Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAIA) that exhibits analgesic and antipyretic activity.100
Ibuprofen is used orally for the symptomatic treatment of rheumatoid arthritis, juvenile arthritis, and osteoarthritis.100,106 Ibuprofen also is used orally to relieve mild to moderate pain, to manage primary dysmenorrhea, and to reduce fever.100,106
Ibuprofen is used IV to relieve mild to moderate pain, to relieve moderate to severe pain (in conjunction with opiates), and to reduce fever.210
Ibuprofen lysine is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates.198
Ibuprofen has been used in combination with colchicine for the management of acute and recurrent pericarditis† .1207,1208,1209,1210
The potential benefits and risks of ibuprofen as well as alternative therapies should be considered prior to initiating ibuprofen therapy.100,106 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.100,106
Ibuprofen is available in various over-the-counter (OTC) preparations; OTC preparations are used to provide temporary relief of minor aches and pains (including those of arthritis and dysmenorrhea), to relieve migraine headaches, and to reduce fever.522,523
Ibuprofen is used orally for the symptomatic treatment of rheumatoid arthritis and osteoarthritis in adults.100,106 Ibuprofen oral suspension is also used for the symptomatic treatment of juvenile arthritis in pediatric patients.106 Ibuprofen is available in fixed combination with famotidine for the symptomatic treatment of rheumatoid arthritis and osteoarthritis; the famotidine component is used to decrease the risk of developing upper GI ulcers.216 Consult the prescribing information for additional information on the fixed-combination ibuprofen/famotidine preparation.
Nonsteroidal anti-inflammatory agents (NSAIAs), including ibuprofen, have also been used in other inflammatory diseases including ankylosing spondylitis†, gout†, and psoriatic arthritis† .2006,2007,2008
In patients with osteoarthritis, ibuprofen has demonstrated a 50-60% improvement in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores compared to placebo.1203 In clinical studies of patients with rheumatoid arthritis and osteoarthritis, ibuprofen tablets were comparable to aspirin in terms of controlling pain and inflammation; adverse GI effects were decreased with ibuprofen compared to aspirin.100,1204 Ibuprofen has also been shown to be comparable to indomethacin in terms of controlling disease activity in patients with rheumatoid arthritis, with decreased adverse GI effects.100,1204 In patients with juvenile rheumatoid arthritis, a small double-blind randomized controlled trial found no significant differences in efficacy between ibuprofen and aspirin; however, patients receiving aspirin were more likely to discontinue treatment early due to adverse reactions.1205
The American College of Rheumatology (ACR) guideline on the treatment of rheumatoid arthritis recommends initiation of a disease-modifying antirheumatic drug (DMARD) in DMARD-naïve patients with rheumatoid arthritis; methotrexate is recommended over other DMARDs for the initial treatment of patients with moderate-to-high disease activity, while hydroxychloroquine is recommended initially for patients with low disease activity.2001 Addition of a biologic or target-specific DMARD is recommended for patients who do not attain treatment goals on methotrexate monotherapy (“treat-to-target” approach).2001 The role of NSAIAs is not discussed in the current ACR guideline on rheumatoid arthritis.2001
Medical management of osteoarthritis of the hip, knee, and/or hand includes both pharmacologic therapy and nonpharmacologic (e.g., educational, behavioral, psychosocial, physical) interventions to reduce pain, maintain and/or improve joint mobility, limit functional impairment, and enhance overall well-being.2002 The ACR strongly recommends exercise, weight loss when necessary in patients with osteoarthritis of the knee and/or hip, self-efficacy and self-management programs, tai chi, cane use, hand orthoses, knee bracing, topical NSAIAs for osteoarthritis of the knee, oral NSAIAs, and intra-articular glucocorticoid injections for osteoarthritis of the knee or hip.2002 Other pharmacologic or nonpharmacologic interventions may be recommended conditionally.2002 Interventions and the order of their selection are patient specific.2002 Factors to consider when making decisions regarding therapy for osteoarthritis include patients' values and preferences, the presence of risk factors for serious adverse GI effects, existing comorbidities (e.g., hypertension, heart failure, other cardiovascular disease, chronic kidney disease), injuries, disease severity, surgical history, and access to and availability of the interventions.2002 Pharmacologic therapy should be initiated with treatments resulting in the least systemic exposure or toxicity.2002 For some patients with limited disease, topical NSAIAs may be an appropriate initial choice for pharmacologic therapy; for other patients, particularly those with osteoarthritis of the hip or with polyarticular involvement, oral NSAIAs may be more appropriate.2002
