Motrin (Ibuprofen)

MOTRIN®

Pharmacia & Upjohn

Ibuprofen

Anti-inflammatory – Analgesic – Antipyretic

Action And Clinical Pharmacology: Ibuprofen has demonstrated anti-inflammatory, analgesic and antipyretic activity in animal studies designed to specifically demonstrate these effects. Its mode of action, like that of other nonsteroidal anti-inflammatory agents, is not completely understood, but may be related to prostaglandin synthetase inhibition. Ibuprofen does not alter the course of the underlying disease. Ibuprofen has no demonstrable glucocorticoid effect.

Ibuprofen has been found to be less likely to cause gastrointestinal bleeding in doses usually used than is ASA.

Clinical trials in man have shown that a daily dose of 1 200 to 1 800 mg of ibuprofen is comparable in activity, to a daily dose of 3.6 g of ASA.

Pharmacokinetics: Following a single 200 mg dose of ibuprofen in humans, blood levels were demonstrable in 45 minutes and still present in 6 hours but at barely detectable levels. Peak serum iduprofen levels are generally attained 1 to 1.5 hours after administration of an ibuprofen tablet.

When ibuprofen is administered immediately after a meal, there is a reduction in the rate of absorption but no appreciable decrease in the extent of absorption.

Ibuprofen is extensively bound (99%) to human serum albumin. Approximately 15% of the primary binding sites were estimated to be occupied at therapeutic drug concentrations. Studies suggest that ibuprofen binds to a single binding site on the albumin molecule.

Ibuprofen is rapidly metabolized and eliminated in the urine. The excretion of ibuprofen is virtually complete in 24 hours after the last dose. The serum half-life is 1.8 to 2.0 hours. There is no evidence of drug accumulation or enzyme induction.

The pharmacokinetic parameters presented in Table I are representative of parameters obtained in bioavailability studies using ibuprofen tablets.

Pharmacokinetics in the Elderly: Studies have shown no statistically significant differences in pharmacokinetic parameters between elderly and young women treated with ibuprofen. In elderly males, however, a significant prolongation of ibuprofen half-life and a decrease in weight corrected total metabolic clearance has been reported. The clinical significance of these findings has not been established since the half-life of ibuprofen exceeded 3 hours in only 1 individual.

Indications And Clinical Uses: The treatment of rheumatoid arthritis and osteoarthritis.

The relief of mild to moderate pain accompanied by inflammation, in conditions such as musculoskeletal trauma and post dental extraction.

The relief of pain associated with dysmenorrhea.

Contra-Indications: Should not be used in patients who have peptic ulcer or active inflammatory disease of the gastrointestinal system. Should not be used in patients who have previously exhibited hypersensitivity to the drug, or in individuals with the syndrome of nasal polyps, bronchospastic reactivity and angioedema to ASA, ibuprofen or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals.

Manufacturers’ Warnings In Clinical States: Ulceration, perforation and bleeding of the stomach, small intestine or large intestine, sometimes severe and occasionally fatal have been reported during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen.

Should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including ibuprofen should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).

Pregnancy: Reproductive studies conducted in rats and rabbits at doses somewhat less than the maximal clinical dose did not demonstrate evidence of developmental abnormalities. As there are no adequate data concerning use in pregnant women, and because of the known effects of NSAIDs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided. As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats. Administration of ibuprofen is not recommended during pregnancy.

Lactation: In limited studies, an assay capable of detecting 1 g/mL did not demonstrate ibuprofen in the milk of lactating mothers. However, because of the limited nature of the studies, and the possible adverse effects of prostaglandin-inhibiting drugs on neonates, ibuprofen is not recommended for use in nursing mothers.

Children: Controlled clinical trials to establish the safety and efficacy of ibuprofen in children have not been conducted; therefore, the use of ibuprofen is not recommended in children under 12 years of age.

Pre-existing Asthma: About 10% of patients with asthma may have ASA-sensitive asthma. The use of ASA in patients with ASA-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between ASA and other NSAIDs has been reported in such ASA-sensitive patients, ibuprofen should not be administered to patients with this form of ASA-sensitivity and should be used with caution in all patients with pre-existing asthma.

Precautions: Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, ibuprofen should be discontinued, an appropriate treatment instituted and the patient closely monitored.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of therapy when and if these adverse reactions appear.

Renal Function: 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 pre-renal conditions leading to a reduction in renal blood flow or volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of NSAIDs 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 usually followed by recovery to the pretreatment state.

Glomerular filtration rate and renal blood flow decreased in patients with mild impairment of renal function who took 1 200 mg of ibuprofen for 1 week.

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.

During long-term therapy, kidney function should be monitored periodically, particularly in those patients at high risk for developing renal dysfunction.

Hepatic: As with other NSAIDs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other NSAIDs. 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.) ibuprofen should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If ibuprofen is to be used in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in association with ibuprofen. Therefore, as with many other NSAIDs the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Ibuprofen should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

Serum electrolytes should be monitored periodically during-long-term therapy, especially in those patients at risk.

