Ibuprofen, Ibuprofen Lysine

[Section Outline]

Administration
Dosage
Pharmacogenomic Dosage Considerations

Administration

The potential benefits and risks of ibuprofen therapy as well as alternative therapies should be considered prior to initiating ibuprofen therapy.192

Ibuprofen is administered orally or IV. Ibuprofen lysine is administered IV.198

Ibuprofen is administered by IV infusion over a period of at least 30 minutes in adults and at least 10 minutes in pediatric patients 6 months to 17 years of age.210 All patients receiving IV ibuprofen should be well hydrated.210

For self-medication in pediatric patients, ibuprofen is commercially available as oral drops, an oral suspension, chewable tablets, and film-coated tablets.164,179,189,212,213 The calibrated dosing device provided by the manufacturer should be used by parents or caregivers for measurement of the dose of oral drops;164 the calibrated dosage cup provided by the manufacturer should be used by parents or caregivers for measurement of the dose of pediatric oral suspension.212 Ibuprofen oral drops generally are used in infants 6-23 months of age, the oral suspension and the 100-mg chewable tablets commonly are used in children 2-11 years of age, and the 100-mg film-coated tablets may be used in children 6-11 years of age.164,179,189,212,213

If GI disturbances occur, ibuprofen should be administered with meals or with milk or dosage should be reduced.

Tablets containing ibuprofen in fixed combination with famotidine should be swallowed whole, and should not be chewed, divided, crushed, or cut to provide a lower dose.216

For IV administration, ibuprofen injection concentrate containing 100 mg/mL must be diluted with a compatible IV solution (e.g., 0.9% sodium chloride injection, 5% dextrose injection, lactated Ringer's injection) to provide a solution containing 4 mg/mL (less-concentrated solutions are acceptable).210 IV administration of the undiluted concentrate can result in hemolysis.210 The commercially available ibuprofen 4-mg/mL (800 mg in 200 mL) premixed injection should be used for administration of 800-mg doses only.210 Parenteral solutions of ibuprofen should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.210 The solution should not be used if opaque particles, discoloration, or other foreign particulate matter is present.210

For IV administration, ibuprofen lysine injection should be diluted with an appropriate volume of dextrose injection or sodium chloride injection and administered within 30 minutes of preparation.198 The drug should be administered using the IV port that is nearest to the IV insertion site.198 The dose should be infused over a period of 15 minutes.198 Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues.198 Ibuprofen lysine should not be infused simultaneously through the same IV line as parenteral nutrition solutions; if the same IV line must be used, infusion of the nutrition solution should be interrupted for 15 minutes before and after ibuprofen lysine administration, and patency of the IV line maintained by infusion of dextrose injection or sodium chloride injection.198 Parenteral solutions of ibuprofen lysine should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit.198 The solution should be discarded if particulate matter is observed.198 Ibuprofen lysine injection contains no preservatives and is intended for single use only; any unused portion should be discarded.198

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.192 Dosage of ibuprofen must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.192

Patients receiving ibuprofen for self-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.194,195

Dosage of ibuprofen lysine is expressed in terms of ibuprofen.198

Patients should be warned that the risk of GI bleeding is increased when recommended durations of self-medication are exceeded and when more than one NSAIA are used concomitantly.

Inflammatory Diseases

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

The usual adult oral dosage of ibuprofen in the symptomatic treatment of rheumatoid arthritis and osteoarthritis is 400-800 mg 3 or 4 times daily. Dosage should be adjusted according to the response and tolerance of the patient and should not exceed 3.2 g daily. Although well-controlled clinical studies did not show that the average response was greater with 3.2 g daily than with 2.4 g daily, some patients may have a better response with 3.2 g daily; in patients receiving 3.2 g daily, an adequate increase in clinical benefit should be evident to justify potential increased risks associated with this dosage. Optimum therapeutic response may occur within a few days to 1 week but usually occurs within 2 weeks after beginning ibuprofen therapy if the dosage is adequate. The manufacturers state that patients with rheumatoid arthritis usually require a higher dosage of ibuprofen than do patients with osteoarthritis. When a satisfactory response to ibuprofen therapy occurs, dosage of the drug should be reviewed and adjusted as required.

When ibuprofen is used in fixed combination with famotidine (to reduce the risk of upper GI ulcers), the recommended ibuprofen dosage for symptomatic treatment of rheumatoid arthritis or osteoarthritis is 800 mg orally 3 times daily.216

For the management of juvenile rheumatoid arthritis, the recommended ibuprofen oral dosage is 30-40 mg/kg daily divided into 3 or 4 doses.106 An ibuprofen dosage of 20 mg/kg daily in divided doses may be adequate for children with mild disease.106 Dosages exceeding 50 mg/kg daily are not recommended in children with juvenile arthritis, since such dosages have not been studied.106 In addition, dosages exceeding 40 mg/kg daily may increase the risk of drug-induced adverse effects.106 Optimum therapeutic response occurs from a few days to several weeks in children with juvenile rheumatoid arthritis.106 Once a clinical effect is obtained, the dosage should be reduced to the lowest dosage needed to maintain adequate control of symptoms.106 Children receiving ibuprofen dosages exceeding 30 mg/kg daily and those who have had abnormal liver function test results associated with prior NSAIA therapy should be carefully monitored for signs and symptoms of early liver dysfunction.106

Pain

For relief of mild to moderate pain, the usual adult oral dosage of ibuprofen is 400 mg every 4-6 hours as necessary. Alternatively, for self-medication of minor aches and pain, the usual adult dosage is 200 mg every 4-6 hours; dosage may be increased to 400 mg every 4-6 hours if pain does not respond to the lower dosage but should not exceed 1.2 g daily unless directed by a clinician.165 For self-medication of migraine pain, the usual adult dosage of ibuprofen liquid-filled capsules is 400 mg; unless directed by a clinician, dosage should not exceed 400 mg in a 24-hour period.105 Self-medication of pain should not exceed 10 days unless otherwise directed by a clinician. Doses greater than 400 mg have not provided a greater analgesic effect than the 400-mg dose.

For self-medication of minor aches and pain in adolescents 12 years of age and older, the usual dosage of ibuprofen is 200 mg every 4-6 hours; dosage may be increased to 400 mg every 4-6 hours if pain does not respond to the lower dosage but should not exceed 1.2 g daily unless directed by a clinician.165 Self-medication of pain should not exceed 10 days unless otherwise directed by a clinician.165

When ibuprofen is used in fixed combination with acetaminophen for self-medication of minor aches and pain in adults and adolescents 12 years of age and older, the usual and maximum dosage (unless otherwise directed by a clinician) of ibuprofen is 250 mg every 8 hours while pain persists.215 Self-medication of pain should not exceed 10 days unless otherwise directed by a clinician.215

For relief of mild to moderate pain in children 6 months up to 2 years of age, the recommended ibuprofen oral dosage is 10 mg/kg every 6-8 hours, administered in a manner that does not disrupt the child's sleep pattern; the maximum dosage of ibuprofen is 40 mg/kg daily.106 For self-medication of minor aches and pain in pediatric patients, ibuprofen dosages should be calculated based on body weight rather than age whenever possible.164,179,189,212,213 (See Pediatric Precautions under Cautions.) Infants 6-11 months of age or those weighing 12-17 pounds (approximately 5-8 kg) may receive 50 mg of ibuprofen, infants 12-23 months of age or those weighing 18-23 pounds (approximately 8-10 kg) may receive 75 mg, children 2-3 years of age or those weighing 24-35 pounds (approximately 11-16 kg) may receive 100 mg, children 4-5 years of age or those weighing 36-47 pounds (approximately 16-21 kg) may receive 150 mg, children 6-8 years of age or those weighing 48-59 pounds (approximately 22-27 kg) may receive 200 mg, children 9-10 years of age or those weighing 60-71 pounds (approximately 27-32 kg) may receive 200-250 mg, and children 11 years of age or those weighing 72-95 pounds (approximately 33-43 kg) may receive 300 mg; these doses may be administered every 6-8 hours and no more than 4 times daily.164,179,189,212,213 Parents and caregivers should be instructed to discontinue use of ibuprofen and contact the child's clinician if minor aches and pain do not improve within 24 hours or if pain increases or lasts longer than 3 days.164,179,189,212,213

