Ketoprofen

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of ketoprofen extended-release capsules before deciding to use ketoprofen extended-release capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Ketoprofen extended-release capsules are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Ketoprofen extended-release capsules are not recommended for treatment of acute pain because of its extended-release characteristics (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ketoprofen extended-release capsules and other treatment options before deciding to use ketoprofen extended-release capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with ketoprofen extended-release capsules, the dose and frequency should be adjusted to suit an individual patient’s needs. Concomitant use of ketoprofen extended-release capsules is not recommended. If minor side effects appear, they may disappear at a lower dose which may still have an adequate therapeutic effect. If well tolerated but not optimally effective, the dosage may be increased. Individual patients may show a better response to 300 mg of ketoprofen capsules daily as compared to 200 mg, although in well-controlled clinical trials patients on 300 mg did not show greater mean effectiveness. They did, however, show an increased frequency of upper- and lower-GI distress and headaches. It is of interest that women also had an increased frequency of these adverse effects compared to men. When treating patients with 300 mg/day, the physician should observe sufficient increased clinical benefit to offset potential increased risk. In patients with mildly impaired renal function, the maximum recommended total daily dose of ketoprofen extended-release capsules is 150 mg. In patients with a more severe renal impairment (GFR less than 25 mL/min/1.73 m 2 or end-stage renal impairment), the maximum total daily dose of ketoprofen extended-release capsules should not exceed 100 mg. In elderly patients, renal function may be reduced with apparently normal serum creatinine and/or BUN levels. Therefore, it is recommended that the initial dosage of ketoprofen extended-release capsules should be reduced for patients over 75 years of age (see PRECAUTIONS: Geriatric Use ). It is recommended that for patients with impaired liver function and serum albumin concentration less than 3.5 g/dL, the maximum initial total daily dose of ketoprofen extended-release capsules should be 100 mg. All patients with metabolic impairment, particularly those with both hypoalbuminemia and reduced renal function, may have increased levels of free (biologically active) ketoprofen and should be closely monitored. The dosage may be increased to the range recommended for the general population, if necessary, only after good individual tolerance has been ascertained. Because hypoalbuminemia and reduced renal function both increase the fraction of free drug (biologically active form), patients who have both conditions may be at greater risk of adverse effects. Therefore, it is recommended that such patients also be started on lower doses of ketoprofen extended-release capsules and closely monitored. Rheumatoid Arthritis and Osteoarthritis The recommended starting dose of ketoprofen in otherwise healthy patients is for ketoprofen extended-release capsules 200 mg administered once a day. Smaller doses of ketoprofen extended-release capsules should be utilized initially in small individuals, or in debilitated or elderly patients. The recommended maximum daily dose of ketoprofen is 200 mg/day for ketoprofen extended-release capsules. Dosages higher than 200 mg/day of ketoprofen extended-release capsules are not recommended because they have not been studied. Concomitant use of ketoprofen extended-release capsules is not recommended. Relatively smaller people may need smaller doses. As with other nonsteroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen extended-release capsules be taken with antacids, food, or milk. Although food delays the absorption of both formulations (see CLINICAL PHARMACOLOGY ) in most of the clinical trials ketoprofen was taken with food or mi…

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ketoprofen, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next 4 years of follow-up. Avoid the use of ketoprofen extended-release capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketoprofen extended-release capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including ketoprofen extended-release capsules, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ketoprofen extended-release capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of…

CONTRAINDICATIONS Ketoprofen extended-release capsules are contraindicated in patients who have shown hypersensitivity to ketoprofen. Ketoprofen extended-release capsules should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic reactions to ketoprofen have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: General: Preexisting Asthma ). Ketoprofen extended-release capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

Drug Interactions The following drug interactions were studied with ketoprofen doses of 200 mg/day. The possibility of increased interaction should be kept in mind when ketoprofen immediate-release doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs. ACE Inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Antacids Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as the immediate-release capsules. Aspirin Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin. The clinical significance of these changes is not known; however, as with other NSAIDs, concomitant administration of ketoprofen and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics NSAIDs can reduce the natriuetic effect of furosemide and thiazides in some patients. Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition (see PRECAUTIONS ). During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects ), as well as to assure diuretic efficacy. Digoxin In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Probenecid Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one-third, as well as decreasing its protein binding. Therefore, the combination of ketoprofen and probenecid is not recommended. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. In a short-term controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time. Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment. Because prostaglandins play an important role in hemostasis and ketoprofen has an effect on platelet function as well (see PRECAUTIONS: Drug/Laboratory Test Interactions: Effect on Blood Coagulation ), concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.

