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ibuprofen 400 mg tablet (generic motrin)

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Uses

Ibuprofen is used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and osteoarthritis. Ibuprofen also is used orally to relieve mild to moderate pain and for the management of primary dysmenorrhea.

Ibuprofen has been used orally in the management of pericarditis.

Ibuprofen also may be used orally for self-medication for analgesic effects to provide temporary relief of minor aches and pains, including those of arthritis, and of dysmenorrhea and for its antipyretic effect to reduce fever.

Ibuprofen is used IV to relieve mild to moderate pain, to relieve moderate to severe pain (in conjunction with opiates), and to reduce fever.

Ibuprofen lysine is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates.

The potential benefits and risks of ibuprofen therapy as well as alternative therapies should be considered prior to initiating ibuprofen therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

Inflammatory Diseases

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

Ibuprofen is used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis. Ibuprofen is also used orally for anti-inflammatory and analgesic effects in the symptomatic treatment of nonarticular (e.g., muscular) inflammation.

When used in the treatment of rheumatoid arthritis, ibuprofen has relieved pain and stiffness, reduced swelling, and improved grip strength and joint flexion. The drug does not, however, alter the basic rheumatoid process. Most clinical studies have shown that the analgesic and anti-inflammatory effects of ibuprofen in the treatment of rheumatoid arthritis and/or osteoarthritis are greater than those of placebo, about equal to those of salicylates or indomethacin and less than those of phenylbutazone or prednisolone. Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent. However, NSAIAs generally are contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs. (See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., abatacept, adalimumab, anakinra, etanercept, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, rituximab, sulfasalazine) have the potential to reduce or prevent joint damage and to preserve joint integrity and function. DMARDs are used in conjunction with anti-inflammatory agents (i.e., NSAIAs, intra-articular and oral glucocorticoids) and physical and occupational therapies for the management of rheumatoid arthritis. DMARD therapy should be initiated early in the disease course to prevent irreversible joint damage. For further information on the treatment of rheumatoid arthritis, including considerations in selecting a DMARD regimen, .

Ibuprofen is used orally in the symptomatic management of juvenile rheumatoid arthritis. In a very limited number of patients with juvenile rheumatoid arthritis receiving alternate-day corticosteroid therapy, ibuprofen relieved joint stiffness when administered on the corticosteroid ''off'' day.

Other Inflammatory Conditions

Ibuprofen has been used with some success in other inflammatory diseases including ankylosing spondylitis, gout, and psoriatic arthritis.

Pericarditis

Ibuprofen has been used to reduce the pain, fever, and inflammation of pericarditis; however, in the treatment of post-myocardial infarction pericarditis, NSAIAs are potentially harmful and aspirin is considered the treatment of choice. (See Cautions: Cardiovascular Effects and Cautions: Precautions and Contraindications.)

Pain

Ibuprofen is used orally or IV for the relief of mild to moderate pain. Ibuprofen also may be used orally for self-medication for the temporary relief of minor aches and pains associated with the common cold, influenza, or sore throat; headache (including migraine); toothache; muscular aches; backache; and minor pain of arthritis.

Some experts state that an NSAIA (e.g., ibuprofen) is a reasonable first-line therapy for mild to moderate migraine attacks or for severe attacks that have responded in the past to similar NSAIAs or non-opiate analgesics. For further information on management and classification of migraine headache,

Ibuprofen has been used to relieve postoperative pain (including that associated with dental or orthopedic surgery or episiotomy). In the relief of postoperative pain, ibuprofen has been shown to be more effective than placebo or propoxyphene and at least as effective as aspirin.

Ibuprofen has been used IV in conjunction with opiates to relieve pain following abdominal hysterectomy, other abdominal surgical procedures, or orthopedic surgery.

The fixed-combination preparation containing ibuprofen and hydrocodone bitartrate is used in the short-term (less than 10 days) treatment of acute pain.

The fixed-combination preparation containing ibuprofen and oxycodone hydrochloride is used in the short-term (no more than 7 days) treatment of acute moderate to severe pain.

Dysmenorrhea

Ibuprofen is used orally for the relief of primary dysmenorrhea. Ibuprofen also may be used for self-medication for the relief of pain of menstrual cramps (dysmenorrhea). Ibuprofen has been used to relieve dysmenorrhea associated with insertion of an intrauterine contraceptive device.

When used to relieve dysmenorrhea, ibuprofen has been reported to be as effective as mefenamic acid and more effective than placebo, aspirin, or propoxyphene. 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.

