Brand names: Caldolor, IBU, NeoProfen
Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Mar 10, 2025. Written by ASHP.

Introduction

Nonsteroidal anti-inflammatory agent (NSAIA); exhibits analgesic and antipyretic activity.¹⁰⁰

Uses for Ibuprofen, Ibuprofen Lysine

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis in adults (oral tablets and suspension).^{100 106 1203 1204}

Guidelines from the American College of Rheumatology (ACR) for treatment of rheumatoid arthritis recommend initiation of a disease-modifying antirheumatic drug (DMARD) for most patients; role of NSAIAs not discussed.²⁰⁰¹

ACR recommends topical/oral NSAIAs for treatment of osteoarthritis, among other interventions.²⁰⁰² Therapy selection is patient-specific; factors to consider include patients' values and preferences, risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.²⁰⁰²

Symptomatic treatment of juvenile arthritis in pediatric patients (oral suspension only).^{106 1205}

ACR and the Arthritis Foundation recommend initial therapy with a DMARD (e.g., methotrexate) over NSAIA monotherapy for children and adolescents with juvenile idiopathic arthritis and polyarthritis; NSAIAs may be used adjunctively, particularly during initiation or escalation of therapy with DMARDs or biologics.²⁰⁰³ For patients with active sacroiliitis or enthesitis, initial treatment with an NSAIA is recommended; no particular NSAIA is preferred.²⁰⁰³ ACR recommends intraarticular glucocorticoids and a trial of scheduled NSAIAs as part of initial therapy for oligoarthritis and temporomandibular joint arthritis.²⁰⁰⁹ For patients with systemic juvenile idiopathic arthritis without macrophage activation syndrome, ACR conditionally recommends initial monotherapy with NSAIAs or biologic DMARDs (i.e., interleukin [IL]-1 and IL-6 inhibitors).²⁰⁰⁹

Also commercially available in fixed combination with famotidine for symptomatic treatment of rheumatoid arthritis and osteoarthritis; famotidine is used in the combination to decrease risk of developing upper GI ulcers.²¹⁶ See full prescribing information for use of this combination product.²¹⁶

NSAIAs, including ibuprofen, have also been used in other inflammatory diseases including ankylosing spondylitis^{† [off-label]}, gout^{† [off-label]}, and psoriatic arthritis^{† [off-label]} .^{2006 2007 2008}

Pain

Oral ibuprofen used for relief of mild to moderate pain; oral tablets used in adults, and oral suspension used in pediatric patients 6 months to 2 years of age.^{100 106 1215 1216 1217}

IV ibuprofen used in adults and pediatric patients ≥3 months of age for relief of mild to moderate pain and, in conjunction with opiates, for relief of moderate to severe pain.^{210 1211 1212 1213}

Self-medication for the temporary relief of minor aches and pain associated with headache (including migraine); toothache; muscular aches; backache; the common cold; and minor pain of arthritis.^{522 523 524}

Also commercially available in fixed combination with hydrocodone bitartrate for the short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.¹⁶¹ See full prescribing information for use of this combination product.¹⁶¹

Current guidelines on postoperative pain management recommend a multimodal approach to analgesia.²⁰¹³ NSAIAs recommended as part of multimodal analgesia in patients without contraindications.²⁰¹³ When selecting therapy for a specific patient, consider potential risks associated with NSAIAs.²⁰¹³

For management of acute postoperative dental pain in patients undergoing simple or surgical tooth extraction, the American Dental Association recommends an NSAIA (either ibuprofen or naproxen [in patients >2 years of age]) alone or in combination with acetaminophen.^{1221 1222}

For treatment of acute migraine, drugs with established efficacy include triptans, ergotamine derivatives, gepants, lasmiditan, NSAIAs (aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen), and the combination of acetaminophen, aspirin, and caffeine.¹²²³ Nonspecific analgesic therapies such as NSAIAs and acetaminophen/aspirin/caffeine are used for mild-to-moderate attacks, while migraine-specific therapies (e.g., triptans, ergotamine derivatives, gepants, lasmiditan) are used for moderate-to-severe attacks or mild-to-moderate attacks that respond poorly to non-specific therapy.¹²²³ When selecting an agent, consider patient-specific factors such as comorbid disease states, individual treatment history, and concomitant medications.¹²²³