The ACR and the Arthritis Foundation issued a joint guideline for the treatment of juvenile idiopathic (rheumatoid) arthritis manifesting as nonsystemic polyarthritis (including polyarticular disease), sacroiliitis, or enthesitis in 2019.2003 Several drug classes are used to treat juvenile idiopathic arthritis, including NSAIAs, systemic and intra-articular corticosteroids, conventional DMARDs (e.g., methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), and biologic DMARDs (e.g., tumor necrosis factor [TNF] blocking agents, abatacept, tocilizumab, rituximab).2003 Specific agents for juvenile idiopathic arthritis treatment are selected according to the presence of certain risk factors (e.g., positive anti-cyclic citrullinated peptide antibodies, positive rheumatoid factor, joint damage), level of disease activity, involvement of specific joints, presence of certain comorbidities (e.g., uveitis), and prior therapies used.2003,2004 An individualized “treat-to-target” approach is typically employed, with the goal of achieving remission or minimal/low disease activity.2005
Initial therapy with a DMARD (e.g., methotrexate) is recommended over NSAIA monotherapy for children and adolescents with juvenile idiopathic arthritis and polyarthritis; NSAIAs may be used adjunctively for symptom management in patients with polyarthritis, particularly during initiation or escalation of therapy with DMARDs or biologics.2003 For patients with active sacroiliitis or enthesitis, initial treatment with an NSAIA is recommended, with no preference given to any particular NSAIA.2003
The ACR published an additional guideline addressing juvenile idiopathic arthritis manifesting as oligoarthritis, temporomandibular joint arthritis, or systemic juvenile idiopathic arthritis in 2022.2009 For oligoarthritis, intraarticular glucocorticoids are strongly recommended as part of initial therapy, and a trial of scheduled NSAIAs is conditionally recommended as part of initial therapy.2009 Similarly, intraarticular glucocorticoids and a trial of scheduled NSAIAs are both conditionally recommended as part of initial therapy for temporomandibular joint arthritis.2009 For patients with systemic juvenile idiopathic arthritis without macrophage activation syndrome, initial monotherapy with either NSAIAs or biologic DMARDs (i.e., interleukin [IL]-1 and IL-6 inhibitors) is conditionally recommended.2009 Patients with systemic juvenile idiopathic arthritis and macrophage activation syndrome should be treated with IL-1 and IL-6 inhibitors and glucocorticoids.2009
Ibuprofen is used orally or IV for the relief of mild to moderate pain.100,106,210 Ibuprofen oral tablets are used in adults, while the ibuprofen oral suspension is used in pediatric patients 6 months to 2 years of a the ibuprofen IV formulation is used in adults and pediatric patients 3 months of age or older.100,106,210 Ibuprofen is also used IV for the management of moderate to severe pain as an adjunct to opioid analgesics in adults and pediatric patients 3 months of age or older.210 Ibuprofen is available in fixed combination with hydrocodone bitartrate for the short-term management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate; consult the prescribing information for additional details on the use of this fixed combination preparation.161
Ibuprofen also may be used orally for self-medication for the temporary relief of minor aches and pains associated with headache (including migraine), toothache, muscular aches, backache, the common cold, and minor arthritis pain.522,523,524
Ibuprofen has been used orally to relieve postoperative pain (including that associated with dental extraction procedures or episiotomy).100,1214,1215,1216,1217 A Cochrane review found that a single dose of oral ibuprofen 200 mg or 400 mg produced good pain relief in approximately 50% of adults with moderate to severe acute postoperative pain.1214 Other meta-analyses have found that ibuprofen is effective for pain relief following dental extractions.1215,1216,1217
Ibuprofen has been used IV in conjunction with opiates to relieve pain following abdominal hysterectomy, other abdominal surgical procedures, or orthopedic surgery.210,1211,1212,1213 In one randomized controlled trial of 406 patients undergoing elective orthopedic or abdominal surgery, ibuprofen 800 mg IV every 6 hours was associated with reduced morphine requirements for the first 24 hours after surgery compared to placebo, as well as reduced pain at rest and reduced pain during movement.1211 Ibuprofen 400 mg IV every 6 hours did not reduce morphine requirements compared to placebo; pain at rest was reduced compared to placebo at 6-24 hours and 12-24 hours, and pain with movement was reduced across all time periods compared to placebo.1211 Another randomized controlled trial in 185 patients undergoing elective orthopedic surgery similarly found that ibuprofen 800 mg IV every 6 hours reduced morphine requirements and postoperative pain (both at rest and with movement) compared to placebo.1212 An additional randomized controlled trial in 319 patients undergoing elective abdominal hysterectomy found that ibuprofen 800 mg IV every 6 hours reduced postoperative morphine requirements and improved pain at rest and with movement compared to placebo.1213
Ibuprofen has also demonstrated efficacy for the treatment of acute pain related to migraine or tension-type headache.1218,1219,1220
A guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists recommends a multimodal approach to treatment of postoperative pain, including both pharmacologic and nonpharmacologic interventions.2013 For most common surgeries, options for systemic pharmacologic therapy include opioids, NSAIAs and/or acetaminophen, and gabapentin or pregabalin.2013 The guideline recommends the use of NSAIAs and/or acetaminophen as part of multimodal analgesia for postoperative pain in patients without contraindications.2013 When selecting therapy for a specific patient, the potential risks associated with NSAIAs should be considered.2013