Fever

Ibuprofen is used orally or IV to reduce fever. Ibuprofen also may be used orally for self-medication to reduce fever.

When used to lower body temperature in febrile children (6 months-12 years of age) with viral infections and temperatures of 39°C or less, single 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 10-mg/kg doses of ibuprofen were most effective.

Patent Ductus Arteriosus

Ibuprofen lysine is used IV in the treatment of patent ductus arteriosus (PDA) in premature neonates and is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition. The drug is used IV to promote closure of a clinically important PDA in premature neonates weighing 500-1500 g who are no more than 32 weeks' gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support) is ineffective. 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. Efficacy was determined by the need for rescue therapy (indomethacin, open-label ibuprofen, or surgery) for a hemodynamically important PDA through study day 14. Rescue therapy was indicated if the neonate developed a hemodynamically important PDA that was confirmed by echocardiograph. Rescue therapy was required by 25% of neonates receiving ibuprofen compared with 48% of those receiving placebo. 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. Use of the drug should be reserved for neonates with clinically important PDA.

Other Uses

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received a NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.

Dosage and Administration

Administration

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

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

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

For self-medication in pediatric patients, ibuprofen is commercially available as oral drops, an oral suspension, chewable tablets, and film-coated tablets. The calibrated dosing device provided by the manufacturer should be used by parents or caregivers for measurement of the dose of oral drops; the calibrated dosage cup provided by the manufacturer should be used by parents or caregivers for measurement of the dose of pediatric oral suspension. Ibuprofen oral drops generally are used in infants 6-23 months of age, the oral suspension commonly is used in children 2 years of age and older, the 50-mg chewable tablets may be used in children 2 years of age and older, and the 100-mg chewable tablets or 100-mg film-coated tablets may be used in children 6 years of age and older.

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

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). Ibuprofen doses are administered over 30 minutes or longer. Parenteral solutions of ibuprofen should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. The solution should not be used if opaque particles, discoloration, or other foreign particulate matter is present.

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. The drug should be administered using the IV port that is nearest to the IV insertion site. The dose should be infused over a period of 15 minutes. Care should be taken to avoid extravasation of the drug since it may be irritating to extravascular tissues. 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. Parenteral solutions of ibuprofen lysine should be inspected visually for particulate matter and/or discoloration prior to administration whenever solution and container permit. Ibuprofen lysine injection contains no preservatives and is intended for single use only; any unused portion should be discarded.

Dosage

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

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.

Dosage of ibuprofen lysine is expressed in terms of ibuprofen.

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 acute and chronic 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.

For the management of juvenile rheumatoid arthritis, the recommended ibuprofen oral dosage is 30-40 mg/kg daily divided into 3 or 4 doses. An ibuprofen dosage of 20 mg/kg daily in divided doses may be adequate for children with mild disease. Dosages exceeding 50 mg/kg daily are not recommended in children with juvenile arthritis, since such dosages have not been studied. In addition, dosages exceeding 40 mg/kg daily may increase the risk of drug-induced adverse effects. Optimum therapeutic response occurs from a few days to several weeks in children with juvenile rheumatoid arthritis.

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 mild to moderate pain, the usual initial 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. 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.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 relief of mild to moderate pain in children 6 months to 12 years of age, the recommended ibuprofen oral dosage is 10 mg/kg every 6-8 hours; the maximum dosage of ibuprofen is 40 mg/kg daily. For self-medication of minor aches and pains in pediatric patients, ibuprofen dosages should be calculated based on body weight rather than age whenever possible.(See Cautions: Pediatric Precautions.) 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 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. Parents and caregivers should be instructed to contact their clinician if minor aches and pain do not improve within 24 hours or if pain increases.Self-medication of pain in children should not exceed 3 days unless otherwise directed by a clinician.

For relief of pain, individuals 17 years of age or older may receive ibuprofen in a dosage of 400-800 mg IV every 6 hours as needed; ibuprofen dosage should not exceed 3.2 g in a 24-hour period.

When ibuprofen is used in fixed combination with hydrocodone bitartrate for short-term (generally less than 10 days) management of acute pain, the usual oral dosage is 200 mg of ibuprofen every 4-6 hours, as needed; ibuprofen dosage should not exceed 1 g in a 24-hour period.

When ibuprofen is used in fixed combination with oxycodone hydrochloride for short-term (not to exceed 7 days) management of acute pain, 400 mg of ibuprofen may be administered up to 4 times daily; ibuprofen dosage should not exceed 1.6 g in a 24-hour period.