For relief of pain, adults may receive ibuprofen in a dosage of 400-800 mg infused IV over at least 30 minutes every 6 hours as needed; ibuprofen dosage should not exceed 3.2 g in a 24-hour period.210 Adolescents 12-17 years of age may receive a dosage of 400 mg infused IV over at least 10 minutes every 4-6 hours as needed; ibuprofen dosage should not exceed 2.4 g in a 24-hour period.210 Children 6 months to younger than 12 years of age may receive a dosage of 10 mg/kg (up to 400 mg) infused IV over at least 10 minutes every 4-6 hours as needed; ibuprofen dosage should not exceed 40 mg/kg or 2.4 g, whichever is less, in a 24-hour period.210

When ibuprofen is used in fixed combination with hydrocodone bitartrate for short-term management of acute pain, the usual oral dosage is 200 mg of ibuprofen every 4-6 hours, as needed;161 ibuprofen dosage should not exceed 1 g in a 24-hour period.161

Dysmenorrhea

For the relief of primary dysmenorrhea, ibuprofen therapy should be started with the earliest onset of pain; the usual adult oral dosage in these patients is 400 mg every 4 hours as necessary for relief of pain. Alternatively, for self-medication of dysmenorrhea in adults and adolescents 12 years of age and older, the usual dosage is 200 mg every 4-6 hours; dosage may be increased to 400 mg every 4-6 hours if necessary but should not exceed 1.2 g daily unless otherwise directed by a clinician.165

Fever

For antipyresis in children 6 months up to 2 years of age, the usual oral dosage of ibuprofen is 5 mg/kg for temperatures below 39°C and 10 mg/kg for temperatures of 39°C or higher.106 The maximum daily dosage of ibuprofen in febrile children is 40 mg/kg.106

For self-medication of fever in pediatric patients, ibuprofen dosages should be calculated based on body weight rather than age whenever possible.164,179,189,212,213 (See Pediatric Precautions under Cautions.) Infants 6-11 months of age or those weighing 12-17 pounds (approximately 5-8 kg) may receive 50 mg of ibuprofen, infants 12-23 months of age or those weighing 18-23 pounds (approximately 8-10 kg) may receive 75 mg, children 2-3 years of age or those weighing 24-35 pounds (approximately 11-16 kg) may receive 100 mg, children 4-5 years of age or those weighing 36-47 pounds (approximately 16-21 kg) may receive 150 mg, children 6-8 years of age or those weighing 48-59 pounds (approximately 22-27 kg) may receive 200 mg, children 9-10 years of age or those weighing 60-71 pounds (approximately 27-32 kg) may receive 200-250 mg, and children 11 years of age or those weighing 72-95 pounds (approximately 33-43 kg) may receive 300 mg; these doses may be administered every 6-8 hours and no more than 4 times daily.164,179,189,212,213 Parents and caregivers should be instructed to contact the child's clinician if fever does not improve within 24 hours or if fever increases or lasts longer than 3 days.164,179,189,212,213

For self-medication of fever in adults and adolescents 12 years of age and older, the usual dosage of ibuprofen is 200 mg every 4-6 hours; dosage may be increased to 400 mg every 4-6 hours if fever is not adequately reduced at the lower dosage but should not exceed 1.2 g daily unless otherwise directed by a clinician.165 In addition, limited data indicate that adequate antipyresis may be maintained in some patients in whom initial doses of ibuprofen were followed with lower doses of the drug.106 Self-medication of fever should not exceed 3 days unless otherwise directed by a clinician.

For reduction of fever, adults may receive an initial dose of ibuprofen 400 mg IV followed by 400 mg IV every 4-6 hours or 100-200 mg IV every 4 hours; doses should be infused over at least 30 minutes.210 Ibuprofen dosage in adults should not exceed 3.2 g in a 24-hour period.210 Adolescents 12-17 years of age may receive a dosage of 400 mg infused IV over at least 10 minutes every 4-6 hours as needed; ibuprofen dosage should not exceed 2.4 g in a 24-hour period.210 Children 6 months to younger than 12 years of age may receive a dosage of 10 mg/kg (up to 400 mg) infused IV over at least 10 minutes every 4-6 hours as needed; ibuprofen dosage should not exceed 40 mg/kg or 2.4 g, whichever is less, in a 24-hour period.210

Patent Ductus Arteriosus

For the treatment of patent ductus arteriosus (PDA) in premature neonates, ibuprofen lysine is administered by IV infusion over 15 minutes.198 A course of therapy consists of 3 doses of ibuprofen lysine administered at 24-hour intervals.198 All doses are based on the neonate's birth weight.198 The first IV dose of ibuprofen in the course is 10 mg/kg; the second and third doses are 5 mg/kg each, administered 24 and 48 hours after the first dose.198 If anuria or oliguria (i.e., urine output less than 0.6 mL/kg per hour) is present at the time of the second or third dose, the dose should be withheld until laboratory determinations indicate that renal function has returned to normal.198 Subsequent doses are not necessary if the ductus arteriosus closes or is substantially constricted after completion of the first course of ibuprofen therapy.198 If the ductus fails to close or reopens, a second course of ibuprofen, alternative pharmacologic therapy, or surgery may be needed.198

Pharmacogenomic Dosage Considerations

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are CYP2C9 poor metabolizers, ibuprofen should be initiated at a dosage that is 25-50% of the lowest recommended initial dosage and cautiously titrated to a clinically effective dosage, up to a dosage that is 25-50% of the maximum recommended dosage.520 Dosage should not be increased until steady-state concentrations are attained (at least 5 days following the initial dose in poor metabolizers).520 Alternatively, a drug that is not metabolized by CYP2C9 or is not substantially affected by CYP2C9 genetic variants in vivo should be considered.520 In addition, CPIC guidelines state that, in patients who are CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1, ibuprofen may be initiated at the lowest recommended initial dosage and cautiously titrated 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 These dosage recommendations apply to both nonprescription (over-the-counter, OTC) and prescription use of the drug.520 (See Pharmacogenomic Precautions under Cautions.)

Cautions ⬆ ⬇

[Section Outline]

Cardiovascular Effects
GI Effects
Nervous System Effects
Otic and Ocular Effects
Hepatic Effects
Dermatologic and Sensitivity Reactions
Hematologic Effects
Renal and Electrolyte Effects
Other Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Pregnancy and Lactation

Cardiovascular Effects

Peripheral edema and fluid retention have been reported during ibuprofen therapy. Congestive heart failure has occurred in patients with marginal cardiac function. Increased blood pressure, hypotension, cerebrovascular accident, and palpitations also have been reported. Although a causal relationship has not been established, arrhythmias, including sinus tachycardia or bradycardia, have been reported during therapy with the drug.

Tachycardia, cardiac failure, hypotension, and pulmonary hypertension have occurred in premature neonates receiving ibuprofen for treatment of patent ductus arteriosus (PDA), although a causal relationship to the drug has not been established.198

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.210,500,502 Use of NSAIAs also is associated with an increased risk of heart failure.210,500

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.197,205,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in 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 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, 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

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.210,505 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).210,500,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.210,511

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.210 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.210

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.199,200,201,205,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.210,507 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.210,500,504 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.210,500,501 Fluid retention and edema also have been observed in some patients receiving NSAIAs.210

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.197,210,502

GI Effects

The most frequent adverse effects of ibuprofen involve the GI tract and have included dyspepsia, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, stomatitis, flatulence, bloating, epigastric pain, and abdominal pain. Peptic ulcer and GI bleeding (including evidence of occult blood in stools), sometimes severe, have also been reported. Although a causal relationship has not been established, a few cases of GI ulceration with perforation and bleeding resulting in death have occurred.

Nonnecrotizing enterocolitis has occurred in premature neonates receiving ibuprofen for treatment of PDA.198 Gastroesophageal reflux, gastritis, ileus, GI perforation, and necrotizing enterocolitis also have occurred, although a causal relationship to the drug has not been established.198

The frequency of mild adverse GI effects with usual dosages of ibuprofen is reported to be less than that with usual dosages of oral aspirin or indomethacin. It is not known whether ibuprofen causes less peptic ulceration than does aspirin. Usual dosages of ibuprofen generally have been associated with only minimal GI blood loss, and limited data indicate that the risk of GI bleeding and/or perforation with ibuprofen appears to be less than that with other prototypical NSAIAs (e.g., piroxicam, indomethacin, ketoprofen, naproxen, diclofenac).

Adverse GI effects of orally administered ibuprofen may be minimized by administering the drug with meals or milk. Close supervision of ibuprofen therapy is necessary, particularly in patients with a history of upper GI disease.

Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.100,104,109,192,210 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.192 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.100,104,192 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding. 210 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.100,104 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.192

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.100,104 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.100,104 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.192 However, short-term therapy is not without risk.192 High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.100,104 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.100,104

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold increased risk of developing GI bleeding than patients without these risk factors.173,177,210 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.173,177,210 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.210 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.154,173,177 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.106

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy.154,157,173,175 (See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.154,157,173 In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.173 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.173 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.154,173 Another approach in high-risk patients who would benefit from NSAIA therapy is use of a NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.154 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.190,191 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.190,191

Nervous System Effects

Adverse CNS effects of ibuprofen include dizziness, headache, and nervousness. Fatigue, drowsiness, malaise, lightheadedness, anxiety, confusion, mental depression, and emotional lability have also been reported. Although a causal relationship has not been established, paresthesia, hallucinations, dream abnormalities, and pseudotumor cerebri also have been reported.

Aseptic meningitis with fever and coma has occurred rarely in patients receiving ibuprofen,100,101,102,103 and has recurred upon rechallenge with the drug.102,103 Although meningitis probably is more likely to occur in patients with systemic lupus erythematosus or related connective tissue diseases,100,101,102,103 it has been reported in some patients without evidence of any underlying chronic disease.100,102,103 Other associated manifestations have included GI symptoms (e.g., nausea, vomiting, abdominal pain),101,102,103 transient conjunctivitis,102,103 CNS signs (e.g., confusion, combativeness, lethargy, headache),101,102,103 and hypotension.103 If signs and/or symptoms of meningitis develop in a patient receiving ibuprofen, the possibility that these effects may be associated with the drug should be considered.100,101,102

Intraventricular (intracranial) hemorrhage has occurred in premature neonates receiving ibuprofen for treatment of PDA.198 Seizures also have occurred, although a causal relationship to the drug has not been established.198

Otic and Ocular Effects

Patients receiving ibuprofen have experienced tinnitus. Decreased hearing and amblyopia (blurred and/or decreased visual acuity, scotomata and/or changes in color vision) have also been reported. Vision generally has gradually improved when the drug was discontinued in patients with visual disturbances. Although a causal relationship has not been established, conjunctivitis, diplopia, optic neuritis, and cataracts have also been reported in patients receiving the drug. Ibuprofen should be discontinued and an ophthalmologic examination performed in patients who experience visual disturbances during therapy with the drug.

Hepatic Effects

Severe (sometimes fatal) reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure have been reported rarely in patients receiving NSAIAs, including ibuprofen.100,210 A transitory rise in serum AST, ALT, and serum alkaline phosphatase also has occurred in patients receiving ibuprofen therapy.

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT or AST concentration have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies. Ibuprofen should be discontinued immediately if signs or symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur, and clinical evaluation of the patient should be performed.210 (See Hepatic Precautions under Cautions.)

Although a causal relationship to the drug has not been established, jaundice and cholestasis have occurred in premature neonates receiving ibuprofen for treatment of PDA.198

Dermatologic and Sensitivity Reactions

Urticarial, vesiculobullous, and erythematous macular rashes, erythema multiforme, exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), and photosensitivity reactions have occurred occasionally during ibuprofen therapy. Pruritus without evidence of a rash has occurred in a few patients. Stevens-Johnson syndrome, flushes, alopecia, rectal itching, and acne have also been reported.

Hypersensitivity reactions manifested as a syndrome of abdominal pain, fever, chills, nausea, and vomiting have occasionally occurred during ibuprofen therapy. Anaphylaxis, anaphylactoid reactions, and bronchospasm have also occurred. Anaphylactic reactions have been reported in patients with or without known hypersensitivity to the drug, as well as in patients with aspirin-sensitivity asthma.210 Although a causal relationship has not been established, serum sickness, lupus erythematosus syndrome, Henoch-Schönlein vasculitis, and angioedema have also been reported during therapy with the drug.

Skin lesion/irritation has occurred in premature neonates receiving ibuprofen for treatment of PDA.198

Hematologic Effects

Adverse hematologic effects of ibuprofen include neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (with or without positive direct antiglobulin test results), and thrombocytopenia (with or without purpura). Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.210 Slight, dose-dependent reductions in serum hemoglobin concentrations and hematocrit have occurred in patients receiving ibuprofen dosages of 1.2-3.2 g daily, and the total decrease in hemoglobin may exceed 1 g in patients receiving 3.2 g or more of the drug. Data from clinical use indicate that a decrease in hemoglobin concentration of 1 g or more occurs in about 17% of patients receiving 1.6 g of ibuprofen daily and in about 23% of patients receiving 2.4 g of the drug daily. In the absence of clinical signs of bleeding, the decrease in hemoglobin probably is not clinically important. Although a causal relationship has not been established, bleeding episodes (e.g., epistaxis, menorrhagia, occult blood in the stool) have been reported during therapy with the drug. Ibuprofen can inhibit platelet aggregation and may prolong bleeding time. It appears that ibuprofen's inhibitory effect on platelet aggregation is of shorter duration and less pronounced than that of aspirin.100,106 Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during ibuprofen therapy.

Anemia and bleeding have occurred in premature neonates receiving ibuprofen for treatment of PDA.198 Neutropenia and thrombocytopenia also have occurred, although a causal relationship to the drug has not been established.198

Renal and Electrolyte Effects

Acute renal failure has been reported in patients receiving ibuprofen and may be accompanied by acute tubular necrosis.116 Such acute deterioration in renal function may be evident soon (e.g., within several days) after initiation of ibuprofen therapy in certain patients at risk (e.g., those with preexisting renal impairment) (see Renal Precautions under Cautions) and may be accompanied by hyperkalemia. Polyuria, azotemia, cystitis, hematuria, and decreased creatinine clearance also have been reported in patients receiving the drug. Elevations in serum creatinine concentrations and increases in BUN without other manifestation of renal failure also have occurred occasionally. In addition, acute interstitial nephritis accompanied by hematuria, proteinuria, and occasionally nephrotic syndrome has occurred. Recurrence of nephrotic syndrome has occurred in at least one patient during ibuprofen therapy. Increases in serum uric acid concentration, tubular necrosis, glomerulitis, and renal papillary necrosis also have been reported. Long-term studies in rats and monkeys have shown histologic evidence of ibuprofen-induced mild renal toxicity manifested as papillary edema and necrosis in some animals. An association between prolonged (e.g., daily for 1 year or longer) NSAIA use, including ibuprofen, and chronic renal failure also has been described in certain high-risk patients,111,112,115 but current evidence suggests that the potential risk, if any, is low overall in patients receiving the drug, and additional study and experience are necessary to confirm and elucidate these findings.111,112,113,114,115,117

Renal insufficiency (including oliguria), increases in BUN (sometimes accompanied by hematuria), increases in serum creatinine concentration, and renal failure have been reported in ibuprofen-treated premature neonates.198 Reversible decreases in urine output have occurred in premature neonates receiving ibuprofen therapy for PDA.198 Urine output usually decreases during the first 2-6 days of life; this is followed by a compensatory increase in output by day 9.198

Hyperkalemia has been reported in patients receiving NSAIAs, including in individuals without renal impairment; in those with normal renal function, this effect has been attributed to a hyporenin-hypoaldosterone state.210

Other Adverse Effects

Other adverse effects of ibuprofen include dry mouth, gingival ulceration, and rhinitis. Although a causal relationship has not been established, gynecomastia, hypoglycemic reactions, and acidosis have also been reported during therapy with the drug.

Infections (e.g., sepsis, respiratory infection, urinary tract infection), apnea, respiratory failure, atelectasis, edema, adrenal insufficiency, hypoglycemia, hypocalcemia, and hypernatremia have occurred in premature neonates receiving ibuprofen for treatment of PDA.198 Hyperglycemia, abdominal distension, feeding problems, inguinal hernia, and injection site reactions also have occurred, although a causal relationship to the drug has not been established.198

Precautions and Contraindications

Patients should be advised that ibuprofen, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur.100,104,161,192,210,500 When preparations containing ibuprofen in combination with other drugs are used, the precautions and contraindications associated with each ingredient also must be considered.159,161,215

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.192

Cardiovascular Precautions

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.192,199,200,201,205,210,500,502 (See Cardiovascular Effects under Cautions.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.192,210,500 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.192,210,500 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.192,210,500 Ibuprofen should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if ibuprofen is used in such patients, the patient should be monitored for cardiac ischemia.210

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.192,197,210,502 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.192 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.192 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.192,210 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.192

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that ibuprofen should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if ibuprofen is used in such patients, the patient should be monitored for worsening heart failure.210 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.210 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).210 (See Antihypertensive Agents and also Diuretics under Drug Interactions.)