The American Dental Association has published guidelines specific to the treatment of acute dental pain in adults and pediatric patients.1221,1222 For the management of acute postoperative dental pain in adults and adolescents undergoing simple or surgical tooth extraction, the American Dental Association recommends an NSAIA (either ibuprofen or naproxen) alone or in combination with acetaminophen.1221 For the management of acute postoperative dental pain in patients <12 years of age undergoing simple or surgical tooth extractions, the American Dental Association recommends an NSAIA (ibuprofen or naproxen suspension or tablet) alone or in combination with acetaminophen; naproxen is only recommended for patients >2 years of age.1222
Guidelines on the acute treatment of migraine have been published by the American Headache Society (AHS) for adults and the American Academy of Neurology (AAN) for pediatric patients.1223,1224 Goals of therapy in acute migraine include rapid freedom from pain and associated symptoms, as well as restored ability to function.1223 Agents with established efficacy in adults with acute migraine include triptans, ergotamine derivatives, gepants, lasmiditan, NSAIAs (aspirin, celecoxib oral solution, diclofenac, ibuprofen, naproxen), and the combination of acetaminophen, aspirin, and caffeine.1223 Nonspecific analgesic therapies such as NSAIAs and acetaminophen/aspirin/caffeine are used for mild-to-moderate attacks, while migraine-specific therapies (e.g., triptans, ergotamine derivatives, gepants, lasmiditan) are used for moderate-to-severe attacks or mild-to-moderate attacks that respond poorly to nonspecific therapy.1223 The AHS guideline states that selection of an agent for acute treatment should be based on patient-specific factors such as comorbid disease states, individual treatment history, and concomitant medications.1223 The AAN guideline recommends ibuprofen oral liquid for the initial treatment of acute migraine pain in children and adolescents; other options for adolescents with acute migraine pain include sumatriptan/naproxen oral tablets, zolmitriptan nasal spray, sumatriptan nasal spray, rizatriptan orally disintegrating tablets, or almotriptan oral tablets.1224 Adolescents with inadequate response to a triptan may be offered ibuprofen or naproxen as add-on therapy to improve migraine relief.1224
Ibuprofen is used orally for the relief of primary dysmenorrhea in adults.100,106
Ibuprofen also may be used for self-medication for the relief of pain due to menstrual cramps (dysmenorrhea).522
A Cochrane review evaluating the efficacy of NSAIAs for the treatment of primary dysmenorrhea found that ibuprofen was more effective than placebo for pain relief.1225 Although data for efficacy comparisons among NSAIAs were limited, ibuprofen was found to be less effective for reducing pain scores than naproxen in a single study.1225 A study comparing ibuprofen and piroxicam did not find substantial differences in pain relief between treatments.1225
First-line treatment options for primary dysmenorrhea include combined oral contraceptives, progesterone-only contraceptives, and NSAIAs; treatment selection should be based on patient-specific considerations (e.g., comorbidities, desire/need for contraception).2012,2015 The American College of Obstetricians and Gynecologists includes ibuprofen as a potential NSAIA for use in patients with primary dysmenorrhea.2012
Ibuprofen oral suspension is used to reduce fever in patients 6 months to 2 years of a ibuprofen is also used IV to reduce fever in adults and pediatric patients 3 months of age and older.106,210
Ibuprofen also may be used orally for self-medication to reduce fever.522
When used to lower body temperature in febrile children (6 months to 12 years of age) with viral infections and temperatures of 39°C or less, single oral ibuprofen doses of 10 mg/kg have been as effective as single ibuprofen doses of 5 mg/kg or single acetaminophen doses of 10-15 mg/kg; however, in children with temperatures exceeding 39°C, single oral 10-mg/kg doses of ibuprofen were most effective.106
IV ibuprofen has been studied for the treatment of fever in 2 randomized, double-blind studies in adults and one randomized open-label study in pediatric patients.210,1226,1227,1228 In one adult study, 120 hospitalized patients with temperatures ≥38.3°C were randomized to receive placebo or ibuprofen (100 mg, 200 mg, or 400 mg) IV every 4 hours for 24 hours.210,1226 At 4 hours, more patients receiving IV ibuprofen at any dosage had temperatures <38.3°C compared to placebo.210,1226 In the second adult study, 60 hospitalized patients with uncomplicated Plasmodium falciparum malaria and fever ≥38°C were randomized to receive placebo or ibuprofen 400 mg IV every 6 hours for 72 hours; patients who received ibuprofen had greater reductions in fever than patients who received placebo, as measured by the area above the temperature 37°C versus time curve.210,1227
