class: Other Nonsteroidal Anti-inflammatory Agents
CAS number: 15687-271

Medically reviewed by Drugs.com on Oct 9, 2023. Written by ASHP.

Introduction

Prototypical NSAIA; propionic acid derivative.^{100 106}

Uses for Ibuprofen

When used for inflammatory diseases, pain, dysmenorrhea, or fever, consider potential benefits and risks of ibuprofen therapy as well as alternative therapies before initiating therapy with the drug.¹⁹² Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹⁹²

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.¹⁰⁰

May be used in fixed combination with famotidine for symptomatic treatment of rheumatoid arthritis and osteoarthritis when use of famotidine to reduce the risk of upper GI ulcers is appropriate.²¹⁶ Efficacy of the fixed combination in reducing the risk of gastric and/or duodenal ulcers was demonstrated in studies of 6 months’ duration in patients without a history of GI ulcer who generally were <65 years of age.^{216 217}

Management of juvenile rheumatoid arthritis in children.¹⁰⁶

Pericarditis

Reduction of pain, fever, and inflammation of pericarditis^{† [off-label]};¹⁷⁴ however, in the treatment of post-MI pericarditis, NSAIAs are potentially harmful and aspirin is the treatment of choice.³²³ (See Cardiovascular Thrombotic Effects under Cautions.)

Pain

Oral ibuprofen used for relief of mild to moderate pain; IV ibuprofen used for relief of mild to moderate pain and, in conjunction with opiates, for relief of moderate to severe pain.^{100 106 210}

NSAIAs considered first-line agents for mild to moderate migraine attacks or for severe attacks that have responded in the past to NSAIAs or nonopiate analgesics.¹⁸⁶

Self-medication for the temporary relief of minor aches and pain associated with the common cold, influenza, or sore throat; headache (including migraine); toothache; muscular aches; backache; minor pain of arthritis.^{105 164 165 179 189}

Used in fixed combination with hydrocodone for short-term treatment of acute pain that is severe enough to require an opiate analgesic and for which alternative treatments are inadequate.¹⁶¹

Dysmenorrhea

Symptomatic management of primary dysmenorrhea.¹⁰⁰

Self-medication for the temporary relief of minor aches and pain associated with menstrual cramps.¹⁶⁵

Fever

Reduction of fever.^{106 210}

Self-medication for reduction of fever.^{164 165 179}

Patent Ductus Arteriosus (PDA)

Treatment of PDA in premature neonates (designated an orphan drug by FDA for this use).^{198 206} Used to promote closure of a clinically important PDA in premature neonates weighing 500–1500 g who are ≤32 weeks' gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support) is ineffective.¹⁹⁸ Limited follow-up data available; reserve for neonates with clinically important PDA.¹⁹⁸

Related/similar drugs

gabapentin, acetaminophen, prednisone, aspirin, meloxicam, cyclobenzaprine, tramadol

Ibuprofen Dosage and Administration

General

• For inflammatory diseases, pain, dysmenorrhea, or fever, consider potential benefits and risks of ibuprofen therapy as well as alternative therapies before initiating therapy with the drug.¹⁹²

Administration

Ibuprofen: Administer orally (for inflammatory diseases, pain, dysmenorrhea, or fever)^{100 106 164} or by IV infusion (for pain or fever).²¹⁰

Ibuprofen lysine: Administer by IV infusion (for PDA).¹⁹⁸

Oral Administration

If GI disturbances occur, administer with meals or milk.¹⁰⁰

Fixed combination of ibuprofen and famotidine: Swallow tablets whole; do not chew, divide, crush, or cut tablets to provide a lower dose.²¹⁶

Pediatric Administration

Ibuprofen oral drops generally used in infants 6–23 months of age.¹⁶⁴ Use the calibrated dosing device provided by the manufacturer for measurement of the dose.¹⁶⁴

Pediatric oral suspension and 100-mg chewable tablets commonly used in children 2–11 years of age.^{106 179 189 212} Use the calibrated dosage cup provided by the manufacturer for measurement of the dose of the suspension.²¹²

The 100-mg film-coated tablets may be used in children 6–11 years of age.²¹³

IV Administration (Ibuprofen)

For solution and drug compatibility information, see Compatibility under Stability.