American Academy of Neurology (AAN) guideline recommends ibuprofen oral liquid for initial treatment of acute migraine pain in children and adolescents; other options for adolescents include sumatriptan/naproxen oral tablets, zolmitriptan nasal spray, sumatriptan nasal spray, rizatriptan orally disintegrating tablets, or almotriptan oral tablets.¹²²⁴ May offer ibuprofen or naproxen as add-on therapy to improve migraine relief in adolescents with inadequate response to a triptan.¹²²⁴

Dysmenorrhea

Relief of primary dysmenorrhea in adults.^{100 106 1225}

Self-medication for the relief of pain associated with menstrual cramps (dysmenorrhea).⁵²²

First-line treatment options for primary dysmenorrhea include combined oral contraceptives, progesterone-only contraceptives, and NSAIAs; treatment selection should be based on patient-specific considerations (e.g., comorbidities, desire/need for contraception²⁰¹⁵ The American College of Obstetricians and Gynecologists includes ibuprofen as a potential NSAIA for use in patients with primary dysmenorrhea, but does not recommend one NSAIA over others.²⁰¹²

Fever

Reduction of fever; oral suspension used in patients 6 months to 2 years of age, IV used in adults and pediatric patients ≥3 months of age.^{106 210 1226 1227 1228}

Self-medication for reduction of fever.⁵²²

American Academy of Pediatrics (AAP) states that acetaminophen and ibuprofen are safe and effective options for treating fever in most patients when used in appropriate doses; ibuprofen may be more effective than acetaminophen for lowering body temperature, but relative efficacy for improving patient comfort unknown.²⁰¹⁶ Use ibuprofen with caution in dehydrated patients and patients with certain comorbidities (e.g., cardiovascular disease, pre-existing renal disease, concomitant use of nephrotoxic agents); nephrotoxicity can occur.²⁰¹⁶

Patent Ductus Arteriosus (PDA)

Ibuprofen lysine is used IV to promote closure of a clinically important PDA in premature neonates weighing 500–1500 g who are no more than 32 weeks’ gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support) is ineffective (designated an orphan drug by FDA for this use).^{198 1229 1230 1231}

Ibuprofen also has been used orally^{† [off-label]} for treatment of PDA.^{1230 1231}

Decision to initiate pharmacologic treatment for PDA depends on patient-specific factors such as gestational age, chronological age, size of PDA, and presence of symptoms (e.g., requirement for greater than minimal respiratory support).^{1232 1233} If targeted early prophylactic treatment with indomethacin is not indicated or not effective, early targeted pharmacologic treatment with ibuprofen or indomethacin is recommended <6 days after birth for infants <28 weeks’ gestational age with a moderate-to-large hemodynamically important shunt requiring greater than minimal respiratory support.¹²³³ Screen all infants with very low birth weight ≥6 days of age requiring greater than minimal respiratory support for PDA via echocardiogram; if a moderate-to-large hemodynamically important PDA is present and patient has additional risk factors (e.g., failure to wean from the ventilator, fraction of inspired oxygen >0.25), consider treatment with ibuprofen.¹²³³

Pericarditis

Has been used in combination with colchicine for treatment of acute and recurrent pericarditis^{† [off-label]} .^{1207 1208 1209 1210}

Some experts recommend colchicine plus aspirin or an NSAIA (typically ibuprofen) first-line for treatment of acute or recurrent pericarditis.¹²¹⁰

Other Uses

Has been used to slow loss of lung function in patients 6–17 years of age with cystic fibrosis^† and forced expiratory volume in 1 second (FEV₁) ≥60%.^{1234 1235}

Ibuprofen, Ibuprofen Lysine Dosage and Administration

General

Patient Monitoring

• Monitor renal function during ibuprofen therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.²¹⁰

• Monitor BP closely during initiation and throughout NSAIA therapy.^{100 106 210}

• Monitor patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors for signs of bleeding.²¹⁰

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

• Periodically obtain a CBC and chemistry profile during long-term ibuprofen therapy.²¹⁰