The pediatric study enrolled 100 hospitalized patients ≥6 months of age with temperatures ≥38.3°C.210,1228 Patients were randomized to receive ibuprofen 10 mg/kg IV or acetaminophen 10 mg/kg orally or per rectum every 4 hours as needed for fever.210,1228 Patients who received ibuprofen had greater reductions in temperature compared to those who received acetaminophen, as measured by the area under the curve of temperature versus time for the first 2 hours.210,1228
The American Academy of Pediatrics (AAP) has published a guideline on fever and antipyretic use in children.2016 According to AAP, the primary goal of treating fever should be to improve the overall comfort of the patient, not to normalize body temperature.2016 Acetaminophen and ibuprofen are safe and effective options for most patients when used in appropriate doses; ibuprofen may be more effective than acetaminophen for lowering body temperature, but the relative efficacy for improving patient comfort is unknown.2016 Ibuprofen should be used with caution in dehydrated patients and patients with certain comorbidities (e.g., cardiovascular disease, pre-existing renal disease, concomitant use of nephrotoxic agents), because nephrotoxicity can occur.2016
Ibuprofen lysine is used IV to promote closure of clinically important patent ductus arteriosus (PDA) in premature neonates weighing 500-1500 g who are no more than 32 weeks' gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support) is ineffective.198
Ibuprofen also has been used orally† for the treatment of PDA.1230,1231
Ibuprofen lysine has been evaluated in premature neonates with echocardiographic evidence of PDA who were asymptomatic from their PDA at the time of study enrollment.198,1229 Efficacy was determined by the need for rescue therapy (indomethacin, open-label ibuprofen, or surgery) for a hemodynamically important PDA through study day 14.198 Rescue therapy was indicated if the neonate developed a hemodynamically important PDA that was confirmed by echocardiography.198 Rescue therapy was required by 25% of neonates receiving ibuprofen compared with 48.5% of those receiving placebo.198,1229 Neonates enrolled in this study were followed for a short period of time (up to 8 weeks) following treatment; long-term consequences of such therapy have not been determined.198 Use of the drug should be reserved for neonates with clinically important PDA.198
Cochrane reviews have found that ibuprofen (IV or oral) is as effective as indomethacin for PDA closure, with reduced risk of necrotizing enterocolitis and transient renal insufficiency.1230,1231 Oral ibuprofen may be more effective than IV ibuprofen for PDA closure.1230,1231
In most term infants, the ductus arteriosus closes within 1 to 3 days after birth; when this closure fails to occur, it is referred to as PDA.1232,1233 Preterm infants frequently present with persistent PDA.1232,1233 Although spontaneous closure of PDA is common, patients with prolonged hemodynamically important PDA may experience end-organ injury, including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, acute pulmonary hemorrhage, or renal failure, and death.1232 The decision to initiate pharmacologic treatment for PDA will depend on patient-specific factors such as gestational age, chronological age, the size of the PDA, and the presence of symptoms (e.g., requirement for greater than minimal respiratory support).1231,1232
Select infants at high risk of persistent PDA (e.g., infants with gestational age <26 weeks, weight <750 g) are candidates for targeted early prophylactic treatment with indomethacin within 6-24 hours after birth.1232,1233 If prophylactic treatment is not indicated or not effective, early targeted pharmacologic treatment with ibuprofen or indomethacin is recommended <6 days after birth for infants <28 weeks' gestational age with a moderate-to-large hemodynamically important shunt requiring greater than minimal respiratory support.1233 All infants with very low birth weight ≥6 days of age who require greater than minimal respiratory support should be screened for PDA via echocardiogram; in the presence of a moderate-to-large hemodynamically important PDA and additional risk factors (e.g., failure to wean from the ventilator, fraction of inspired oxygen >0.25), treatment with ibuprofen should be considered.1233 If treatment with ibuprofen is ineffective, rescue treatment with acetaminophen or catheter-based closure/surgical intervention may be considered.1233
Ibuprofen has been used in combination with colchicine for the treatment of acute and recurrent pericarditis†.1207,1208,1209,1210 Some experts recommend colchicine plus aspirin or an NSAIA (typically ibuprofen) first-line for the treatment of acute or recurrent pericarditis.1210
Oral ibuprofen has been used chronically to slow the loss of lung function in patients 6-17 years of age with cystic fibrosis† and forced expiratory volume in 1 second (FEV1) ≥60%.1234,1235
Ibuprofen is administered orally or IV.100,106,198,210 Ibuprofen lysine is administered IV.198
Ibuprofen is also commercially available in the following fixed-combination tablets for oral use: ibuprofen and famotidine (Duexis®); ibuprofen and hydrocodone bitartrate.161,216 See the full prescribing information for administration of each of these combination products.161,216
Ibuprofen is also commercially available in various over-the-counter (OTC) preparations as a single ingredient or in combination with other analgesics (e.g., acetaminophen), antihistamines, or decongestants. See the FDA Orange Book and the manufacturer's Drug Facts for further information.