GI Precautions

The risk of potentially serious adverse GI effects should be considered in patients receiving ibuprofen, particularly in patients receiving chronic therapy with the drug.100,104 Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug,100 patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.192

To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.192,210 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.) In addition, use of NSAIAs should be avoided in patients at higher risk (see GI Effects under Cautions) unless the benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.192,210

Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution.

Hepatic Precautions

Liver function should be monitored periodically during long-term ibuprofen therapy. Elevations in serum ALT may be the most sensitive indicator of NSAIA-induced liver dysfunction. Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving ibuprofen should be evaluated for evidence of the development of a more severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs.192 Although such reactions are rare, ibuprofen should be discontinued immediately if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations (e.g., eosinophilia, rash) occur. Patients receiving ibuprofen should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, anorexia, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, flu-like syndrome) and advised to discontinue ibuprofen therapy and seek immediate medical care if they experience such symptoms.210

Renal Precautions

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.192 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.192 Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients.192,196 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.192 Fluid depletion should be corrected prior to initiation of ibuprofen therapy, and renal function should be monitored during ibuprofen therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.210 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy.192

The renal effects of ibuprofen may hasten the progression of renal dysfunction in patients with preexisting renal disease.210 Patients with preexisting renal disease should be monitored for worsening renal function.210

Ibuprofen has not been evaluated in patients with severe renal impairment, and the manufacturers state that use of the drug should be avoided in patients with advanced renal disease unless the benefits of therapy are expected to outweigh the risk of worsening renal function.210 If ibuprofen is used in patients with advanced renal disease, close monitoring of renal function is recommended.210

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

Pharmacogenomic Precautions

In patients with the cytochrome P-450 isoenzyme 2C9 (CYP2C9) poor metabolizer phenotype, metabolism of ibuprofen may be decreased substantially; the half-life of ibuprofen is prolonged and higher plasma concentrations of the drug may increase the likelihood and/or severity of adverse effects.520 Metabolism of ibuprofen may be moderately reduced in CYP2C9 intermediate metabolizers with a diplotype functional activity score (AS) of 1 and mildly reduced in those with an AS of 1.5.520 Higher plasma concentrations of the drug in intermediate metabolizers with an AS of 1 may increase the likelihood of adverse effects.520 The presence of other factors affecting clearance of the drug (e.g., hepatic impairment, advanced age) also may increase the risk of adverse effects in intermediate metabolizers.520 Further caution is 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 metabolism of ibuprofen.520 (See Pharmacogenomic Dosage Considerations under Dosage and Administration and also see Elimination under Pharmacokinetics.) The Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs should be consulted for additional information on interpretation of CYP2C9 genotype testing.520

Precautions Related to Dermatologic or Hypersensitivity Reactions

Anaphylactoid reactions have been reported in patients receiving NSAIAs.192 Patients receiving NSAIAs should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.192

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.192 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.192 NSAIAs should be discontinued at the first appearance of rash or any other sign of hypersensitivity.192

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.100 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.100 Symptoms may resemble those of an acute viral infection.100 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.100 If such signs or symptoms develop, the NSAIA should be discontinued and the patient evaluated immediately.100

Hematologic Precautions

Ibuprofen should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), since the drug may inhibit platelet function.

NSAIAs, including ibuprofen, may increase the risk of bleeding.210 Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk and should be monitored for signs of bleeding.210 (See Drug Interactions.)

If signs and/or symptoms of anemia occur during therapy with ibuprofen, hemoglobin concentration and hematocrit should be determined.210

Premature neonates receiving ibuprofen lysine should be observed closely for bleeding tendencies.198 Ibuprofen lysine is contraindicated in neonates with active bleeding, such as those with intracranial hemorrhage or GI bleeding, and in neonates with thrombocytopenia or underlying coagulation defect.198

Precautions for Self-medication

Adults receiving ibuprofen forself-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.194 Unless otherwise directed by a clinician, adults receiving ibuprofen for self-medication should be advised to discontinue the drug and consult a clinician if pain persists for more than 10 days or fever persists for longer than 3 days.194 Patients should not use ibuprofen for self-medication immediately before or after cardiac surgery, or if they have experienced an allergic reaction to any analgesic or antipyretic.194 Patients receiving ibuprofen for self-medication of acute migraine attacks should be advised that headaches may worsen if the drug is used on 10 or more days per month.105

Patients receiving ibuprofen for self-medication should be advised to consult a clinician before initiating ibuprofen if they have experienced adverse effects associated with any analgesic or antipyretic; if they have hypertension, cardiac disease, asthma, hepatic cirrhosis, or renal disease; if they have had a stroke; if they have a history of bleeding events or GI disorders (e.g., heartburn, peptic ulcer); if they are receiving therapy with a diuretic, an anticoagulant, a corticosteroid, or any other NSAIA-containing preparation; if they consume 3 or more alcohol-containing drinks per day; or if they are 60 years of age or older.165,194,214 Patients receiving the drug for self-medication should consult a clinician or pharmacist before initiating ibuprofen if they are under a clinician's care for any continuing serious medical condition, are taking aspirin for reduction of cardiovascular risk, or are receiving any other drugs.165,194

Patients should be advised to stop taking ibuprofen for self-medication and consult their clinician if symptoms of GI bleeding (e.g., faintness, vomiting blood, bloody or black stools, persistent stomach pain) develop; if cardiac symptoms or symptoms of stroke (e.g., chest pain, difficulty breathing, weakness in one part or side of the body, slurred speech, leg swelling) occur; if any new symptoms occur during self-medication with the drug; or if redness or swelling is present in the painful area.165,194,214 Patients should be advised that the risk of GI bleeding is increased if they are 60 years of age or older, have a GI disorder (e.g., history of GI bleeding or peptic ulceration), are receiving an anticoagulant or corticosteroid, are receiving another NSAIA (including aspirin) concomitantly, generally consume 3 or more alcohol-containing drinks per day, or exceed the recommended dosage or duration of ibuprofen therapy.192,214 In addition, patients should be advised that NSAIAs (except aspirin) increase the risk of myocardial infarction, heart failure, and stroke and that the risk is increased if they exceed the recommended dosage or duration of ibuprofen therapy.165,500

For additional information on use of ibuprofen for self-medication in children, see Pediatric Precautions under Cautions.

Other Precautions

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.100

The possibility that the antipyretic and anti-inflammatory effects of ibuprofen may mask the usual signs and symptoms of infection or other diseases should be considered. Ibuprofen lysine should be used with caution in premature neonates at risk for infection and in those with an existing infection that is adequately controlled.198 Clinicians should be alert to the masking effect of the drug in these neonates.198 The drug is contraindicated in neonates with proven or suspected, untreated infection.198

Ibuprofen can interfere with the antiplatelet effect of low-dose aspirin.202,203,500 Patients receiving low-dose aspirin for its cardioprotective effects should be informed of this potential interaction and advised about appropriate timing of ibuprofen administration relative to aspirin administration in order to minimize the interaction.202,203,500 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

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

Because NSAIAs, including ibuprofen, have caused adverse ocular effects (e.g., blurred or diminished vision, scotoma, changes in color vision), patients who experience such visual disturbances during ibuprofen therapy should discontinue the drug and have an ophthalmologic examination, including testing of central visual fields and color vision.