Ensure patient is well hydrated.²¹⁰

Injection concentrate (100 mg/mL) must be diluted prior to IV administration.²¹⁰ IV administration of the undiluted concentrate can cause hemolysis.²¹⁰

Use the commercially available ibuprofen 4-mg/mL (800 mg in 200 mL) premixed injection to administer 800-mg doses only.²¹⁰

Dilution

Dilute ibuprofen injection concentrate with an appropriate volume of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to provide a solution containing ≤4 mg/mL.²¹⁰

Rate of Administration

Adults: Administer dose over ≥30 minutes.²¹⁰

Pediatric patients 6 months to 17 years of age: Administer dose over ≥10 minutes.²¹⁰

IV Administration (Ibuprofen Lysine)

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using IV port nearest to the IV insertion site.¹⁹⁸

Do not infuse simultaneously through same line as parenteral nutrition solutions.¹⁹⁸ If same line must be used, interrupt infusion of the nutrition solution for 15 minutes before and after administration of ibuprofen; maintain line patency by infusing dextrose injection or sodium chloride injection.¹⁹⁸

Avoid extravasation (irritating to extravascular tissues).¹⁹⁸

Dilution

Dilute ibuprofen lysine injection with an appropriate volume of dextrose injection or sodium chloride injection.¹⁹⁸

Administer within 30 minutes of preparation; discard any unused solution.¹⁹⁸

Rate of Administration

Administer dose over 15 minutes.¹⁹⁸

Dosage

Dosage of ibuprofen lysine expressed in terms of ibuprofen.¹⁹⁸

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.¹⁹² Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{100 106 192}

Pediatric Patients

Dosage in children should be guided by body weight.¹⁰⁶

Inflammatory Diseases

Juvenile Rheumatoid Arthritis

Oral

30–40 mg/kg daily divided into 3 or 4 doses.¹⁰⁶ 20 mg/kg daily in divided doses may be adequate for children with mild disease.¹⁰⁶

Once clinical effect obtained, reduce dosage to lowest level that maintains adequate symptomatic control.¹⁰⁶

If dosage >30 mg/kg daily, carefully monitor for signs and symptoms of early liver dysfunction.¹⁰⁶

Pain

Oral

For mild to moderate pain in children 6 months to 2 years of age, 10 mg/kg every 6–8 hours; avoid disrupting the child's sleep pattern.¹⁰⁶ (See Pediatric Use under Cautions.)

See Table 1 for recommended analgesic dosages for self-medication in children 6 months to 11 years of age.

Dose may be administered every 6–8 hours.^{164 179 189 212 213}

For self-medication of minor aches and pain in adolescents ≥12 years of age, 200 mg every 4–6 hours; may increase dosage to 400 mg every 4–6 hours (maximum 1.2 g daily) if needed.¹⁶⁵

In fixed combination with acetaminophen for self-medication of minor aches and pain in adolescents ≥12 years of age, 250 mg of ibuprofen every 8 hours.²¹⁵

IV

For children 6 months to <12 years of age, 10 mg/kg (up to 400 mg) every 4–6 hours as needed; do not exceed 40 mg/kg or 2.4 g (whichever is less) per 24-hour period.²¹⁰

For adolescents 12–17 years of age, 400 mg every 4–6 hours as needed (maximum 2.4 g per 24-hour period).²¹⁰

Fever

Oral

For children 6 months to 2 years of age: 5 mg/kg for temperatures <39°C; 10 mg/kg for temperatures ≥39°C.¹⁰⁶ (See Pediatric Use under Cautions.)

See Table 2 for recommended antipyretic dosages for self-medication in children 6 months to 11 years of age.