The bioavailability of ibuprofen tablets is minimally affected by administration with food.100
If GI disturbances occur with ibuprofen therapy, administer with meals or milk.100
Shake ibuprofen oral suspension well before administering.106
Store oral preparations containing ibuprofen at 20-25°C.100,106 Store oral tablets in a tight, light-resistant container.100
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
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
Ibuprofen is administered by IV infusion over a period of ≥30 minutes in adults and ≥10 minutes in pediatric patients 3 months to 17 years of age.210 All patients receiving IV ibuprofen should be well hydrated.210
IV Administration (Ibuprofen Lysine)
Ibuprofen lysine injection should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°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
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 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
Ibuprofen lysine should be infused over a period of 15 minutes.198
To minimize the potential risk of adverse cardiovascular and/or GI events, use the lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient.100,106,210 Dosage of ibuprofen must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.100,106,210
Dosage of ibuprofen lysine is expressed in terms of ibuprofen.198
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 In children with pain and a concomitant fever of <39°C, choose the ibuprofen dose that effectively treats the predominant symptom.106
For relief of pain in pediatric patients 3 months to <6 months of age, infants may receive a single dose of 10 mg/kg (up to 100 mg) infused IV over at least 10 minutes.210
For relief of pain, children 6 months to <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 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
Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for pain management for pediatric patients as well.522,523
For antipyresis in children 6 months up to 2 years of age, the usual oral dosage of ibuprofen is 5 mg/kg for temperatures <39°C and 10 mg/kg for temperatures of ≥39°C.106 The maximum daily dosage of ibuprofen in febrile children is 40 mg/kg.106 In children with a fever of <39°C and concomitant pain, choose the ibuprofen dose that effectively treats the predominant symptom.106
For antipyresis in pediatric patients 3 months to <6 months of age, infants may receive a single dose of 10 mg/kg (up to 100 mg) infused IV over at least 10 minutes.210
For antipyresis in pediatric patients, children 6 months to <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 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
Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for fever management for pediatric patients as well.522
For the management of juvenile 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 A few days to several weeks of therapy may be required to achieve a therapeutic response in children with juvenile 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
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
The usual adult oral dosage of ibuprofen in the symptomatic treatment of rheumatoid arthritis is 400-800 mg 3 or 4 times daily.100,106 Alternatively, a dosage of 300 mg 4 times daily is also suggested.106 Dosage should be adjusted according to the response and tolerance of the patient and should not exceed 3.2 g daily.100,106 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.100,106 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.100,106 The manufacturers state that patients with rheumatoid arthritis usually require a higher dosage of ibuprofen than do patients with osteoarthritis.100,106 When a satisfactory response to ibuprofen therapy occurs, dosage of the drug should be reviewed and adjusted as required.100,106
The usual adult oral dosage of ibuprofen in the symptomatic treatment of osteoarthritis is 400-800 mg 3 or 4 times daily.100,106 Alternatively, a dosage of 300 mg 4 times daily is also suggested.106 Dosage should be adjusted according to the response and tolerance of the patient and should not exceed 3.2 g daily.100,106 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.100,106 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.100,106 When a satisfactory response to ibuprofen therapy occurs, dosage of the drug should be reviewed and adjusted as required.100,106
For relief of mild to moderate pain in adults, the recommended ibuprofen oral dosage is 400 mg every 4-6 hours, administered as necessary for the relief of pain.100 In well-controlled clinical studies, ibuprofen doses >400 mg were no more effective for analgesia compared to doses of 400 mg.100
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
Clinicians should note that the dosages provided above are for prescription ibuprofen products only; OTC oral ibuprofen products provide labeled dosages for pain management for adult patients as well.522,523
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.100,106
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
Clinicians should note that the dosages provided above are for a prescription ibuprofen product only; OTC oral ibuprofen products provide labeled dosages for fever management for adult patients as well.522
The manufacturers make no specific dosage recommendations for patients with hepatic impairment.100,106,198,210 Liver function should be monitored periodically during long-term ibuprofen therapy.106
The manufacturers make no specific dosage recommendations for patients with renal impairment.100,106,198,210
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.100,106,210
The manufacturers make no specific dosage recommendations in geriatric patients; however, geriatric patients are generally at a greater risk for NSAIA-associated serious cardiovascular, GI, and/or renal adverse effects.210 If the expected benefits outweigh the potential risks of therapy, initiate at the lower end of the dosage range and monitor for adverse effects.210
Pharmacogenomic Considerations in Dosing
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that, in patients who are poor metabolizers of cytochrome P-450 (CYP) 2C9, 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
A boxed warning concerning the increased risk of serious cardiovascular thrombotic events is included in the prescribing information for ibuprofen.100,106,210 Clinical trials of NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, of up to 3 years' duration have shown an increased 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.100,106,210 Based on available evidence, it is unclear if the risk of cardiovascular thrombotic events is similar for selective COX-2 inhibitors and prototypical NSAIAs.100,106,210 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.100,106,210 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.100,106,210