• Monitor for GI ulceration and bleeding; even closer GI monitoring is recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.^{100 106 210}

• In patients with asthma but without known aspirin sensitivity, monitor for changes in asthma.^{100 106 210}

• Monitor for worsening renal function in patients with preexisting renal disease.²¹⁰

Premedication and Prophylaxis

• Correct dehydration before initiating ibuprofen therapy.^{100 106 210}

Other General Considerations

• 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.^{100 106 210} Consider potential benefits and risks of ibuprofen therapy as well as alternative therapies before initiating therapy with the drug.^{100 106}

• Avoid using more than one NSAIA at a time.^{100 106 210}

• Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if use is necessary, monitor patient for cardiac ischemia.^{100 106 210}

• Avoid 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.^{100 106 210}

• In patients receiving low-dose aspirin for cardiac prophylaxis, consider using an alternative NSAIA that does not interfere with the antiplatelet effects of aspirin or the use of a non-NSAIA analgesic agent.²¹⁰

• Ibuprofen is not a substitute for corticosteroid therapy, and the drug is not effective in the management of adrenal insufficiency.¹⁰⁰ Abrupt withdrawal of corticosteroids may exacerbate corticosteroid-responsive conditions.¹⁰⁰ If corticosteroid therapy is to be discontinued after prolonged therapy, the dosage should be tapered gradually.¹⁰⁰

Administration

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

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

Ibuprofen also is commercially available in fixed combination with famotidine (Duexis) and in fixed combination with hydrocodone bitartrate.^{161 216} See prescribing information for additional details on these fixed combination preparations.^{161 216}

Ibuprofen is also commercially available in various over-the-counter (OTC) preparations as a single ingredient or in combination with other analgesics (e.g., acetaminophen), antihistamines, or decongestants. See the FDA Orange Book and the manufacturer's drug facts for information,

Oral Administration

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

Shake ibuprofen oral suspension well before administering.¹⁰⁶

IV Administration (Ibuprofen)

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 3 months to 17 years of age: Administer dose over ≥10 minutes.²¹⁰

IV Administration (Ibuprofen Lysine)

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.^{100 106 210} Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.^{100 106 210}

Pediatric Patients

Dosage in children should be guided by body weight.¹⁰⁶

Inflammatory Diseases

Juvenile 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 Dosages >50 mg/kg daily not studied and recommended.¹⁰⁶

A few days to several weeks may be required to achieve therapeutic response; 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 to maximum of 40 mg/kg daily; avoid disrupting the child's sleep pattern.¹⁰⁶ In children with a fever of <39°C and concomitant pain, choose the ibuprofen dose that effectively treats the predominant symptom.¹⁰⁶

Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for pain management for pediatric patients as well.^{522 523}

IV

For infants 3 months to <6 months of age, 10 mg/kg (up to 100 mg) as a single dose.²¹⁰

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 (maximum 40 mg/kg daily).¹⁰⁶ In children with a fever of <39°C and concomitant pain, choose the ibuprofen dose that effectively treats the predominant symptom.¹⁰⁶

Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for fever management for pediatric patients as well.⁵²²

IV

For children 3 months to <6 months of age, 10 mg/kg (up to 100 mg) as a single dose.²¹⁰

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

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

Pain

Oral

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

Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for pain management for adult patients as well.^{522 523}

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

Fever

IV

400 mg initially; then 400 mg every 4–6 hours or 100–200 mg every 4 hours.²¹⁰ Maximum 3.2 g in a 24-hour period.²¹⁰

Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for pain management for adult patients as well.⁵²²

Special Populations

Hepatic Impairment

Manufacturers make no specific dosage recommendations for patients with hepatic impairment.^{100 106 198 210}

Renal Impairment

Manufacturers make no specific dosage recommendations for patients with renal impairment.^{100 106 198 210}

Avoid use in patients with advanced renal disease unless benefits expected to outweigh risk of worsening renal function.²¹⁰

Geriatric Patients

Geriatric patients generally at greater risk for NSAIA-associated serious cardiovascular, GI, and/or renal adverse effects.²¹⁰ If expected benefits outweigh potential risks, initiate at low end of dosage range and monitor.²¹⁰