Hematology: Ibuprofen, (like other nonsteroidal anti-inflammatory agents), can inhibit platelet aggregation but the effect is quantitatively less and of shorter duration than that seen with ASA. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal subjects. This prolonged bleeding effect may be exaggerated in patients with underlying hemostatic defects. The safety of ibuprofen in combination with anticoagulants has not been established, and if such use is necessary, special caution should be used.

Blood dyscrasias associated with the use of NSAIDs are rare, but could be with severe consequences.

Infection: The anti-inflammatory, antipyretic and analgesic effects may mask the usual signs of infection and the physician should be alert to the development of infection in patients receiving the drug. Aseptic meningitis has been reported in connection with ibuprofen therapy in patients with systemic lupus erythematosus. Such patients may also develop a hypersensitivity reaction to ibuprofen such as fever, rash or abnormal liver function more often than those with other disorders. Caution should therefore be exercised when considering ibuprofen therapy for patients with systemic lupus erythematosus.

When ibuprofen is added to the treatment program of patients who have been on prolonged corticosteroid therapy, and it is decided to discontinue this therapy, the corticosteroid should be tapered slowly to avoid exacerbation of the disease or adrenal insufficiency.

Ophthalmology: Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported. Any patient who develops eye complaints while receiving ibuprofen should discontinue the drug and have an ophthalmologic examination. Ophthalmic examinations should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Elderly: Should be used with caution in the elderly, and the dosage should be adjusted individually.

Drug Interactions: ASA: Animal studies show that ASA given with nonsteroidal anti-inflammatory agents including ibuprofen yield a net decrease in anti-inflammatory activity with lowered blood levels of the non-ASA drug. Although correlative clinical studies have not been done, the use of ASA as an analgesic in patients stabilized on ibuprofen is questioned on pharmacokinetic grounds. While single dose bioavailability studies in normal volunteers have failed to show an effect of ASA on ibuprofen blood levels, multiple dose studies show that ibuprofen serum levels are decreased by 50% when given in conjunction with ASA.

Coumarin-type Anticoagulants: Several short-term controlled studies failed to show that ibuprofen significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, 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 the drug to patients on anticoagulants.

Furosemide: Ibuprofen antagonizes the action of i.v. or oral furosemide.

Antihypertensives: In 12 patients with essential hypertension taking at least 2 antihypertensive drugs and ibuprofen 400 mg every 8 hours, a mean increase in blood pressure after 3 weeks’ treatment was noted as compared to placebo. Ibuprofen could interfere with blood pressure control in certain patients with treated mild-to-moderate hypertension.

Antacids: A bioavailability study has shown that there was no interference with the absorption of ibuprofen when given in conjunction with an antacid containing both aluminum hydroxide and magnesium hydroxide.

Methotrexate: Ibuprofen and other NSAIDs have been reported to reduce renal tubular secretion of methotrexate in vitro. This may enhance the toxicity of methotrexate. Caution should be used if ibuprofen is administered concomitantly with methotrexate.

Lithium: Plasma lithium levels should be carefully monitored in patients taking combination therapy of ibuprofen and lithium. Ibuprofen has been shown to increase plasma lithium levels and to decrease renal lithium clearance.

Gold Salts/Corticosteroids: Ibuprofen can be used in combination with gold salts and/or corticosteroids.

Protein Binding: Ibuprofen is extensively bound (99%) to human serum albumin. Approximately 15% of the primary binding sites were estimated to be occupied at therapeutic drug concentrations. Studies suggest that ibuprofen binds to a single binding site on the albumin molecule. Although drugs such as anticoagulants, sulfonamides and phenytoin do not bind to this site on albumin, patients receiving such combination therapy should be monitored.

Adverse Reactions: The most frequently encountered adverse reactions ocurring with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly. In controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints ranged from 4 to 16%.

In 2 postmarketing clinical studies, the incidence of a decreased hemoglobin level was greater than previously reported. Decrease in hemoglobin of 1 g or more was observed in 17.1% of 193 patients on 1 600 mg ibuprofen daily (osteoarthritis), and in 22.8% of 189 patients taking 2 400 mg of ibuprofen daily (rheumatoid arthritis). Positive stool occult blood tests, anemia, and elevated serum creatinine levels were also observed in these studies.

The occurrence rates for adverse reactions are as follows:

Gastrointestinal (4 to 16%): 3 to 9%: nausea, epigastric pain, heartburn; 1 to 3%: diarrhea, abdominal cramps or pain, fullness of the gastrointestinal tract (bloating or flatulence); Less than 1%: gastric or duodenal ulcers with bleeding and/or perforation, gastritis, gastrointestinal hemorrhage, melena (see Warnings).

Allergic (less than 1%): anaphylaxis, (see Contraindications) syndrome of abdominal pain, fever, chills, nausea, vomiting, bronchospasm, serum sickness, lupus erythematosus syndrome and Henoch-Schölein vasculitis.

CNS (4 to 13%): 3 to 9%: dizziness; 1 to 3%: headache, nervousness; less than 1%: depression, insomnia, confusion, emotional lability, somnolence, aseptic meningitis with fever and coma (probably more common in patients with systemic lupus erythematosus and related connective tissue disease). Causal relationship unknown: paresthesia, hallucinations, dream abnormalities and pseudo-tumor cerebri.