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, the usual initial adult 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.

Fever

For antipyresis in children 6 months to 12 years of age, the usual oral dosage of ibuprofen is 5 or 10 mg/kg for temperatures below or above 39°C, respectively. The maximum daily dosage of ibuprofen in febrile children is 40 mg/kg.

For self-medication of fever in pediatric patients, ibuprofen dosages should be calculated based on body weight rather than age whenever possible.(See Cautions: Pediatric Precautions.) 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 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. Parents and caregivers should be instructed to contact their clinician if fever does not improve or worsens within 24 hours.Self-medication of fever in children should not exceed 3 days unless otherwise directed by a clinician.

For self-medication of fever, the usual initial adult 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. 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.Self-medication of fever should not exceed 3 days unless otherwise directed by a clinician.

For reduction of fever, individuals 17 years of age or older 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. Ibuprofen dosage should not exceed 3.2 g in a 24-hour period.

Patent Ductus Arteriosus

For the treatment of patent ductus arteriosus (PDA) in premature neonates, ibuprofen lysine is administered by IV infusion over 15 minutes. A course of therapy consists of 3 doses of ibuprofen lysine administered at 24-hour intervals. All doses are based on the neonate's birth weight. 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. 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. Subsequent doses are not necessary if the ductus arteriosus closes or is substantially constricted after completion of the first course of ibuprofen therapy. If the ductus fails to close or reopens, a second course of ibuprofen, alternative pharmacologic therapy, or surgery may be needed.

Cautions

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, and hypotension 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.

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. Use of NSAIAs also is associated with an increased risk of heart failure.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. 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 information 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. 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. 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.

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. 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). 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.

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. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

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. 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. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. 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. 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. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

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

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. Gastroesophageal reflux, gastritis, ileus, GI perforation, and necrotizing enterocolitis also have occurred, although a causal relationship to the drug has not been established.

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).

The risk of GI bleeding is increased in geriatric patients older than 60 years of age and in patients with a history of GI ulcers or bleeding, those receiving an anticoagulant or taking multiple NSAIAs concomitantly, those consuming 3 or more alcohol-containing beverages daily, and those receiving prolonged therapy.

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 adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. 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. 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. 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.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic 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. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. 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. 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.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. 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 or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. 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.

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. 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. 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. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. 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. 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. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

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, and has recurred upon rechallenge with the drug. 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. Other associated manifestations have included GI symptoms (e.g., nausea, vomiting, abdominal pain), transient conjunctivitis, CNS signs (e.g., confusion, combativeness, lethargy, headache), and hypotension. 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.

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

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 hepatic reactions (sometimes fatal) including jaundice and hepatitis have occurred rarely during ibuprofen therapy. A transitory rise in serum AST (SGOT), ALT (SGPT), and serum alkaline phosphatase has occurred in a few patients during 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 less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Ibuprofen should be discontinued if signs or symptoms of a severe hepatic reaction occur. (See Cautions: Precautions and Contraindications.)

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.

Dermatologic Effects

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.

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

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). 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. 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. Neutropenia and thrombocytopenia also have occurred, although a causal relationship to the drug has not been established.

Renal Effects

Acute renal failure has been reported in patients receiving ibuprofen and may be accompanied by acute tubular necrosis. 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 Cautions: Precautions and Contraindications) 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, 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.

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. Reversible decreases in urine output have occurred in premature neonates receiving ibuprofen therapy for PDA. Urine output usually decreases during the first 2-6 days of life; this is followed by a compensatory increase in output by day 9.

Other Adverse Effects

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. Although a causal relationship has not been established, serum sickness, lupus erythematosus syndrome, Henoch-Schonlein vasculitis, and angioedema have also been reported during therapy with the drug.

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. 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.

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. When preparations containing ibuprofen in combination with other drugs are used, the precautions and contraindications associated with each ingredient also must be considered. Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain. Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without a NSAIA may represent an acceptable alternative to both the patient and clinician.

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

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. 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. 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.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving an NSAIA should be advised not to take aspirin.

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. 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. NSAIAs should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.

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. 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. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. 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).(See Drug Interactions.)

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).

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

NSAIAs should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or GI bleeding. To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.

Ibuprofen lysine is contraindicated in premature neonates with suspected necrotizing enterocolitis.

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.

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. Clinicians should be alert to the masking effect of the drug in these neonates. The drug is contraindicated in neonates with proven or suspected, untreated infection.

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.

Premature neonates receiving ibuprofen lysine should be observed closely for bleeding tendencies. 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.