Dose may be administered every 6–8 hours.^{164 179 189 212 213}

For self-medication of fever in adolescents ≥12 years of age, 200 mg every 4–6 hours; may increase dosage to 400 mg every 4–6 hours (maximum 1.2 g daily) if needed.¹⁶⁵

IV

For children 6 months to <12 years of age, 10 mg/kg (up to 400 mg) every 4–6 hours as needed; do not exceed 40 mg/kg or 2.4 g (whichever is less) per 24-hour period.²¹⁰

For adolescents 12–17 years of age, 400 mg every 4–6 hours as needed (maximum 2.4 g per 24-hour period).²¹⁰

Dysmenorrhea

Oral

For self-medication in adolescents 12–17 years of age, 200 mg every 4–6 hours; may increase to 400 mg every 4–6 hours (maximum 1.2 g daily) if necessary.¹⁶⁵

PDA

IV

Each course of therapy consists of 3 doses of ibuprofen lysine administered at 24-hour intervals.¹⁹⁸

Base dosage on neonate’s birth weight.¹⁹⁸

First dose is 10 mg/kg; second and third doses are 5 mg/kg each.¹⁹⁸

If anuria or oliguria (urine output <0.6 mL/kg per hour) is present at the time of a second or third dose, withhold the dose until laboratory determinations indicate that renal function has returned to normal.¹⁹⁸

If ductus arteriosus closes or is substantially constricted after completion of the first course, no further doses are necessary.¹⁹⁸

If ductus arteriosus fails to close or reopens, a second course of ibuprofen, alternative pharmacologic therapy, or surgery may be needed.¹⁹⁸

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

1.2–3.2 g daily, given as 300 mg 4 times daily, or 400, 600, or 800 mg 3 or 4 times daily.¹⁰⁰

In fixed combination with famotidine, 800 mg of ibuprofen 3 times daily.²¹⁶

Pain

Oral

For mild to moderate pain, 400 mg every 4–6 hours as needed.¹⁰⁰

In fixed combination with hydrocodone, 200 mg of ibuprofen every 4–6 hours (maximum 1 g daily) as needed.¹⁶¹

For self-medication of minor aches and pain, 200 mg every 4–6 hours; may increase dosage to 400 mg every 4–6 hours (maximum 1.2 g daily) if needed.¹⁶⁵

In fixed combination with acetaminophen for self-medication of minor aches and pain, 250 mg of ibuprofen every 8 hours.²¹⁵

For self-medication of migraine pain, 400 mg once in a 24-hour period.¹⁰⁵

IV

400–800 mg every 6 hours as needed.²¹⁰

Dysmenorrhea

Oral

400 mg every 4 hours as necessary; initiate at earliest onset of pain.¹⁰⁰

For self-medication, 200 mg every 4–6 hours; may increase to 400 mg every 4–6 hours (maximum 1.2 g daily) if necessary.¹⁶⁵

Fever

Oral

For self-medication, 200 mg every 4–6 hours; may increase to 400 mg every 4–6 hours (maximum 1.2 g daily) if needed.¹⁶⁵

IV

400 mg initially; then 400 mg every 4–6 hours or 100–200 mg every 4 hours.²¹⁰

Prescribing Limits

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis

Oral

Maximum 50 mg/kg daily.¹⁰⁶

Pain

Oral

For mild to moderate pain in children 6 months to 2 years of age, maximum 40 mg/kg daily.¹⁰⁶

For self-medication of minor aches and pain in children 6 months to 11 years of age, do not exceed recommended dosage; do not administer recommended dose more than 4 times daily.^{164 179 189 212 213} (See Pediatric Use under Cautions.) Self-medication should not exceed 3 days unless otherwise directed by a clinician.^{164 179 189 212 213}

For self-medication of minor aches and pain in adolescents ≥12 years of age, maximum 1.2 g daily.¹⁶⁵ Self-medication should not exceed 10 days unless otherwise directed by a clinician.¹⁶⁵

In fixed combination with acetaminophen for self-medication of minor aches and pains in adolescents ≥12 years of age, maximum 250 mg of ibuprofen every 8 hours.²¹⁵ Self-medication should not exceed 10 days unless otherwise directed by a clinician.²¹⁵

IV

For children 6 months to <12 years of age, maximum 40 mg/kg or 2.4 g (whichever is less) per 24-hour period.²¹⁰