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.100,106,210 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).100,106,210 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.100,106,210 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.100,106,210
In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following CABG surgery, the incidence of myocardial infarction and stroke was increased.100,106,210 NSAIAs are contraindicated in the setting of CABG surgery.100,106,210
To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.100,106,210 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.100,106,210 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.100,106,210
There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.210 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.210
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
A boxed warning concerning the increased risk of serious adverse GI events is included in the prescribing information for ibuprofen.100,106,210 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.100,106,210 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic.100,106,210 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy.100,106,210 Patients receiving concomitant low-dose aspirin therapy for cardiac prophylaxis should be monitored even more closely for evidence of GI bleeding.100,106,210 In addition, patients should be advised about the signs and symptoms of ulceration and bleeding (e.g., epigastric pain, dyspepsia, melena, hematemesis) and to report these symptoms to their healthcare provider.100,106,210 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.100,106,210 In patients receiving NSAIAs in clinical studies, 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.100,106,210 A longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.100,106,210 However, short-term therapy is not without risk.100,106,210
Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than 10-fold increased risk of developing GI bleeding than patients without these risk factors.100,106,210 In addition to a history of ulcer disease, other factors 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.100,106,210 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.210 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.100,106,210 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.100,106,210 In addition, use of NSAIAs should be avoided in patients at higher risk 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.100,106,210
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
Severe (sometimes fatal) reactions including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure have been reported rarely in patients receiving NSAIAs, including ibuprofen.100,106,210
Borderline elevations of 1 or more liver function test results (<3 times the upper limit of normal [ULN]) may occur in up to 15% of patients treated with NSAIAs; meaningful (≥3 times the ULN) elevations of serum ALT or AST concentration have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies.100,106,210 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.100,106,210
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
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.100,106,210 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.100,106,210 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.100,106,210
Results from Danish National Registry data indicate that use of NSAIAs in patients with chronic heart failure is associated with an increase in the risk of death, an increased risk of myocardial infarction, and an increased risk of hospitalization for heart failure.100,106,210 Fluid retention and edema also have been observed in some patients receiving NSAIAs.100,106,210
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.100,106,210 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.100,106,210 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).100,106,210
Renal Toxicity and Hyperkalemia
Direct renal injury, including renal papillary necrosis, has been reported in patients receiving long-term NSAIA therapy.100,106,210 Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion.100,106,210 Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation.100,106,210 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.100,106,210
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.210
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
Renal insufficiency (including oliguria), increases in BUN (sometimes accompanied by hematuria), increases in serum creatinine concentration, and renal failure have been reported in ibuprofen lysine-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
Anaphylactoid reactions have been reported in patients receiving NSAIAs with or without a known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma.210 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.210
Exacerbation of Asthma Related to Aspirin Sensitivity
Because patients with asthma may have aspirin-sensitive 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 can manifest as severe, potentially fatal bronchospasm with chronic rhinosinusitis and nasal polyps and/or an intolerance to aspirin or other NSAIAs.210 Ibuprofen is contraindicated in patients with aspirin-sensitive asthma.210
Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.100,106,198,210 Acute generalized exanthematous pustulosis (AGEP) has also been reported.198 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.210 NSAIAs should be discontinued at the first appearance of rash or any other sign of hypersensitivity.100,106,198,210
Skin lesion/irritation has occurred in premature neonates receiving ibuprofen for treatment of PDA.198
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug reaction with eosinophilia and systemic symptoms (DRESS), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.100,106,210 DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. 100,106,210 Other clinical manifestations may include hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.100,106,210 Symptoms may resemble those of an acute viral infection.100,106,210 Eosinophilia is often present.100,106,210 Clinical presentation is variable, and other organ systems may be involved. 100,106,210 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.100,106,210 If such signs or symptoms develop, ibuprofen should be discontinued and the patient evaluated immediately.100,106,210
Fetal/Neonatal Morbidity and Mortality
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.100,106,210 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.100,106,210 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.100,106,210 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they also 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.100,106,210