Pregnancy Risk Summary Use of NSAIDs, including ketoprofen extended-release capsules, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ketoprofen extended-release capsules use between about 20 and 30 weeks of gestation, and avoid ketoprofen extended-release capsules use at about 30 weeks of gestation and later in pregnancy (see WARNINGS: Fetal Toxicity ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ketoprofen extended-release capsules, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m 2 /day) and rats at doses up to 9 mg/kg/day (54 mg/m 2 /day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m 2 /day, showed no teratogenic or embryotoxic effects. In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but not teratogenicity. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ketoprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ketoprofen extended-release capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS: Fetal Toxicity ). Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ketoprofen extended-release capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ketoprofen extended-release capsules and follow up according to clinical practice (see WARNINGS: Fetal Toxicity ). Data Human Data Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, alth…

Nursing Mothers It is not known whether this drug is excreted in human milk. Data on secretion in human milk after ingestion of ketoprofen do not exist. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m 2 /day; approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development. Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level. As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.

ADVERSE REACTIONS The incidence of common adverse reactions (above 1%) was obtained from a population of 835 ketoprofen capsules-treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 ketoprofen extended-release capsules treated (200 mg/day) patients in trials lasting from 4 to 16 weeks. Minor gastrointestinal side effects predominated; upper gastrointestinal symptoms were more common than lower gastrointestinal symptoms. In crossover trials in 321 patients with rheumatoid arthritis or osteoarthritis, there was no difference in either upper or lower gastrointestinal symptoms between patients treated with 200 mg of ketoprofen extended-release capsules once a day or 75 mg of ketoprofen capsules TID (225 mg/day). Peptic ulcer or GI bleeding occurred in controlled clinical trials in less than 1% of 1,076 patients; however, in open label continuation studies in 1,292 patients the rate was greater than 2%. The incidence of peptic ulceration in patients on NSAIDs is dependent on many risk factors including age, sex, smoking, alcohol use, diet, stress, concomitant drugs such as aspirin and corticosteroids, as well as the dose and duration of treatment with NSAIDs (see WARNINGS ). Gastrointestinal reactions were followed in frequency by central nervous system side effects, such as headache, dizziness, or drowsiness. The incidence of some adverse reactions appears to be dose-related (see DOSAGE AND ADMINISTRATION ). Rare adverse reactions (incidence less than 1%) were collected from one or more of the following sources: foreign reports to manufacturers and regulatory agencies, publications, U.S. clinical trials, and/or U.S. postmarketing spontaneous reports. Reactions are listed below under body system, then by incidence or number of cases in decreasing incidence. Incidence Greater Than 1% (Probable Causal Relationship) Digestive: Dyspepsia (11%), nausea*, abdominal pain*, diarrhea*, constipation*, flatulence*, anorexia, vomiting, stomatitis. Nervous System: Headache*, dizziness, CNS inhibition (i.e., pooled reports of somnolence, malaise, depression, etc.) or excitation (i.e., insomnia, nervousness, dreams, etc.)*. Special Senses: Tinnitus, visual disturbance. Skin and Appendages: Rash. Urogenital: Impairment of renal function (edema, increased BUN)*, signs or symptoms of urinary-tract irritation. *Adverse events occurring in 3 to 9% of patients. Incidence Less than 1% (Probable Causal Relationship) Body as a Whole: Chills, facial edema, infection, pain, allergic reaction, anaphylaxis. Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular disease, vasodilation. Digestive: Appetite increased, dry mouth, eructation, gastritis, rectal hemorrhage, melena, fecal occult blood, salivation, peptic ulcer, gastrointestinal perforation, hematemesis, intestinal ulceration, hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice. Hemic: Hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia. Metabolic and Nutritional: Thirst, weight gain, weight loss, hyponatremia. Musculoskeletal: Myalgia. Nervous System: Amnesia, confusion, impotence, migraine, paresthesia, vertigo. Respiratory: Dyspnea, hemoptysis, epistaxis, pharyngitis, rhinitis, bronchospasm, laryngeal edema. Skin and Appendages: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, bullous rash, exfoliative dermatitis, photosensitivity, skin discoloration, onycholysis, toxic epidermal necrolysis, erythema multiforme, Stevens‑Johnson syndrome, and fixed drug eruption (FDE). Special Senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal hemorrhage and pigmentation change, taste perversion. Urogenital: Menometrorrhagia, hematuria, renal failure, interstitial nephritis, nephrotic syndrome. Incidence Less Than 1% (Causal Relationship Unknown) The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being listed to se…