For adolescents 12–17 years of age, maximum 2.4 g per 24-hour period.²¹⁰

Fever

Oral

Maximum 40 mg/kg daily in children 6 months to 2 years of age.¹⁰⁶

For self-medication in children 6 months to 11 years of age, do not exceed recommended dosage; do not administer recommended dose more than 4 times daily.^{164 179 189 212 213} (See Pediatric Use under Cautions.) Self-medication should not exceed 3 days unless otherwise directed by a clinician.^{164 179 189 212 213}

For self-medication in adolescents ≥12 years of age, maximum 1.2 g daily.¹⁶⁵ Self-medication should not exceed 3 days unless otherwise directed by a clinician.¹⁶⁵

IV

For children 6 months to <12 years of age, maximum 40 mg/kg or 2.4 g (whichever is less) per 24-hour period.²¹⁰

For adolescents 12–17 years of age, maximum 2.4 g per 24-hour period.²¹⁰

Dysmenorrhea

Oral

For self-medication in adolescents 12–17 years of age, maximum 1.2 g daily.¹⁶⁵

Adults

Inflammatory Diseases

Osteoarthritis or Rheumatoid Arthritis

Oral

Maximum 3.2 g daily.¹⁰⁰

Pain

Oral

For mild to moderate pain, maximum 3.2 g daily.¹⁰⁰

In fixed combination with hydrocodone, maximum 1 g of ibuprofen daily.¹⁶¹

For self-medication of minor aches and pain, maximum 1.2 g daily.¹⁶⁵ Self-medication should not exceed 10 days unless otherwise directed by a clinician.¹⁶⁵

In fixed combination with acetaminophen for self-medication of minor aches and pains, maximum 250 mg of ibuprofen every 8 hours.²¹⁵ Self-medication should not exceed 10 days unless otherwise directed by a clinician.²¹⁵

For self-medication of migraine pain, maximum 400 mg in a 24-hour period unless otherwise directed by a clinician.¹⁰⁵

IV

Maximum 3.2 g in a 24-hour period.²¹⁰

Dysmenorrhea

Oral

Maximum 3.2 g daily.¹⁰⁰

For self-medication, maximum 1.2 g daily.¹⁶⁵

Fever

Oral

For self-medication, maximum 1.2 g daily.¹⁶⁵ Self-medication should not exceed 3 days unless otherwise directed by a clinician.¹⁶⁵

IV

Maximum 3.2 g in a 24-hour period.²¹⁰

Special Populations

Renal Impairment

Avoid use in patients with advanced renal disease unless benefits expected to outweigh risk of worsening renal function.^{100 106 210} (See Renal Impairment under Cautions.)

CYP2C9 Poor or Intermediate Metabolizers

CYP2C9 poor metabolizers: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend initiating ibuprofen at a dosage that is 25–50% of the lowest recommended initial dosage and cautiously titrating to a clinically effective dosage, up to a dosage that is 25–50% of the maximum recommended dosage.⁵²⁰ Do not increase dosage until steady-state concentrations are attained (≥5 days after initial dose).⁵²⁰ Alternatively, consider a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo.⁵²⁰ (See Pharmacogenomic Considerations under Cautions.)

CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1: CPIC guidelines recommend initiating ibuprofen at the lowest recommended initial dosage and cautiously titrating to a clinically effective dosage, up to the maximum recommended dosage.⁵²⁰

Intermediate metabolizers with an AS of 1.5 may receive dosages recommended for normal metabolizers.⁵²⁰

CPIC dosage recommendations apply to both OTC and prescription use of the drug.⁵²⁰

Cautions for Ibuprofen

Contraindications

• Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to ibuprofen or any ingredient in the formulation.^{100 106 210}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{100 106 210}

• In the setting of CABG surgery.²¹⁰

IV Therapy for PDA

• Known or suspected untreated infection.¹⁹⁸

• Bleeding, especially active intracranial hemorrhage or GI bleeding; thrombocytopenia; coagulation defects.¹⁹⁸

• Known or suspected necrotizing enterocolitis.¹⁹⁸

• Substantial renal impairment.¹⁹⁸

• Congenital heart disease if patency of the ductus arteriosus is necessary for pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).¹⁹⁸

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.^{210 500 502}

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information^{500 501 502} indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.^{210 500 502 506}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{210 500 502 505 506}

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.²¹⁰

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{210 505}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{210 500 511} absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.^{210 511}

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.^{199 200 201 205 500 501 502 503 506} FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.^{192 210 500}

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.^{505 511 512 516} Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.²¹⁰ Contraindicated in the setting of CABG surgery.²¹⁰

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{192 197 210 502} (See Specific Drugs under Interactions.)