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.100,106,210 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.100,106,210 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.100,106,210 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.100,106,210 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.100,106,210
NSAIAs, including ibuprofen, may increase the risk of bleeding.210 Ibuprofen can inhibit platelet aggregation and may prolong bleeding time.100,106 It appears that ibuprofen's inhibitory effect on platelet aggregation is of shorter duration and less pronounced than that of aspirin.100,106 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
Anemia has been reported in patients receiving NSAIAs.100,106,210 Anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.100,106,210 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
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
Masking of Inflammation and Fever
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.210
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
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning, patients receiving long-term NSAIA therapy should have a CBC and chemistry profile performed periodically.100,106,210
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.100,210
Aseptic meningitis with fever and coma has been reported in patients receiving ibuprofen.100,106,210 Although meningitis probably is more likely to occur in patients with systemic lupus erythematosus or related connective tissue diseases, it has been reported in some patients without evidence of any underlying chronic disease.100,106,210 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.100,106,210
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
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
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 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
Use of NSAIAs during pregnancy at about 30 weeks' gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks' gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.100,106,210 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks' gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks' gestation, the lowest effective dosage and shortest possible duration of treatment should be used.100,106,210 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.100,106,210 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they also 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.100,106,210
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.100,106,210 Oligohydramnios is often, but not always, reversible following discontinuance of NSAIA therapy.100,106,210 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.100,106,210 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.100,106,210 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.100,106,210 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.100,106,210 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.100,106,210 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.100,106,210
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 preimplantation and postimplantation 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.100,106,210 In studies in rats, drugs that inhibit prostaglandin synthesis, including NSAIAs, delayed parturition and increased the incidence of stillbirth.210
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
Females and Males of Reproductive Potential
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
The manufacturers state that the safety and efficacy of oral ibuprofen in children <6 months of age have not been established.106
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 have been established for treatment of pain and fever in pediatric patients 3 months of age and older.210 Use of IV ibuprofen for these indications is supported by evidence from one open-label and acetaminophen-controlled study of fever, as well as additional safety data from four studies in 164 pediatric patients, supportive pediatric data from other approved ibuprofen preparations, 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 <3 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
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.100,106 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 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
Adverse effects reported in at least 5% of adults receiving IV ibuprofen include nausea, flatulence, vomiting, headache, hemorrhage, and dizziness.210
Adverse effects reported in at least 2% of pediatric patients receiving IV ibuprofen include infusion site pain, vomiting, nausea, anemia, and headache.210
The most common type of adverse effect occurring with ibuprofen tablets is GI, and was reported in 4-16% of patients in clinical studies.100
Adverse effects occurring in 1-10% of patients receiving ibuprofen oral suspension include abnormal renal function, anemia, dizziness, edema, elevated transaminases, fluid retention, GI effects (e.g., abdominal pain, bloating, constipation, diarrhea, dyspepsia, epigastric pain, flatulence, heartburn, nausea, vomiting), headaches, increased bleeding times, nervousness, pruritis, rashes (including maculopapular), and tinnitus.106
Adverse effects occurring in at least 10% of premature infants receiving IV ibuprofen lysine for the treatment of patent ductus arteriosus (PDA) include sepsis, anemia, intraventricular bleeding, apnea, GI disorders, impaired renal function, respiratory infection, skin lesions, hypoglycemia, hypocalcemia, and respiratory failure.198
Ibuprofen is metabolized mainly via cytochrome P-450 (CYP) isoenzyme 2C9-mediated hydroxylation of R- and S-ibuprofen.198 There is no evidence of enzyme induction.100
A bioavailability study in adults showed that administration of ibuprofen in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide did not interfere with the absorption of ibuprofen.100,106
Ibuprofen may decrease the clearance of amikacin.198
The effects of anticoagulants (e.g., warfarin) and ibuprofen on bleeding (e.g., GI bleeding) are synergistic.210 Concomitant use of ibuprofen and anticoagulants is associated with a higher risk of serious bleeding compared with use of either agent alone.100,210
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 bleeding, inhibit platelet aggregation, and prolong bleeding time and because bleeding has occurred when ibuprofen and coumarin-derivative anticoagulants were administered concomitantly, ibuprofen should be used with caution if the drug is used concomitantly with any anticoagulant (e.g., warfarin).100,106
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
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.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 deterioration of renal function, which is usually reversible; such patients should be monitored for signs of worsening renal function.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