Ibuprofen should be used with caution in patients with increased total bilirubin because of the potential for ibuprofen to displace bilirubin from albumin binding sites.198

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that Motrin^® chewable tablets contain aspartame (NutraSweet^®), which is metabolized in the GI tract to provide 6 mg of phenylalanine for each 100-mg tablet following oral administration189 and that 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 should be warned that some commercially available preparations of ibuprofen may contain sucrose.106

Contraindications

Ibuprofen is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation.100,106,210 NSAIAs generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients.192 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving ibuprofen should be monitored for changes in manifestations of asthma.210 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.192 Patients who are considering use of ibuprofen for self-medication should be advised that ibuprofen is contraindicated in patients who have experienced asthma, urticaria, or other sensitivity reaction to other analgesics or antipyretics.194,195 For further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

NSAIAs are contraindicated in the setting of CABG surgery.210

Ibuprofen lysine is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta); in premature neonates with suspected necrotizing enterocolitis; in neonates with proven or suspected, untreated infection; and in neonates with substantially impaired renal function.198

Pediatric Precautions

The manufacturers state that the safety and efficacy of oral ibuprofen in children younger than 6 months of age have not been established. Ibuprofen should not be used for self-medication in children younger than 6 months of age unless otherwise directed by a clinician.164 Ibuprofen should not be used for self-medication in children immediately before or after cardiac surgery or in children who have experienced an allergic reaction to any analgesic or antipyretic.195

Clinicians should be consulted before initiating ibuprofen for self-medication in children if the child has experienced adverse effects associated with any analgesic or antipyretic; if the child has hypertension, cardiac disease, asthma, hepatic cirrhosis, or renal disease; if the child has had a stroke; if the child has a history of bleeding events or GI disorders (e.g., heartburn, peptic ulcer) or is receiving therapy with a diuretic, an anticoagulant, a corticosteroid, or any other NSAIA-containing preparation; or if dehydration associated with vomiting, diarrhea, or lack of fluid intake has occurred.164,165,179,195,214 A clinician or pharmacist should be consulted before initiating ibuprofen for self-medication in children if the child is under a clinician's care for any continuing serious medical condition or is taking any other drugs.164,195

Ibuprofen self-medication should be discontinued and a clinician should be contacted if symptoms of GI bleeding (e.g., faintness, vomiting blood, bloody or black stools, persistent stomach pain) develop; if cardiac symptoms or symptoms of stroke (e.g., chest pain, difficulty breathing, weakness in one part or side of the body, slurred speech, leg swelling) occur; if any new symptoms occur during self-medication with the drug; if fever worsens during therapy or lasts more than 3 days; if pain worsens during therapy or lasts more than 10 days in adolescents 12 years of age or older or more than 3 days in children younger than 12 years of a if no relief is observed within the first 24 hours of therapy; or if redness or swelling is present in the painful area.164,165,179,195,214 In addition, a clinician should be contacted promptly if the child experiences severe or persistent sore throat or if sore throat is associated with high fever, headache, nausea, or vomiting.179,195 Ibuprofen should not be used for self-medication of sore throat in children for more than 2 days' duration unless otherwise directed by a clinician, and should not be used for self-medication of sore throat in children younger than 3 years of age unless directed by a clinician.179 The risk of GI bleeding is increased if the child has a GI disorder (e.g., history of GI bleeding or peptic ulceration), is receiving an anticoagulant or corticosteroid, is receiving another NSAIA (including aspirin) concomitantly, or if the recommended dosage or duration of ibuprofen therapy is exceeded.195 NSAIAs (except aspirin) increase the risk of myocardial infarction, heart failure, and stroke and the risk is increased if the recommended dosage or duration of ibuprofen therapy is exceeded.164,165,179

Results of a large (about 84,000 children) double-blind, randomized study indicate that risk of hospitalization for GI bleeding, renal failure, anaphylaxis, or Reye's syndrome in febrile children (6 months to 12 years of age) receiving ibuprofen doses of 5 or 10 mg/kg is similar to that in children receiving acetaminophen doses of 12 mg/kg.150,151 These data, however, provide no information on the risks of less severe adverse effects or the risks associated with prolonged use of ibuprofen in children.150

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, 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 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by FDA) have not been established.207 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations have agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in Pseudoephedrine 12:12.12.

Pediatric patients receiving ibuprofen dosages exceeding 30 mg/kg daily and those who have had abnormal liver function test results associated with prior NSAIA therapy should be carefully monitored for signs and symptoms of early liver dysfunction.106

Safety and efficacy of IV ibuprofen for relief of pain or reduction of fever in pediatric patients 6 months of age and older are supported by evidence of fever reduction from a multicenter, open-label study in hospitalized febrile pediatric patients, safety data from 3 studies in which 143 pediatric patients 6 months of age or older received IV ibuprofen for pain relief or antipyresis, supportive data involving other ibuprofen preparations labeled for use in pediatric patients, and evidence from adequate and well-controlled studies in adults.210 The most common adverse effects of IV ibuprofen in pediatric patients are infusion site pain, vomiting, nausea, anemia, and headache.210 Efficacy of IV ibuprofen for relief of pain or reduction of fever has not been established in pediatric patients younger than 6 months of age.210

Long-term follow-up (beyond a postconceptional age of 36 weeks) of premature neonates receiving ibuprofen lysine for patent ductus arteriosus (PDA) has not been conducted.198 The effects of ibuprofen on neurodevelopmental outcome, growth, and other complications of prematurity (e.g., retinopathy of prematurity, chronic lung disease) have not been assessed.198

Safety and efficacy of ibuprofen lysine have been established only in premature infants.198 Ibuprofen lysine is contraindicated in neonates with substantially impaired renal function, thrombocytopenia, coagulation disorders, active bleeding (e.g., intracranial hemorrhage, GI bleeding), known or suspected necrotizing enterocolitis, or proven or suspected infection that is untreated.198 The drug also is contraindicated in neonates with congenital heart disease when patency of the ductus arteriosus is necessary for adequate pulmonary or systemic blood flow (e.g., neonates with pulmonary atresia, severe tetralogy of Fallot, or severe coarctation of the aorta).198

Geriatric Precautions

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.210 Many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.106 If the anticipated benefits of ibuprofen therapy outweigh the potential risks, ibuprofen should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects.210

Clinical studies of IV ibuprofen did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.210 Dosage should be selected with caution, starting at the low end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy observed in the elderly.210

Pregnancy and Lactation

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.100,1200 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.100,1200 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.100,1200 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.100,1200

Known effects of NSAIAs on the human fetus during the 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

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.100,1200 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.100,1200 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.100,1200 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.100,1200 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.100,1200 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.100 These limitations preclude establishing 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, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.100

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.210 In animal studies, inhibitors of prostaglandin synthesis, such as ibuprofen, were associated with increased pre- and post-implantation losses.210 Prostaglandins also have an important role in fetal kidney development.100 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.100

There are no adequate and well-controlled studies of ibuprofen in pregnant women.210 In animal reproduction studies, no clear developmental effects were observed in rabbits or rats given ibuprofen throughout the gestational period at dosages up to 0.4 or 0.5 times, respectively, the maximum recommended human dosage (MRHD).210 An increase in membranous ventricular septal defects was reported in rats given ibuprofen on gestation days 9 and 10 at a dosage of 0.8 times the MRHD.210

The effects of ibuprofen on labor and delivery are unknown.210 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.210

Fertility

Use of NSAIAs, including ibuprofen, may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.210 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.210 In animal studies, ibuprofen did not alter male or female fertility or affect litter size in rats; in mice, the drug decreased ovulation in females but did not alter sperm motility or viability in males.210 Withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.210

Lactation

Limited data indicate that ibuprofen is distributed into milk, resulting in infant exposures of 0.06-0.6% of the maternal weight-adjusted daily dosage.210 Adverse effects on breast-fed infants or effects on milk production have not been reported to date.210 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ibuprofen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.210

Drug Interactions ⬆ ⬇

[Section Outline]

Amikacin
Anticoagulants and Thrombolytic Agents
Antihypertensive Agents
Cyclosporine
Digoxin
Diuretics
Histamine H2-receptor Antagonists
Lithium
Methotrexate
Nonsteroidal Anti-inflammatory Agents
Pemetrexed
Serotonin-reuptake Inhibitors

Amikacin

Ibuprofen may decrease the clearance of amikacin.198

Anticoagulants and Thrombolytic Agents

The effects of anticoagulants (e.g., warfarin) and NSAIAs on GI bleeding are synergistic.192,210 Concomitant use of an NSAIA and anticoagulants is associated with a higher risk of GI bleeding compared with use of either agent alone.192,210

In several short-term, controlled studies, ibuprofen did not have a substantial effect on the prothrombin time of patients receiving oral anticoagulants; however, because ibuprofen may cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time and because bleeding has occurred when ibuprofen and coumarin-derivative anticoagulants were administered concomitantly, the drug should be used with caution and the patient carefully observed for signs of bleeding if the drug is used concomitantly with any anticoagulant (e.g., warfarin) or thrombolytic agent (e.g., streptokinase).