GI Effects

Serious, sometimes fatal, GI toxicity (e.g., bleeding, ulceration, or perforation of esophagus, stomach, or small or large intestine) can occur with or without warning symptoms.^{100 104 109 192 210}

Risk for GI bleeding increased more than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.^{173 177 210}

Other risk factors for GI bleeding include concomitant use of oral corticosteroids, anticoagulants, aspirin, or SSRIs; longer duration of NSAIA therapy (however, short-term therapy is not without risk); smoking; alcohol use; older age; poor general health status; and advanced liver disease and/or coagulopathy.^{173 177 210}

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.¹⁰⁶

Frequency of NSAIA-associated upper GI ulcers, gross bleeding, or perforation is approximately 1% in patients receiving NSAIAs for 3–6 months and 2–4% at one year.^{100 104}

Use at lowest effective dosage for the shortest duration necessary.^{192 210}

Avoid use of more than one NSAIA at a time.²¹⁰ (See Specific Drugs under Interactions.)

Avoid use of NSAIAs in patients at higher risk for GI toxicity unless expected benefits outweigh increased risk of bleeding; consider alternate therapies in high-risk patients and those with active GI bleeding.^{192 210}

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{154 157 173 175} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{154 157 173} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).¹⁵⁴

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.^{100 104 192 210}

If serious adverse GI event suspected, promptly initiate evaluation and discontinue ibuprofen until serious adverse GI event ruled out.¹⁹²

Contraindicated in neonates with necrotizing enterocolitis.¹⁹⁸

Other Warnings and Precautions

Hepatic Effects

Severe, sometimes fatal, reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure reported rarely with NSAIAs.^{100 106 210}

Elevations of serum ALT or AST reported.^{100 106 210}

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{100 106 210} Discontinue immediately and perform clinical evaluation if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.^{100 106 210}

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.^{192 210} Monitor BP during initiation of ibuprofen and throughout therapy.^{192 210}

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{192 210} (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.^{100 106 192 210}

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{210 500 501 504 507}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.²¹⁰ (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.²¹⁰

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{100 106 210}

Potential for overt renal decompensation.^{100 106 116 192 210} Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.^{192 196 210} (See Renal Impairment under Cautions.)

Correct dehydration before initiating ibuprofen therapy; monitor renal function during therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.^{100 106 210}

Renal insufficiency (including oliguria), increases in BUN, increases in S_cr, and renal failure reported in neonates.¹⁹⁸ Decreases in urine output in ibuprofen-treated neonates noted on days 2–6 of life; compensatory increase in output noted on day 9.¹⁹⁸

Hyperkalemia

Hyperkalemia reported with NSAIAs, even in some patients without renal impairment; in such patients, effects attributed to a hyporenin-hypoaldosterone state.²¹⁰

Hypersensitivity Reactions

Anaphylactic reactions reported.^{100 106 210} Immediate medical intervention and discontinuance for anaphylaxis.^{100 106 210}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); in patients with asthma but without known aspirin sensitivity, monitor for changes in manifestations of asthma.^{100 106 210}

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs.¹⁰⁰ Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).¹⁰⁰ Symptoms may resemble those of acute viral infection.¹⁰⁰ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.¹⁰⁰ If signs or symptoms of DRESS develop, discontinue the NSAIA and immediately evaluate the patient.¹⁰⁰

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{192 210} Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^{192 210}

Pharmacogenomic Considerations

CYP2C9 poor metabolizers: Ibuprofen metabolism may be decreased substantially, half-life may be prolonged, and higher plasma concentrations of the drug may increase likelihood and/or severity of adverse effects.⁵²⁰