Pharmacogenomic Considerations in Dosing

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

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: CPIC guidelines state that these patients 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, Ibuprofen Lysine

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; potential for cross-sensitivity between NSAIAs and aspirin and severe, potentially fatal, bronchospasm.^{100 106 210}

• In the setting of CABG surgery.^{100 106 210}

Contraindications with IV Ibuprofen Lysine for PDA

• Known or suspected untreated infection.¹⁹⁸

• Bleeding, especially active intracranial hemorrhage or GI bleeding; thrombocytopenia; or underlying 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 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 (see Boxed Warning).^{100 106 210}

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.^{100 106 210}

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.^{100 106 210}

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.^{100 106 210}

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{100 106 210}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; 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.^{100 106 210}

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.^{100 106 210}

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.^{100 106 210} Contraindicated in the setting of CABG surgery.^{100 106 210}

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.²¹⁰

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 (see Boxed Warning).^{100 106 210}

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.^{100 106 210}

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.^{100 106 210}

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.^{100 106 210}

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.^{100 106 210}

Use at lowest effective dosage for the shortest duration necessary.^{100 106 210}

Avoid use of more than one NSAIA at a time.^{100 106 210}

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.^{100 106 210}

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiac prophylaxis.^{100 106 210}

If serious adverse GI event suspected, promptly initiate evaluation and discontinue ibuprofen until serious adverse GI event ruled out.^{100 106 210}

Contraindicated in neonates with necrotizing enterocolitis.¹⁹⁸

Other Warnings and Precautions

Hepatotoxicity

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.^{100 106 210} Monitor BP during initiation of ibuprofen and throughout therapy.^{100 106 210}

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.^{100 106 210}

Heart Failure and Edema

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

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{100 106 210}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.^{100 106 210}

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.^{100 106 210}

Renal Toxicity and Hyperkalemia

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

Potential for overt renal decompensation.^{100 106 210} 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.^{100 106 210}

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 treated with ibuprofen lysine.¹⁹⁸ Decreases in urine output noted on days 2–6 of life; compensatory increase in output noted on day 9.¹⁹⁸

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

Anaphylactic Reactions

Anaphylactic reactions reported.^{100 106 210} Seek immediate medical intervention and discontinue drug for anaphylaxis.^{100 106 210}

Exacerbation of Asthma Related to Aspirin Sensitivity

Avoid ibuprofen use 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}

Serious Skin Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.^{100 106 198 210} Acute generalized exanthematous pustulosis (AGEP) also reported.¹⁹⁸ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).^{100 106 198 210}

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), a potentially fatal or life-threatening syndrome, reported in patients receiving NSAIAs.^{100 106 210} DRESS typically presents with fever, rash, lymphadenopathy, and/or facial swelling; other clinical manifestations may include hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).^{100 106 210} Symptoms may resemble those of acute viral infection.¹⁰⁰ Eosinophilia is often present.^{100 106 210} Clinical presentation is variable, and other organ systems may be involved. ^{100 106 210} Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.^{100 106 210} If signs or symptoms of DRESS develop, discontinue ibuprofen and immediately evaluate the patient.^{100 106 210}

Fetal/Neonatal Morbidity and Mortality

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.^{100 106 210}

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.^{100 106 210} 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.^{100 106 210}

Hematologic Toxicity

Anemia reported rarely.^{100 106 210} May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.^{100 106 210} Determine hemoglobin concentration or hematocrit if signs or symptoms of anemia occur.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

May inhibit platelet aggregation and prolong bleeding time.^{100 106}

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

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

Masking of Inflammation and Fever

May mask certain signs of infection.²¹⁰

Laboratory Monitoring

Obtain CBC and chemistry profile periodically during long-term use.^{100 106 210}

Ophthalmologic 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

Other CNS Effects

Intraventricular (intracranial) hemorrhage reported in preterm neonates.¹⁹⁸ Seizures also reported.¹⁹⁸

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

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

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.^{100 106 210}

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.^{100 106 210} 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.^{100 106 210}

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.^{100 106 210} Oligohydramnios is often, but not always, reversible following NSAIA discontinuance.^{100 106 210} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{100 106 210} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{100 106 210} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{100 106 210} 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.^{100 106 210} Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.^{100 106 210}