Because reduced CYP2C9 function is associated with an increased risk of major bleeding or supratherapeutic international normalized ratios (INRs) in patients receiving concomitant therapy with warfarin (a CYP2C9 substrate) and NSAIAs, some experts state that concomitant use of warfarin and NSAIAs should be avoided in patients who are CYP2C9 intermediate or poor metabolizers.520

Antihypertensive Agents

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent.106,135,136,137,138,139,140,141,210 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.210

Concomitant use of NSAIAs with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function; such patients should be monitored for signs of worsening renal function.136,142,210 Patients receiving concomitant therapy with ibuprofen and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.210

Cyclosporine

Concomitant use of ibuprofen and cyclosporine may increase the nephrotoxic effects of cyclosporine.210 Patients receiving such concomitant therapy should be monitored for signs of worsening renal function.210

Digoxin

Concomitant use of ibuprofen and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.210 Serum digoxin concentrations should be monitored.210

Diuretics

NSAIAs may reduce the natriuretic effect of furosemide or thiazide diuretics, and concomitant use of diuretics and NSAIAs may increase the risk of NSAIA-associated nephrotoxicity in dehydrated patients.192,198 The reduction in natriuretic effect may be related to inhibition of renal prostaglandin synthesis.192 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for changes in renal function and for adequacy of diuretic and antihypertensive effects.192,198,210

Histamine H2-receptor Antagonists

In healthy individuals, cimetidine and ranitidine (no longer commercially available in the US) did not substantially alter serum concentrations of ibuprofen.100 Concomitant administration of ibuprofen (800 mg) and famotidine (40 mg) did not alter the area under the concentration time-curve (AUC) of ibuprofen; peak plasma concentrations of ibuprofen and famotidine and AUC of famotidine were increased by 16, 22, and 16%, respectively.216

Lithium

Concomitant use of NSAIAs has been reported to increase mean trough lithium concentrations by 15% and to decrease mean renal lithium clearance by approximately 20%.210 Ibuprofen has been reported to increase plasma or serum lithium concentrations by 12-67% and to reduce renal lithium clearance.118,119,120,121,122,123,124,125 The mechanism involved in the reduction of lithium clearance by NSAIAs (including ibuprofen) is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium.119,120,210 Some clinicians recommend that patients receiving lithium should not receive ibuprofen.119 However, if ibuprofen and lithium are used concurrently, the patient should be observed closely for signs of lithium toxicity, and plasma or serum lithium concentrations should be monitored carefully during the initial stages of combined therapy or subsequent dosage adjustment.118,119,121,123,124 Dosage of lithium may have to be reduced in some patients;124 appropriate adjustment of lithium dosage may be required when therapy with ibuprofen is discontinued.118

Methotrexate

Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).210 Patients receiving concomitant ibuprofen and methotrexate therapy should be monitored for methotrexate toxicity.210 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)

Nonsteroidal Anti-inflammatory Agents

In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.210 However, concomitant use of aspirin and an NSAIA increases the risk of adverse GI events.210 Because of the potential for bleeding, concomitant use of ibuprofen with other NSAIAs or with analgesic dosages of aspirin generally is not recommended.210 Patients should be advised that many nonprescription antipyretic formulations, cough and cold preparations, and sleep aids contain NSAIAs.210

In animal studies, blood concentrations of ibuprofen decreased when aspirin and ibuprofen were administered concomitantly. Although limited studies in humans have not shown decreased blood concentrations of ibuprofen when these drugs were administered concurrently, this possibility should be considered.

When ibuprofen is administered with aspirin, protein binding of ibuprofen is reduced, although clearance of the free (unbound) ibuprofen is not altered; the clinical relevance of this interaction has not been established.100

Some NSAIAs (e.g., ibuprofen, naproxen) can interfere with the antiplatelet effect of low-dose aspirin.500 Ibuprofen can antagonize the irreversible inhibition of platelet aggregation induced by aspirin and therefore may limit the cardioprotective effects of aspirin in patients with increased cardiovascular risk.176,500 Administration of 400 mg of ibuprofen 3 times daily in patients receiving aspirin 81 mg daily blocked the aspirin-induced inhibition of platelet cyclooxygenase-1 activity as well as the impairment of platelet aggregation achieved with aspirin during prolonged dosing.176 Administration of aspirin 2 hours before the morning dose of ibuprofen failed to circumvent the interaction with such multiple-dose administration, although such dose timing did effectively obviate the interaction when only single doses of each drug were administered.176 FDA has recommended that patients taking a single dose of ibuprofen 400 mg for self-medication in conjunction with immediate-release, low-dose aspirin therapy be advised to administer the ibuprofen dose at least 8 hours before or at least 30 minutes after administration of aspirin.202,203 Data currently are insufficient to support recommendations regarding the timing of ibuprofen administration relative to that of enteric-coated, low-dose aspirin.202,203 The occasional use of ibuprofen is likely to be associated with minimal risk of attenuating the effects of low-dose aspirin.202,203 Use of alternative analgesics that do not interfere with the antiplatelet effect of low-dose aspirin (e.g., acetaminophen, opiates) should be considered for patients at high risk of cardiovascular events.202,203 Patients receiving ibuprofen should be advised not to take low-dose aspirin without consulting their clinician.210 Ibuprofen is not a substitute for low-dose aspirin therapy for prophylaxis of cardiovascular events, and patients receiving antiplatelet agents such as aspirin concomitantly with ibuprofen should be monitored closely for bleeding.210 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.197,210,502

Pemetrexed

Concomitant use of ibuprofen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.210 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.210 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.210 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant ibuprofen and pemetrexed therapy.210

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.210 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.210 Patients receiving concomitant therapy with ibuprofen and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.210

Other Information ⬆ ⬇

[Section Outline]

Manifestations
Treatment
Anti-inflammatory, Analgesic, and Antipyretic Effects
Genitourinary and Renal Effects
GI Effects
Hematologic Effects
Cardiovascular Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

Manifestations

Limited information is available on the acute toxicity of ibuprofen. Adverse effects associated with overdosage of ibuprofen usually depend on the amount of drug ingested and time elapsed; however, because individual response may vary, each occurrence should be evaluated individually.106 Occasionally, overdosage of ibuprofen has been associated with severe toxicity, including death.106

The most frequent manifestations of ibuprofen overdosage reportedly are abdominal pain, nausea, vomiting, lethargy, and drowsiness.106 In addition, other adverse effects, including headache, tinnitus, CNS depression, seizures, GI bleeding, hypotension, bradycardia, tachycardia, and atrial fibrillation, may occur.106,210 Metabolic acidosis, coma, acute renal failure, hypertension, hyperkalemia, apnea (mainly in young children), respiratory depression, and respiratory failure have been reported rarely.106,144,145,146,147,148,149,210 There appears to be little correlation between severity of manifestations associated with ibuprofen overdosage and plasma ibuprofen concentrations.144

Drowsiness was the only adverse effect experienced by a child 1 year of age who ingested 1.2 g (120 mg/kg) of the drug even though the blood ibuprofen concentration 90 minutes after ingestion was 700 mcg/mL (nearly 10 times the highest concentration previously recorded in adults following a single oral 800-mg dose of the drug). Signs of acute intoxication or late sequelae also were not present following ingestion of a 120-mg/kg dose of the drug in another child. However, in a 12-kg child who ingested 2.8-4 g of the drug, apnea, cyanosis, and response only to painful stimuli were present about 1.5 hours after ingestion; respiration could be induced by painful stimuli. The blood ibuprofen concentration in this child was about 103 mcg/mL at about 8.5 hours after ingestion and the child appeared to have completely recovered at 12 hours following treatment with oxygen, sodium bicarbonate, and parenteral infusion of dextrose and 0.9% sodium chloride. Dizziness and nystagmus occurred in a 19-year-old who ingested 8 g of the drug over a period of a few hours.

Treatment

Treatment of acute toxicity associated with ibuprofen overdosage mainly is supportive.106,144 When acute overdosage of ibuprofen occurs, the stomach should be emptied by inducing emesis with syrup of ipecac or by lavage, particularly if there is evidence that the drug has been ingested recently (within 30-60 minutes), and standard measures to maintain urine output should be instituted. Administration of activated charcoal may be useful in reducing absorption and reabsorption of ibuprofen.106,144 Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful because of the drug's high protein binding.210 Management of hypotension, GI bleeding, and acidosis may be necessary.106

In children, the estimated amount ingested per unit of body weight may be helpful in predicting the development of toxicity, but each case should be evaluated individually.106 One manufacturer and some clinicians state that toxicity is unlikely in children who have ingested less than 100 mg/kg of ibuprofen.106,144 In children who have ingested 100-200 mg/kg, the stomach should be emptied by inducing emesis and the child observed for at least 4 hours; in children who have ingested 200-400 mg/kg of the drug, the stomach should be emptied and the child observed in a health-care facility for at least 4 hours.106,144 Children who have ingested more than 400 mg/kg of ibuprofen require immediate medical referral, careful observation, and appropriate supportive therapy; syrup of ipecac is not recommended in these children because of risk of seizures and potential aspiration of gastric contents.106,144 In adults, the amount of ibuprofen ingested does not appear to predict toxicity; therefore, the need for referral and follow-up treatment should be assessed individually.106 Adults with symptomatic toxicity should be admitted to a health-care facility for observation.106

Pharmacology

Ibuprofen has pharmacologic actions similar to those of other prototypical NSAIAs. Ibuprofen has shown anti-inflammatory, antipyretic, and analgesic activity in both animals and humans. The exact mechanisms of action of the drug have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.166,167,168,169,170 Ibuprofen inhibits synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.166,167,168,169,170 Ibuprofen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.166,167,168,169,170 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.166,167,168,169,170

Anti-inflammatory, Analgesic, and Antipyretic Effects

The anti-inflammatory, analgesic, and antipyretic effects of ibuprofen and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis.166,167,168,169,170 While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.166,167,168,169,170

Ibuprofen does not possess glucocorticoid or adrenocorticoid-stimulating properties. Higher doses usually are required for anti-inflammatory effects than for analgesia.