Dermatologic (4 to 13%): 3 to 9%: rash (including maculopapular type); 1 to 3%: pruritus; less than 1%: vesiculobullous eruptions, urticaria, erythema multiforme, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis and photoallergic skin reactions.

Cardiovascular (less than 1%): congestive heart failure in patients with marginal cardiac function, elevated blood pressure and palpitations. Causal relationship unknown: arrhythmias (sinus tachycardia, sinus bradycardia).

Special Senses (2 to 4%): 1 to 3%: tinnitus; less than 1%: amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision) (see Precautions) and hearing loss; causal relationship unknown: conjunctivitis, diplopia, optic neuritis.

Hematologic (1 to 20%): 1 to 20%: decrease in hemoglobin (by 1 g or more) and hematocrit; 3 to 9%: anemia; less than 1%: leukopenia, hemolytic anemia (sometimes coombs positive), thrombocytopenia (with or without purpura), neutropenia, agranulocytosis, aplastic anemia and eosinophilia; causal relationship unknown: bleeding episodes (e.g., epistaxis, menorrhagia).

Renal (1 to 9%): 3 to 9%: decreased creatinine clearance; less than 1%: acute renal failure in patients with pre-existing significantly impaired renal function, cystitis, hematuria, polyuria, azotemia and interstitial nephritis, nephrotic syndrome and renal papillary necrosis.

Hepatic (less than 1%): hepatitis, jaundice, abnormal liver function [AST, serum bilirubin and alkaline phosphatase].

Metabolic (1 to 3%): decreased appetite, edema, fluid retention (see Precautions).

Endocrine (less than 1%): Causal relationship unknown: gynecomastia, hypoglycemic reaction.

Miscellaneous (less than 1%): dry eyes and mouth, gingival ulcer and rhinitis. Causal relationship unknown: pancreatitis.

Rare events are derived principally from worldwide marketing experience and the literature. Accurate rate estimates are generally impossible. These include the following: colitis, exacerbation of inflammatory bowel disease, perforation of the colon, inflammation of the small intestine with loss of blood and protein, collagenous colitis, small bowel perforation, ulcer or stricture, complications of colonic diverticula (perforation, fistula).

Symptoms And Treatment Of Overdose: Symptoms: A nineteen-month-old child weighing 12 kg ingested from 2 800 to 4 000 mg and presented with apnea, cyanosis and responded only to painful stimuli. Oxygen and parenteral fluids were given and at 12 hours she appeared completely recovered. Two other children (10 kg each) ingested 1 200 mg of ibuprofen each and there were no signs of acute intoxication or late sequelae. A 19-year-old male who had ingested 8 000 mg of ibuprofen reported dizziness, and nystagmus was noted. He recovered with no reported sequelae after parenteral hydration and 3 days’ bed rest.

Treatment: In cases of acute overdosage, the stomach should be emptied by vomiting or lavage, though little drug will likely be recovered if more than an hour has elapsed since ingestion. Because the drug is acidic and is excreted in the urine, it is theoretically beneficial to administer alkali and induce diuresis.

Dosage And Administration: Rheumatoid arthritis and osteoarthritis: The initial daily dosage in adults is 1 200 mg divided into 3 or 4 equal doses. Depending on the therapeutic response, the dose may be adjusted downward or upward. The daily dosage should not exceed 2 400 mg.

Maintenance therapy, once maximum response is obtained, will range from 800 to 1 200 mg per day.

Mild to moderate pain accompanied by inflammation or dysmenorrhea: 400 mg repeated as required every 4 to 6 hours. The daily dosage should not exceed 2 400 mg.

Children: Due to the lack of clinical experience, ibuprofen is not indicated for use in children under 12 years of age.

Availability And Storage: 300 mg: Each white, film-coated tablet contains: ibuprofen 300 mg. Nonmedicinal ingredients: branding ink, carnauba wax, cornstarch, hydroxymethylcellulose, pregelatinized starch, propylene glycol, silicon dioxide and stearic acid. Gluten- and lactose-free. Bottles of 100.

400 mg: Each orange, film-coated tablet, branded “MOTRIN 400 MG” contains: ibuprofen 400 mg. Nonmedicinal ingredients: carnauba wax, cornstarch, hydroxymethylcellulose, pregelatinized starch, opaspray dark orange, propylene glycol, silicon dioxide and stearic acid. Gluten- and lactose-free. Bottles of 100 and 1 000.

600 mg: Each peach, film-coated tablet, branded “MOTRIN 600 MG” contains: ibuprofen 600 mg. Nonmedicinal ingredients: carnauba wax, cornstarch, hydroxymethylcellulose, pregelatinized starch, opaspray orange, propylene glycol, silicon dioxide and stearic acid. Gluten- and lactose-free. Bottles of 100 and 1 000. (Shown in Product Recognition Section)

MOTRIN® Pharmacia & Upjohn Ibuprofen Anti-inflammatory – Analgesic – Antipyretic

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