CYP2C9 intermediate metabolizers: Ibuprofen metabolism may be moderately or mildly reduced in those with an AS of 1 or 1.5, respectively.⁵²⁰ Higher plasma ibuprofen concentrations in intermediate metabolizers with an AS of 1 may increase likelihood of adverse effects.⁵²⁰ Presence of other factors affecting ibuprofen clearance (e.g., hepatic impairment, advanced age) also may increase risk of adverse effects in intermediate metabolizers.⁵²⁰ Further caution advised in patients carrying the CYP2C9*2 allele, since this allele is strongly linked to the decreased-function CYP2C8*3 allele, and CYP2C8 also contributes to ibuprofen metabolism.⁵²⁰

Dosage reduction may be required based on CYP2C9 phenotype.⁵²⁰ (See CYP2C9 Poor or Intermediate Metabolizers under Dosage and Administration.)

Consult Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs for additional information on interpretation of CYP2C9 genotype testing.⁵²⁰

Hematologic Effects

Anemia reported rarely.^{100 210} May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.²¹⁰ Determine hemoglobin concentration or hematocrit if signs or symptoms of anemia occur.^{192 210}

NSAIAs may increase the risk of bleeding.²¹⁰ Patients with certain coexisting conditions (e.g., coagulation disorders) or receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk; monitor such patients for bleeding.²¹⁰ (See Specific Drugs under Interactions.)

May inhibit platelet aggregation and prolong bleeding time.^{106 210}

Potential for spontaneous intraventricular hemorrhage in neonates.¹⁹⁸ Observe premature infants for signs of bleeding.¹⁹⁸

Contraindicated in neonates who are bleeding and those with thrombocytopenia or coagulation defects.¹⁹⁸

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.²¹⁰

Aseptic Meningitis

Aseptic meningitis reported rarely.^{100 106 210} Consider possibility that meningitis in a patient receiving ibuprofen is drug related.^{100 106 210}

Hyperbilirubinemia

Ibuprofen can displace bilirubin from serum albumin; caution in patients with elevated total bilirubin concentrations.¹⁹⁸

Individuals with Phenylketonuria

Motrin chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 6 mg of phenylalanine for each 100-mg tablet.¹⁸⁹

Advil Junior Strength chewable tablets contain aspartame, which is metabolized to provide 4.2 mg of phenylalanine for each 100-mg tablet.¹⁷⁹

Diabetic Patients

Some commercially available preparations of ibuprofen may contain sucrose.¹⁰⁶

Use of Fixed Combinations

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.^{159 161 215}

Concomitant NSAIA Therapy

Concomitant use with other NSAIAs not recommended.²¹⁰ (See Specific Drugs under Interactions.) Do not use multiple ibuprofen-containing preparations concomitantly.¹⁶⁵

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.¹⁰⁰

May mask certain signs of infection.^{100 106 198}

Obtain CBC and chemistry profile periodically during long-term use.¹⁰⁰

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.^{100 1200}

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.¹²⁰²

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice.^{100 1200} (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs.^{100 1200} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{100 1200} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{100 1200} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{100 1200} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{100 1200} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.¹⁰⁰ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.¹⁰⁰

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.²¹⁰ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.^{100 210}

No adequate and well-controlled studies of ibuprofen in pregnant women.²¹⁰ No clear developmental effects observed in animal reproduction studies, although one study indicated an increase in membranous ventricular septal defects.²¹⁰

Effects of ibuprofen on labor and delivery not known.²¹⁰ In animal studies, NSAIAs delayed parturition and increased stillbirths.²¹⁰

Lactation

Limited data indicate ibuprofen distributes into milk, resulting in infant doses of 0.06–0.6% of the maternal weight-adjusted daily dosage.²¹⁰ Adverse effects on breast-fed infants or effects on milk production not reported to date.²¹⁰

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ibuprofen and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.²¹⁰

Fertility

NSAIAs may be associated with reversible infertility in some women.²¹⁰ Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.²¹⁰

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.²¹⁰

Pediatric Use

Safety and efficacy of ibuprofen lysine established only in premature neonates receiving the drug for PDA.¹⁹⁸ Long-term follow-up (>36 weeks postconception age) of these neonates has not been conducted.¹⁹⁸ Effects of ibuprofen on neurodevelopmental outcome, growth, and other complications of prematurity (e.g., retinopathy of prematurity, chronic lung disease) not assessed.¹⁹⁸ (See Contraindications under Cautions.)