Patients receiving ibuprofen forself-medicationshould be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy. Unless otherwise directed by a clinician, patients receiving ibuprofen for self-medication should be advised to discontinue the drug and consult a clinician if pain persists for more than 10 days in adults or 3 days in children or fever persists for longer than 3 days. 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. Patients receiving the drug for self-medication also 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 a GI disorder, coagulation disorder, hypertension, cardiac disease, or renal disease; if they are receiving therapy with a diuretic; or if they are 60 years of age or older. 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; they are receiving an anticoagulant, a corticosteroid, or any other NSAIA-containing preparation; or they are taking any other drugs on a regular basis. They also should be advised to stop taking the drug and to report to their clinician symptoms of GI bleeding (faintness, vomiting blood, bloody or black stools); any new, unusual, or unexpected symptoms that occur during self-medication with the drug; if pain or fever gets worse during therapy; or if stomach pain intensifies or persists with use of the drug. 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, if they generally consume 3 or more alcohol-containing drinks per day, or if they exceed the recommended dosage or duration of ibuprofen therapy. In addition, patients should be advised that NSAIAs may increase the risk of a cardiovascular event. For additional information on use of ibuprofen for self-medication in children, see Pediatric Precautions.

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 3 or 6 mg of phenylalanine for each 50- or 100-mg tablet, respectively, following oral administration and that Advil Children's chewable tablets and Advil Junior Strength chewable tablets contain aspartame, which is metabolized to provide 2.1 and 4.2 mg of phenylalanine for each tablet, respectively. Diabetic patients should be warned that some commercially available preparations of ibuprofen may contain sucrose.

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.

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. 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. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Some clinicians recommend that renal function be monitored periodically in all patients receiving long-term NSAIA therapy, but other clinicians question the cost-effectiveness of this recommendation and instead recommend selective monitoring in patients considered at risk.

The manufacturers state that ibuprofen should be used with caution and close monitoring in patients with substantial renal impairment, since the drug and its metabolites are eliminated principally by the kidneys. To avoid excessive accumulation of the drug, the manufacturers recommend that decreased dosages of ibuprofen be considered in these patients. The safety of ibuprofen in patients with chronic renal failure has not been established.

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

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. Although such reactions are rare, ibuprofen should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).

Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration, and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during ibuprofen therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.

Ibuprofen can interfere with the antiplatelet effect of low-dose aspirin. 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.(See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Anaphylactoid reactions have been reported in patients receiving NSAIAs. 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.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs. 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. NSAIAs should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Ibuprofen is contraindicated in patients with known hypersensitivity to the drug. 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. 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, NSAIAs should be used with caution in patients with asthma. 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. 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. For further discussion of cross-sensitivity of NSAIAs,

NSAIAs are contraindicated in the setting of CABG surgery.

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. 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. 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 a GI disorder, coagulation disorder, hypertension, cardiac disease, or renal disease or is receiving therapy with a diuretic; or if dehydration associated with vomiting, diarrhea, or lack of fluid intake has occurred. 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; is receiving an anticoagulant, a corticosteroid, or any other NSAIA-containing preparation; or is taking any other drugs on a regular basis. Ibuprofen self-medication should be discontinued and a clinician should be contacted if symptoms of GI bleeding (faintness, vomiting blood, bloody or black stools) develop; if any new, unusual, or unexpected symptoms occur during self-medication with the drug; if pain or fever gets worse during therapy or lasts more than 3 days; if no relief is observed within the first 24 hours of therapy; or if stomach pain intensifies or persists with use of the drug. In addition, a clinician should be contacted if the child experiences severe sore throat, if a sore throat of more than 2 days' duration occurs, or if sore throat is associated with fever, headache, rash, nausea, or vomiting. 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. Ibuprofen should not be used for self-medication in children for longer than 10 days unless directed by a clinician.

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. 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.

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. Such preparations also may contain analgesics and antipyretics. There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by the US Food and Drug Administration [FDA]) have not been established. Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of age; 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,

Safety and efficacy of IV ibuprofen for relief of pain or reduction of fever have not been established in pediatric patients younger than 17 years of age.

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. 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.

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. 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).

Geriatric Precautions

Geriatric individuals appear to tolerate GI ulceration and bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.

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. 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.

Pregnancy and Lactation

Pregnancy

Although animal reproduction studies have not demonstrated any teratogenic effects, the safe use of ibuprofen during pregnancy has not been established. Ibuprofen inhibits prostaglandin synthesis and release, which may cause dystocia, interfere with labor, and delay parturition. Inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus). Use of ibuprofen is not recommended during pregnancy (especially during the last trimester) or during labor and delivery.