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.^{100 106 210} 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

Females and Males of Reproductive Potential

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

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 have been established for treatment of pain and fever in pediatric patients 3 months of age and older.²¹⁰ Efficacy of IV ibuprofen for pain relief or antipyresis not established in infants <3 months of age.²¹⁰

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

Common Adverse Effects

With oral ibuprofen tablets, GI complaints.¹⁰⁰

With oral ibuprofen suspension, abnormal renal function, anemia, dizziness, edema, elevated transaminases, fluid retention, GI effects, headaches, increased bleeding times, nervousness, pruritis, rashes, tinnitus.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 in premature infants, sepsis, anemia, intraventricular bleeding, apnea, GI disorders, impaired renal function, respiratory infection, skin lesions, hypoglycemia, respiratory failure.¹⁹⁸

Drug Interactions

Metabolized mainly via CYP2C9-mediated hydroxylation of R- and S-ibuprofen.¹⁹⁸ No evidence of enzyme induction.¹⁰⁰

Specific Drugs

Ibuprofen, Ibuprofen Lysine Pharmacokinetics

Absorption

Bioavailability

Rapid absorption following oral administration;¹⁰⁶ peak plasma concentration usually attained within 1–2 hours.¹⁰⁰

Onset

Antipyretic activity achieved within 1 hour.¹⁰⁶

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 human milk in small amounts.²¹⁰

Plasma Protein Binding

>99%.¹⁰⁶

Elimination

Metabolism

Metabolized mainly by hepatic CYP2C9-mediated hydroxylation of R- and S-ibuprofen; ibuprofen and metabolites then undergo conjugation to acyl glucuronides.¹⁹⁸

Metabolism of ibuprofen in preterm neonates not evaluated.¹⁹⁸

Elimination Route

Approximately 80% of dose excreted in urine as the hydroxy- and carboxyl metabolites.¹⁹⁸

Excretion of ibuprofen in preterm neonates not evaluated.¹⁹⁸

Half-life

2 hours.¹⁰⁶

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, 1.3 hours in those 3 months to <6 months of age.²¹⁰

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

Stability

Storage

Oral

Tablets

20–25°C; avoid excessive heat (>40°C).¹⁰⁰ Store in a tight, light-resistant container.¹⁰⁰

Suspension

20–25°C.¹⁰⁶

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

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.²¹⁰

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

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

• Reduces resting and active intrauterine pressure and the frequency of contractions in dysmenorrhea, likely through inhibition of prostaglandin synthesis.^{100 106}

Advice to Patients

• Inform patients of the risk of serious cardiovascular events (e.g., myocardial infarction [MI], stroke).²¹⁰ Stress importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (e.g., chest pain, dyspnea, weakness, slurred speech) occur.²¹⁰

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

• Inform patients of the risk of serious skin reactions,²¹⁰ drug reaction with eosinophilia and systemic symptoms (DRESS),¹⁰⁰ and anaphylactic and other sensitivity reactions.^{100 106 210} Advise patients to stop taking the drug immediately if they develop any type of rash or fever and to promptly contact their clinician.¹⁰⁰ Stress importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{100 106 210}

• Inform patients of the risk of hepatotoxicity.^{100 106 210} Stress 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.^{100 106 210}

• Inform patients of the risk of heart failure or edema; stress importance of reporting dyspnea, unexplained weight gain, or edema.²¹⁰

• Advise patients to consult a clinician prior to taking low-dose aspirin concomitantly.²¹⁰

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

• Counsel pregnant patients to avoid nonsteroidal anti-inflammatory agent (NSAIA) use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; stress 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.^{100 106 210}

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

• Inform parents and caregivers that when used in premature infants with patent ductus arteriosus (PDA), IV ibuprofen lysine can alter signs of infection, inhibit clot formation, and irritate skin or tissues if leakage occurs at the administration site; stress importance of monitoring the infant for signs of infection, bleeding, and skin or tissue irritation.¹⁹⁸

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{100 106 210}

• Stress importance of informing 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

• Inform patients of other important precautionary information.^{100 106 210}

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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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