Genitourinary and Renal Effects

Ibuprofen-induced inhibition of prostaglandin synthesis may result in decreased frequency and intensity of uterine contractility. Prostaglandins E₂ and F₂α increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea also is mediated by these prostaglandins. Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.172 Therapy with ibuprofen has been effective in relieving menstrual pain probably by inhibiting the formation of these prostaglandins. Administration of ibuprofen during late pregnancy may prolong gestation by inhibiting uterine contractions.

Ibuprofen has been reported to adversely affect renal function. (See Renal Effects under Cautions.) The mechanisms of adverse renal effects of ibuprofen have not been determined, but may involve inhibition of renal synthesis of prostaglandins.

Ibuprofen does not appear to have uricosuric activity.

GI Effects

Similar to other prototypical NSAIAs, ibuprofen can cause gastric mucosal damage, which may result in ulceration and/or bleeding. (See GI Effects under Cautions.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.166,167,168,169,170,171,173 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.168,173

Limited data indicate that ibuprofen, in a dosage of 1.2 or 2.4 g daily, produced less severe gastric mucosal abnormalities (observed with endoscopic examination) than did aspirin in a dosage of 3.6 g daily. In addition, ibuprofen in a dosage of 1.2 g daily produces less severe gastric mucosal damage than indomethacin in a dosage of 100 mg daily.

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.170 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.170

Hematologic Effects

Ibuprofen inhibits platelet aggregation and prolongs bleeding time but does not affect prothrombin time or whole blood clotting time. Similar to aspirin and other prototypical NSAIAs, the effects of ibuprofen on platelets appear to be associated with inhibition of the synthesis of prostaglandins produced by COX-1.170

Cardiovascular Effects

In many premature neonates, administration of ibuprofen results in closure of the persistently patent ductus arteriosus.198 During fetal life, the ductus arteriosus apparently is maintained in a dilated state by prostaglandins, presumably of the E series, which are produced in the placenta and in the ductus itself. The ductus usually closes within 24 hours after birth, partly as a result of loss of placental prostaglandins and increased pulmonary blood flow. In premature neonates, however, the ductus may not close promptly, perhaps because of increased sensitivity of the immature ductus to prostaglandins; some of these neonates develop cardiopulmonary decompensation because of large left-to-right cardiac shunts. Ibuprofen appears to inhibit the synthesis of the prostaglandins, thereby permitting closure of the ductus. Other factors such as oxygenation and hydration status of the neonate also may contribute to successful ductus closure.

Pharmacokinetics

Absorption

Approximately 80% of an oral dose of ibuprofen is absorbed from the GI tract. Absorption rate is slower and plasma concentrations are reduced when ibuprofen is taken with food; however, the extent of absorption is not affected.106 When the drug is administered with food, peak plasma ibuprofen concentrations are reduced by 30-50% and time to achieve peak plasma concentrations is delayed by 30-60 minutes.106 Absorption of ibuprofen does not appear to be affected by concomitant administration of antacids containing aluminum hydroxide or magnesium hydroxide.106

In adults, oral bioavailability of ibuprofen (measured by peak plasma concentrations and extent of absorption) is similar following administration of conventional tablets, chewable tablets, or suspension; however, time to reach peak plasma concentrations was reportedly about 120, 62, or 47 minutes following administration of each respective dosage form.211 Following oral administration of a single 200-mg dose of ibuprofen as chewable tablets, suspension, or conventional tablets in adults, peak plasma concentrations were 15, 19, or 20 mcg/mL, respectively.211 Following oral administration of ibuprofen in adults, the area under the serum concentration-time curves (AUCs) of total and free drug increase proportionally with single ibuprofen doses of 50-600 and up to 1200 mg, respectively.211 In febrile children, oral bioavailability (measured by peak plasma concentrations and extent of absorption) of ibuprofen also appears to be similar following administration of the respective dosage form; however, time to reach peak plasma concentrations was reportedly 86 or 58 minutes following administration of chewable tablets or suspension, respectively.211 Following oral administration of a 200-mg dose in adults or a 10-mg/kg dose in febrile children, peak plasma concentrations and plasma concentration-time curves (AUCs) of ibuprofen appear to be increased in children compared with those achieved in adults; these differences appear to result from age- or fever-related changes in the volume of distribution in children and also to the variability of doses (based on body weight) administered to pediatric patients.106 Peak plasma or serum ibuprofen concentrations of about 40-55 mcg/mL occur after about 1-1.5 hours in febrile children receiving a single 10-mg/kg dose of ibuprofen suspension or chewable tablets.107,211 Following oral administration of ibuprofen suspension in febrile children, AUCs increase with increasing single ibuprofen doses up to 10 mg/kg;107,211 it appears that pharmacokinetics of ibuprofen are not affected by age, in children 2 to 11 years of age.211

In children, the antipyretic effect of ibuprofen suspension begins within 1 hour after oral administration107 and peaks within 2-4 hours.106,107 The antipyretic effect of single ibuprofen suspension doses of 5 or 10 mg/kg may last up to 6 or 8 hours, respectively.106,151 Following oral administration of ibuprofen chewable tablets, onset, peak, and duration of antipyretic effects reportedly are similar to that following oral administration of the suspension.211 Plasma concentrations required for anti-inflammatory effect are not known. A few days to 2 weeks of therapy are required before therapeutic response occurs.

Following IV administration of 400 or 800 mg of ibuprofen in adults, peak plasma concentrations were 39.2 or 72.6 mcg/mL, respectively.210 Following IV administration of 10-mg/kg doses of ibuprofen in pediatric patients 6 months to 16 years of age, mean peak plasma concentrations were 59-64 mcg/mL.210

Distribution

Animal studies indicate that ibuprofen distribution varies according to species; human distribution data have not been published. The volume of distribution reportedly is about 0.12 or 0.2 L/kg in adults or febrile children younger than 11 years of age, respectively, suggesting that the volume of distribution may be affected by age or fever;106 however, the clinical importance of this difference is not known.106 In pediatric patients 6 months to 16 years of age receiving IV ibuprofen, the apparent volume of distribution during the terminal phase increased with age.210 In one study in premature neonates receiving IV ibuprofen lysine, the volume of distribution of ibuprofen at birth averaged 0.32 L/kg.198 Approximately 90-99% of a dose is bound to plasma proteins; protein binding appears to be saturable, and at concentrations exceeding 20 mcg/mL, such binding is nonlinear.106 Ibuprofen and its metabolites cross the placenta in rats and rabbits. In preliminary studies, ibuprofen was not detected in the milk of nursing women.