Safety and efficacy of oral ibuprofen not established in infants <6 months of age.¹⁰⁶

Carefully monitor pediatric patients receiving dosages >30 mg/kg daily and those who had abnormal liver function test results associated with prior NSAIA therapy for signs and symptoms of early liver dysfunction.¹⁰⁶

Safety and efficacy of IV ibuprofen for pain relief and antipyresis in pediatric patients ≥6 months of age supported by evidence of fever reduction in an open-label study in hospitalized febrile pediatric patients, safety data from 3 studies in 143 pediatric patients ≥6 months of age receiving IV ibuprofen for pain relief or antipyresis, supportive data for other ibuprofen preparations labeled for use in pediatric patients, and evidence from adequate and well-controlled studies in adults.²¹⁰ Efficacy of IV ibuprofen for pain relief or antipyresis not established in infants <6 months of age.²¹⁰

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.^{207 208} Such preparations also may contain analgesics and antipyretics.²⁰⁷ Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.²⁰⁷ Therefore, FDA recommends not to use such preparations in children <2 years of age;^a safety and efficacy in older children currently under evaluation.^{c e} Because children 2–3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral OTC cough and cold preparations agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age.^{b c d e} FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.^{b c d}

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects.²¹⁰ Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{100 106} If anticipated benefits outweigh potential risks, initiate at lower end of dosing range and monitor for adverse effects.²¹⁰

Experience in those ≥65 years of age insufficient to determine whether they respond differently to IV ibuprofen than do younger adults.²¹⁰ Select dosage with caution, starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.²¹⁰

Renal Impairment

May hasten progression of renal dysfunction in patients with preexisting renal disease.²¹⁰ Monitor patients with preexisting renal disease for worsening renal function.²¹⁰

Not evaluated in patients with severe renal impairment.²¹⁰ Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function; close monitoring of renal function advised if used.^{100 106 210}

Ibuprofen lysine contraindicated in neonates with substantially impaired renal function.¹⁹⁸

Common Adverse Effects

With oral ibuprofen therapy, dizziness, epigastric pain, heartburn, nausea, rash.^{100 106}

With IV ibuprofen therapy, nausea, flatulence, vomiting, headache, hemorrhage, and dizziness in adults; infusion site pain, vomiting, nausea, anemia, and headache in pediatric patients.²¹⁰

With IV ibuprofen lysine therapy, sepsis, anemia, bleeding, apnea, adverse GI effects, renal impairment, respiratory tract infection, dermatologic effects, hypoglycemia, hypocalcemia, respiratory failure.¹⁹⁸

Drug Interactions

No evidence of enzyme induction.¹⁰⁰

Specific Drugs

Ibuprofen Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentration usually attained within 1–2 hours.^{100 211}

Onset

Pain relief and/or antipyretic activity achieved within 1 hour.¹⁰⁷

Food

Food reduces peak plasma concentration by about 30–50% and delays time to reach peak plasma concentration by about 30–60 minutes but does not affect extent of absorption.¹⁰⁶

Distribution

Extent

Distributes into milk in small amounts.²¹⁰

Plasma Protein Binding

>99%.¹⁰⁶

Elimination

Metabolism

Almost completely metabolized, mainly via CYP-mediated oxidative metabolism to inactive metabolites.⁵²¹ Metabolized mainly by CYP2C9 and to a lesser extent by CYP2C8.⁵²¹ CYP3A4 contributes to clearance at high concentrations; CYP2C19 appears to play minor role.⁵²¹ Approximately 10–15% of an ibuprofen dose metabolized to ibuprofen acyl glucuronide.⁵²¹ Multiple uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes can metabolize ibuprofen in vitro; further study needed to characterize the relative contributions of individual UGT isoenzymes to ibuprofen metabolism in vivo.⁵²¹