Lactation

Although ibuprofen has not been reported to distribute into milk in lactating women, the manufacturers state that use of the drug in nursing women is not recommended because of the potential risk of inhibitors of prostaglandin synthesis in neonates.

Drug Interactions

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic. Concomitant use of an NSAIA and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.

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 if the drug is used concomitantly with any anticoagulant (e.g., warfarin) or thrombolytic agent (e.g., streptokinase).

Nonsteroidal Anti-inflammatory Agents

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. In addition, concomitant administration of ibuprofen and salicylates, phenylbutazone, indomethacin, or other NSAIAs could potentiate the adverse GI effects of these drugs, and thus ibuprofen probably should not be administered with these agents.

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving an NSAIA should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

Some NSAIAs (e.g., ibuprofen, naproxen) can interfere with the antiplatelet effect of low-dose aspirin. 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. 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. 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. The US Food and Drug Administration (FDA) recommends 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. Data currently are insufficient to support recommendations regarding the timing of ibuprofen administration relative to that of enteric-coated, low-dose aspirin. The occasional use of ibuprofen is likely to be associated with minimal risk of attenuating the effects of low-dose aspirin. 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.

Lithium

Ibuprofen has been reported to increase plasma or serum lithium concentrations by 12-67% and to reduce renal lithium clearance. 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. Some clinicians recommend that patients receiving lithium should not receive ibuprofen. 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. Dosage of lithium may have to be reduced in some patients; appropriate adjustment of lithium dosage may be required when therapy with ibuprofen is discontinued.

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of drugs that inhibit prostaglandin synthesis, including ibuprofen, may reduce the blood pressure response to angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) and angiotensin II receptor antagonists. Limited data indicate that concomitant use of NSAIAs with ACE inhibitors occasionally may result in acute reductions in renal function; however, the possibility cannot be ruled out that one of the drugs alone may cause such an effect. Blood pressure should be monitored carefully when an NSAIA is initiated in patients receiving an ACE inhibitor or angiotensin II receptor antagonist; in addition, clinicians should be alert for evidence of impaired renal function.

Diuretics

NSAIAs may reduce the natriuretic effect of furosemide or thiazide diuretics. This effect may be related to inhibition of renal prostaglandin synthesis. Patients receiving concomitant NSAIA and diuretic therapy should be monitored for signs of renal failure and for efficacy of the diuretic.

Methotrexate

Because of the possibility of enhanced toxicity of methotrexate, caution is advised if methotrexate and an NSAIA are administered concomitantly.

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 tablets, chewable tablets, or suspension are taken with food; however, the extent of absorption is not affected. 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. Absorption of ibuprofen does not appear to be affected by concomitant administration of antacids containing aluminum hydroxide or magnesium hydroxide.

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. 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. 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. 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. 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. 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. Following oral administration of ibuprofen suspension in febrile children, AUCs increase with increasing single ibuprofen doses up to 10 mg/kg; it appears that pharmacokinetics of ibuprofen are not affected by age, in children 2 to 11 years of age.

In children, the antipyretic effect of ibuprofen suspension begins within 1 hour after oral administration and peaks within 2-4 hours. The antipyretic effect of single ibuprofen suspension doses of 5 or 10-mg/kg may last up to 6 or 8 hours, respectively. 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. The antipyretic effects of conventional ibuprofen tablets have not been studied in children. 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.

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; however, the clinical importance of this difference is not known. In one study in premature neonates receiving IV ibuprofen lysine, the volume of distribution of ibuprofen at birth averaged 0.32 L/kg. 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. 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. The terminal elimination half-life in children reportedly is similar to that in adults; however, total clearance may be affected by age or fever. It has been suggested that changes in total clearance may result from changes in the volume of distribution in febrile children. 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. 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. The terminal elimination half-life is at least tenfold longer in premature neonates than in adults.

Ibuprofen is metabolized via oxidation to form 2 inactive metabolites, (+)-2[4'-(2-hydroxy-2-methylpropyl)phenyl]propionic acid (metabolite A) and (+)-2-[4'-(2-carboxypropyl)phenyl]propionic acid (metabolite B). About 50-60% of an oral dose is excreted in urine as metabolites A and B or their glucuronide conjugates within 24 hours. Less than 10% of the drug is excreted in urine unchanged; the remainder of the drug is eliminated in feces, both as metabolites and unabsorbed drug. 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.

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