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
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
NSAIAs may reduce the effect of diuretics, and concomitant use of diuretics and NSAIAs may increase the risk of NSAIA-associated nephrotoxicity in dehydrated patients.198 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for changes in renal function.198 Patients receiving concomitant NSAIA and diuretic therapy should also be monitored to ensure diuretic efficacy, including antihypertensive effects.210
Histamine H2-receptor Antagonists
In healthy individuals, cimetidine, famotidine, and ranitidine (no longer commercially available in the US) did not substantially alter serum concentrations of ibuprofen.100,106
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 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.210 However, if ibuprofen and lithium are used concurrently, the patient should be monitored for signs of lithium toxicity.210
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
Nonsteroidal Anti-inflammatory Agents
In pharmacodynamic studies, concomitant use of ibuprofen 400 mg given 3 times daily with enteric-coated low-dose aspirin has shown that ibuprofen interferes with the antiplatelet activity of aspirin.210 This interaction persists even with a reduced frequency of ibuprofen (once daily) administration.210 Because of the increased risk of cardiovascular events due to ibuprofen interference with the antiplatelet cardioprotective effects of aspirin, consider the use of an alternative NSAIA in patients receiving cardioprotective low-dose aspirin that does not interfere with the antiplatelet effects of aspirin, or the use of a non-NSAIA analgesic agent.210
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
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.210
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 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
Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAIA) that has pharmacologic actions similar to those of other prototypical NSAIAs.100,106 Ibuprofen demonstrates anti-inflammatory, antipyretic, and analgesic activity.106,210 The exact mechanisms of action of the drug have not been clearly established, but many of the actions appear to be associated with the inhibition of prostaglandin synthesis from arachidonic acid in a process mediated by the cyclooxygenase enzymes.100,106,210,1203 Prostaglandins are inflammatory mediators, and induce pain in animal models by sensitizing afferent nerves and potentiating the action of bradykinin.210 Ibuprofen, like other prototypical NSAIAs, inhibits both cyclooxygenase-1 (COX-1) and -2 (COX-2).210 In patients with primary dysmenorrhea, ibuprofen has reduced resting and active intrauterine pressure and the frequency of uterine contractions, probably as a result of inhibition of prostaglandin synthesis.100,106 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.100,106
In many premature neonates, administration of ibuprofen results in closure of the persistently patent ductus arteriosus, although the mechanism of action by which ibuprofen facilitates this effect is not known.198
Absorption of oral ibuprofen is rapid when administered in the fasting state.106 Peak plasma concentrations of ibuprofen are attained 1-2 hours after oral administration.100 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.100,106
Following oral administration of a 200-mg dose in adults or a 10-mg/kg dose in febrile children, peak plasma concentrations and plasma 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 Ibuprofen is dose proportional at oral dosages of 5 and 10 mg/kg in febrile children.106 In adults, single oral doses of up to 800 mg are dose proportional based on AUC.100 Above 800 mg, AUC increases are less than dose proportional.100 In children, pharmacokinetics (based on AUC and peak plasma concentrations) of IV ibuprofen are similar between children 3 months to <6 months of age and children 6 months to <2 years of age.106 Approximately 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
Plasma concentrations of ibuprofen appear to decline in a biphasic manner with a half-life of approximately 2 hours.106 The terminal elimination half-life of orally administered ibuprofen in children reportedly is similar to that in adults; 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 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, 1.8 hours in those 6 months to <2 years of age, and 1.3 hours in those 3 months to <6 months of a the volume of distribution and clearance increased with age.210
Ibuprofen is metabolized mainly via cytochrome P-450 (CYP) isoenzyme 2C9-mediated hydroxylation of R- and S-ibuprofen.198 The S-isomer is clinically active, while the R-isomer is considered clinically inactive and undergoes conversion to the active S-isomer.106 Approximately 10-15% of an ibuprofen dose is excreted renally.198 Excretion of ibuprofen is essentially complete within 24 hours following oral administration.106 Following oral administration of ibuprofen, approximately 80% of the dose is recovered in urine as the hydroxy- and carboxyl metabolites; ibuprofen undergoes further conjugation to acyl glucuronides.198 Metabolism and excretion of ibuprofen in premature neonates have not been evaluated.198 Renal function and enzymes associated with drug metabolism are underdeveloped in neonates at birth, and increase substantially in the days after birth.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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 400 mg* | IBU® | |
Ibuprofen Tablets | ||||
600 mg* | IBU® | |||
Ibuprofen Tablets | ||||
800 mg* | IBU® | |||
Ibuprofen Tablets | ||||
Oral Suspension | 20 mg/mL* | Ibuprofen Oral Suspension | ||
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
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 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 | ||
Ibuprofen and Famotidine Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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
100. Amneal Pharmaceuticals. Ibuprofen tablets prescribing information. Bridgewater, NJ; 2022 Feb.
106. Actavis Pharma. Ibuprofen oral suspension prescribing information. Parsippany, NJ; 2021 May.
161. Amneal Pharmaceuticals. Hydrocodone bitartrate and ibuprofen tablets prescribing information. Brookhaven, NY; 2024 Jan.
198. Recordati Rare Diseases. NeoProfen® (ibuprofen lysine) injection prescribing information. Lebanon, NJ; 2023 Oct.
210. Cumberland Pharmaceuticals. Caldolor® (ibuprofen) injection prescribing information. Nashville, TN; 2023 May.
216. Horizon Therapeutics. Duexis® (ibuprofen and famotidine) tablets prescribing information. Lake Forest, IL; 2021 Apr.
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