Elimination

Plasma concentrations of ibuprofen appear to decline in a biphasic manner.106 The terminal elimination half-life of orally administered ibuprofen in children reportedly is similar to that in adults;106 however, total clearance may be affected by age or fever.106 It has been suggested that changes in total clearance may result from changes in the volume of distribution in febrile children.106 The plasma half-life of the drug has been reported to be 2-4 hours. Blood concentrations decline as rapidly after multiple doses as after single doses. In one study in premature neonates receiving IV ibuprofen lysine, clearance of ibuprofen at birth averaged 3 mL/kg per hour.198 Clearance increased rapidly (by an average of about 0.5 mL/kg per hour each day) as postnatal age increased, and interindividual variability (55%) in clearance was observed.198 The terminal elimination half-life is at least tenfold longer in premature neonates than in adults.198 The elimination half-life in pediatric patients receiving IV ibuprofen is shorter than that observed in adults.210 Following IV administration of 10-mg/kg doses of ibuprofen, the mean half-life was 1.5-1.6 hours in pediatric patients 2-16 years of age and 1.8 hours in those 6 months to less than 2 years of a the volume of distribution and clearance increased with age.210

Ibuprofen is almost completely metabolized, mainly via cytochrome P-450 (CYP)-mediated oxidative metabolism to inactive metabolites.521 Ibuprofen is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C8.521 CYP3A4 contributes to ibuprofen clearance at high concentrations; CYP2C19 appears to play a minor role in metabolism of the drug.521 Approximately 10-15% of an ibuprofen dose is metabolized to ibuprofen acyl glucuronide.521 Multiple uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes are capable of metabolizing ibuprofen in vitro; however, further study is needed to characterize the relative contributions of individual UGT isoenzymes to ibuprofen metabolism in vivo.521

Approximately 37 and 25% of an administered dose of ibuprofen is 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 (e.g., 3-hydroxyibuprofen, 1-hydroxyibuprofen) also have been recovered in urine.521 Little or no unchanged drug is recovered in urine.521 Excretion of ibuprofen is essentially complete within 24 hours following oral administration. Some biliary excretion of the drug probably occurs in humans. Metabolism and excretion of ibuprofen in premature neonates have not been evaluated.198

Chemistry and Stability

Chemistry

Ibuprofen is a prototypical nonsteroidal anti-inflammatory agent (NSAIA). Ibuprofen is commercially available as the acid and as the potassium salt. Ibuprofen is a racemic mixture of 2 optical isomers.106 In vivo and in vitro studies indicate that only the l -isomer of ibuprofen has clinical activity.106 However, the d -isomer, which is considered clinically inactive, is slowly and incompletely (by about 60%) converted to the l -isomer in adults;106 the degree of such conversion is believed to be similar in children.106 It also has been suggested that the d -isomer serves as a circulating reservoir to maintain concentration of the active drug.106 Ibuprofen occurs as a white to off-white, crystalline powder having a slight, characteristic odor and is practically insoluble in water and very soluble in alcohol. The apparent pK_a of ibuprofen is about 4.4.

Commercially available ibuprofen lysine injection occurs as a clear sterile solution of the drug in water for injection.198 Sodium hydroxide or hydrochloric acid may be added during the manufacture of the injection to adjust the pH to 7.198

Stability

Oral preparations containing ibuprofen should be stored in well-closed, light-resistant containers at 20-25°C.

Ibuprofen injection concentrate and the commercially available ibuprofen premixed injection for IV administration should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.210 The products contain no preservatives and are intended for single use only; any unused portions should be discarded.210

Ibuprofen lysine injection should be stored at 20-25°C; the injection should be stored in the manufacturer's carton until time of use and should be protected from light.198 The product contains no preservatives and is intended for single use only; any unused portions should be discarded.198

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.

Ibuprofen

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	equivalent to 200 mg ibuprofen (as free acid and ibuprofen potassium)*	Advil^® Liqui-Gels^®	GlaxoSmithKline
			Advil^® Migraine^®	GlaxoSmithKline
			Ibuprofen Liquid-filled Capsules
			Motrin^® IB Liquid Gels	McNeil
			Motrin^® IB Migraine	McNeil
	Suspension	40 mg/mL*	Advil^® Infants' Concentrated Drops	GlaxoSmithKline
			Ibuprofen Infants' Concentrated Drops
			Motrin^® Infants' Concentrated Drops	McNeil
		100 mg/5 mL*	Advil^® Children's Suspension	GlaxoSmithKline
			Ibuprofen Oral Suspension
			Motrin^® Children's Suspension	McNeil
	Tablets	200 mg*	Ibuprofen Tablets
		400 mg*	Ibuprofen Tablets
		600 mg*	Ibuprofen Tablets
		800 mg*	Ibuprofen Tablets
	Tablets, chewable	100 mg*	Advil^® Junior Strength Chewable Tablets	GlaxoSmithKline
			Ibuprofen Chewable Tablets
			Motrin^® Children's Chewable Tablets	McNeil
	Tablets, film-coated	100 mg	Advil^® Junior Strength Tablets	GlaxoSmithKline
		200 mg*	Advil^® Caplets^®	GlaxoSmithKline
			Advil^® Gel Caplets	GlaxoSmithKline
			Advil^® Tablets	GlaxoSmithKline
			Ibuprofen Film-coated Tablets
			Ibutab^®	Cintas
			Motrin^® IB Tablets	McNeil
		400 mg*	IBU^®	Dr. Reddy's
			Ibuprofen Film-coated Tablets
		600 mg*	IBU^®	Dr Reddy's
			Ibuprofen Film-coated Tablets
		800 mg*	IBU^®	Dr. Reddy's
			Ibuprofen Film-coated Tablets
Parenteral	Injection, for IV use	4 mg/mL (800 mg)	Caldolor^® in Sterile Water Injection (available in ready-to-use polypropylene bags)	Cumberland
	Injection concentrate, for IV use	100 mg/mL	Caldolor^®	Cumberland

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

Ibuprofen Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules, liquid-filled	equivalent to 200 mg ibuprofen (as free acid and ibuprofen potassium) with Diphenhydramine Hydrochloride 25 mg*	Advil^® PM Liqui-Gels^®	GlaxoSmithKline
			Ibuprofen and Diphenhydramine Hydrochloride Liquid-filled Capsules
	Tablets, film-coated	125 mg with Acetaminophen 250 mg	Advil^® Dual Action	GlaxoSmithKline
		200 mg with Diphenhydramine Citrate 38 mg*	Advil^® PM	GlaxoSmithKline
			Ibuprofen and Diphenhydramine Citrate Film-coated Tablets
			Motrin^® PM	McNeil
		200 mg with Hydrocodone Bitrate 2.5 mg*	Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-II)
		200 mg with Hydrocodone Bitartrate 5 mg*	Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-II)
		200 mg with Hydrocodone Bitartrate 7.5 mg*	Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-II)
		200 mg with Hydrocodone Bitartrate 10 mg*	Hydrocodone Bitartrate and Ibuprofen Film-coated Tablets (C-II)
		800 mg with Famotidine 26.6 mg	Duexis^®	Horizon

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

Ibuprofen Lysine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use only	10 mg/mL (of ibuprofen)*	Ibuprofen Lysine Injection
			NeoProfen^®	Recordati Rare Diseases

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

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

100. Amneal Pharmaceuticals. Ibuprofen tablets prescribing information. Bridgewater, NJ; 2020 Nov.

101. Perera DR, Seiffert AK, Greeley HM. Ibuprofen and meningoencephalitis. Ann Intern Med . 1984; 100:619. [PubMed 6703566]

102. Bouland DL, Specht NL, Hegstad DR. Ibuprofen and aseptic meningitis. Ann Intern Med . 1986; 104:732.

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104. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull . 1989; 19:3-4.

105. GlaxoSmithKline Consumer Healthcare. Advil^® (ibuprofen) migraine liquid-filled capsules patient information. Warren, NJ. Undated. Accessed 2021 Jun 4. [Web]

106. Actavis Pharma. Ibuprofen oral suspension prescribing information. Parsippany, NJ; 2021 Mar.

107. Walson PD, Galletta G, Braden NJ et al. Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther . 1989; 46:9-17. [PubMed 2663318]

108. Searle. Cytotec^® (misoprostol) prescribing information. Skokie, IL; 1989 Jan.

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110. Whelton A, Stout RL, Spilman PS et al. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure: a prospective, randomized, crossover comparison. Ann Intern Med . 1990; 112:568-76. [PubMed 2183665]

111. Sandler DP, Burr FR, Weinberg CR. Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease. Ann Intern Med . 1991; 115:165-72. [PubMed 2058870]

112. Wagner EH. Nonsteroidal anti-inflammatory drugs and renal disease—still unsettled. Ann Intern Med . 1991; 115:227-8. [PubMed 2058878]

113. Stillman MT, Schlesinger PA. Nonsteroidal anti-inflammatory drug nephrotoxicity: should we be concerned? Arch Intern Med . 1990; 150:268-70.

114. Murray MD, Brater DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Ann Intern Med . 1990; 112:559-60. [PubMed 2327675]

115. Murray MD, Brater DC, Tierney WM et al. Ibuprofen-associated renal impairment in a large general medicine practice. Am J Med Sci . 1990; 299:222-9. [PubMed 2321664]

116. Fong HJ, Cohen AH. Ibuprofen induced acute renal failure with acute tubular necrosis. Am J Nephrol . 1982; 2:28. [PubMed 7180901]

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section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Ibuprofen

Ibuprofen Combinations

Ibuprofen Lysine

Copyright ⬆ ⬇

References ⬆