Elimination Route

Approximately 37 and 25% of dose excreted in urine as the 2 major metabolites, carboxyibuprofen and 2-hydroxyibuprofen (and their corresponding acyl glucuronides), respectively.⁵²¹ Small amounts of other hydroxylated metabolites also recovered in urine.⁵²¹ Little or no unchanged drug recovered in urine.⁵²¹

Half-life

1.8–2.4 hours.^{100 210}

Following oral administration, terminal elimination half-life reportedly similar in children and adults, but clearance in children may be affected by age or fever.¹⁰⁶

Following IV administration, elimination half-life shorter in pediatric patients than in adults: 1.5–1.6 hours in pediatric patients 2–16 years of age, 1.8 hours in those 6 months to <2 years of age.²¹⁰

Half-life 10-fold longer in neonates than in adults.¹⁹⁸

Stability

Storage

Oral

Capsules and Tablets

20–25°C; avoid excessive heat (>40°C).^{100 165}

Suspension

20–25°C.^{106 164 212}

Parenteral

Injection

Ibuprofen: 20–25°C (may be exposed to 15–30°C).²¹⁰

Ibuprofen lysine: 20–25°C (may be exposed to 15–30°C); store vials in carton until use to protect from light.¹⁹⁸

Compatibility

Parenteral

Solution Compatibility (Ibuprofen)218

Drug Compatibility (Ibuprofen)218

Solution Compatibility (Ibuprofen Lysine)219

Drug Compatibility (Ibuprofen Lysine)219

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{166 167 168 169 170 210}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{100 106 166 167 168 169 170 210}

• Permits closure of the ductus arteriosus in premature neonates by inhibiting prostaglandin synthesis.¹⁹⁸

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.¹⁹²

• When used for self-medication, importance of reading the product labeling.^{164 194}

• When used for self-medication, importance of using the lowest effective dosage and of not exceeding the recommended dosage or duration of therapy.^{194 195} (See Dosage and Administration.)

• When used for self medication, importance of reviewing the warning information provided by the manufacturer.^{164 194}

• Risk of serious cardiovascular events (e.g., MI, stroke).^{192 210 500} Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (e.g., chest pain, dyspnea, weakness, slurred speech) occur.^{192 210 500}

• Risk of GI bleeding and ulceration.^{100 106 210} Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding develop.^{100 106 192 210} Inform patients receiving concomitant low-dose aspirin of the increased risk of GI bleeding.²¹⁰

• Risk of serious skin reactions,^{192 210} DRESS,¹⁰⁰ and anaphylactic and other sensitivity reactions.^{100 106 192 210} Advise patients to stop taking the drug immediately if they develop any type of rash or fever and to promptly contact their clinician.¹⁰⁰ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{100 106 210}

• Risk of hepatotoxicity.^{100 106 210} Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^{100 106 192 210}

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.²¹⁰

• Potential for ibuprofen to interfere with antiplatelet effect of low-dose aspirin.⁵⁰⁰ Importance of consulting clinician prior to taking low-dose aspirin concomitantly.²¹⁰

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{100 106 210}

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.^{100 1200}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.²¹⁰

• When used in premature infants with PDA, advise parents or caregivers that ibuprofen can alter signs of infection, inhibit clot formation, and irritate skin or tissues if leakage occurs at the administration site; importance of monitoring the infant for signs of infection, bleeding, and skin or tissue irritation.¹⁹⁸

• Advise patients using ibuprofen for self-medication of migraine headaches that headaches may worsen if the drug is used on ≥10 days per month.¹⁰⁵

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{100 106 210} Advise patients that concomitant use of other NSAIAs with ibuprofen provides little or no increase in efficacy but increases risk of GI toxicity, and is not recommended.²¹⁰ Alert patients to the presence of NSAIAs, including ibuprofen, in many OTC preparations.²¹⁰

• Importance of informing patients of other important precautionary information.^{100 106 210} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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