WARNINGS
Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy. Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
Anaphylactoid Reactions: Anaphylactoid reactions may occur even in patients without prior exposure to ibuprofen. Extreme caution should be exercised when giving MOTRIN to patients with bronchospastic reactivity (e.g., asthma), nasal polyps, or those with a history of angiodema. Emergency help should be sought in case such anaphylactoid reaction occurs. Advanced Renal Disease: In cases with advanced kidney disease, treatment with MOTRIN should not be initiated; if MOTRIN is used in such cases, close monitoring of the patient's kidney functions is advisable (see PRECAUTIONS --Renal Effects).
PRECAUTIONS
Renal Effects: Caution should be used when initiating treatment with MOTRIN in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with MOTRIN. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS --Advanced Renal Disease).
As with other NSAIDs, long-term administration of ibuprofen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pre-treatment state.
Those patients at high risk, who chronically take ibuprofen, should have renal function monitored if they have signs or symptoms which may be consistent with mild azotemia, such as malaise, fatigue, loss of appetite, etc. Occasional patients may develop some elevation of serum creatinine and BUN levels without signs or symptoms.
Since ibuprofen is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored and a reduction in dosage should be anticipated to avoid drug accumulation. Prospective studies on the safety of ibuprofen in patients with chronic renal failure have not been conducted. Fluid Retention: Fluid retention and edema have been reported in association with ibuprofen, therefore, the drug should be used with caution in patients with a history of cardiac decompensation or hypertension.
Hematologic Effects: MOTRIN can inhibit platelet aggregation but, unlike aspirin, its effect on platelet function is reversible, quantitatively less, and of shorter duration. Because this prolonged bleeding effect may be exaggerated in patients with underlying hemostatic defects, MOTRIN should be used with caution in persons with intrinsic coagulation defects and those on anticoagulant therapy.
Hepatic Effects: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver laboratory tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The ALT (SGPT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of ALT and AST (SGOT) occurred in controlled clinical trials in less than 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reactions while on therapy with MOTRIN. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with ibuprofen as with other nonsteroidal anti-inflammatory drugs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), treatment with MOTRIN should be discontinued. Aseptic Meningitis: Aseptic meningitis, with fever and coma, has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient receiving MOTRIN, the possibility of its being related to ibuprofen should be considered. Other Precautions-- The pharmacological activity of MOTRIN may induce reduction of fever and inflammation, thus diminishing their utility as diagnostic signs in detecting underlying conditions.
In order to avoid exacerbation of manifestations of adrenal insufficiency, patients who have been on prolonged corticosteroid therapy should have their therapy tapered slowly rather than discontinued abruptly when ibuprofen is added to the treatment program.
Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. If a patient develops such complaints while receiving MOTRIN Chewable Tablets, the drug should be discontinued and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.
Phenylketonurics: MOTRIN Chewable Tablets 50 mg contain phenylalanine 3 mg per tablet, and the 100 mg tablets contain phenylalanine 6 mg per tablet.
Diabetics: MOTRIN Suspension and MOTRIN Oral Drops contain 0.3 g sucrose and 1.6 calories per mL, or 1.5 g sucrose and 8 calories per teaspoon, which should be taken into consideration when treating diabetic patients with this product.
Information for Patients-- MOTRIN, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.
NSAIDs are often essential agents in the management of arthritis, pain and fever, but they also may be commonly employed for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Patients on MOTRIN should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, blurred vision or other eye symptoms, skin rash, weight gain, or edema.
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS).
Patients should also be instructed to seek medical emergency help in case of an occurrence of an anaphylactoid reaction (see WARNINGS).
LABORATORY TESTS
Hemoglobin Levels: In cross-study comparisons, in adults, with doses ranging from 1200 mg to 3200 mg daily for several weeks, a slight dose-response decrease in hemoglobin/hematocrit was noted. This has been observed with other nonsteroidal anti-inflammatory drugs; the mechanism is unknown. However, even with daily doses of 3200 mg, the total decrease in hemoglobin usually does not exceed 1 g/dL; if there are no signs of bleeding, it is probably not clinically important.
In two postmarketing clinical studies with ibuprofen, the incidence of a decreased hemoglobin level was greater than previously reported. Decrease in hemoglobin of 1 g/dL or more was observed in 17.1% of 193 patients on 1600 mg ibuprofen daily (osteoarthritis), and 22.8% of 189 patients taking 2400mg of ibuprofen daily (rheumatoid arthritis). Positive stool occult blood tests and elevated serum creatinine levels were also observed in these studies.
DRUG INTERACTIONS
Coumarin-type anticoagulants: Several short-term controlled studies failed to show that iburprofen significantly affected prothrombin times or a variety of other clotting factors administered to individuals on coumarin-type anticoagulants. Because bleeding has been reported when ibuprofen and other nonsteroidal anti-inflammatory agents have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering MOTRIN to patients on anticoagulants. Aspirin: Animal studies show that aspirin given with NSAIDs, including ibuprofen, yields a net decrease in anti-inflammatory activity with lowered blood levels of the non-aspirin drug. Single-dose bioavailability studies in normal volunteers have failed to show an effect of aspirin on ibuprofen blood levels. Correlative clinical studies have not been done. Methotrexate: Ibuprofen, as well as other NSAIDs, has been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that ibuprofen could enhance the toxicity of methotrexate. Caution should be used, therefore, if MOTRIN is administered concomitantly with methotrexate.
H-2 Antagonists: In studies with human volunteers, coadministration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations. ACE-inhibitors: Reports suggest that NSAIDs, including ibuprofen, may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking MOTRIN concomitantly with ACE-inhibitors. Furosemide: Clinical studies, as well as random observations, have shown that ibuprofen can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with MOTRIN, the patient should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as to assure diuretic efficacy.
Lithium: Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when MOTRIN and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.)
Teratogenic Effects--Pregnancy Category B: Reproductive studies conducted in rats and rabbits at doses somewhat less than the maximal clinical dose did not demonstrate evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. As there are no adequate and well-controlled studies in pregnant women, this drug should be used during pregnancy only if clearly needed. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided. Administration of MOTRIN is not recommended during pregnancy.
Labor and Delivery: As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats. Administration of MOTRIN is not recommended during labor and delivery.
Nursing Mothers: In limited studies, an assay capable of detecting 1 µg/mL did not demonstrate ibuprofen in the milk of lactating mothers. Because of the limited nature of these studies, however, and the possible adverse effects of prostaglandin inhibiting drugs on neonates, MOTRIN is not recommended for use in nursing mothers. Pediatric Use: Safety and efficacy of MOTRIN in children below the age of 6 months has not been established (see CLINICAL PHARMACOLOGY -Clinical Studies). There is no evidence of age-dependent kinetics in patients 2 to 11 years old (see CLINICAL PHARMACOLOGY -Pharmacokinetics). Dosing of MOTRIN in children 6 months or older should be guided by their body weight (see DOSAGE AND ADMINISTRATION).
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