KETOPROFEN- ketoprofen_capsule

CLINICAL PHARMACOLOGY
Ketoprofen is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties. The anti-inflammatory, analgesic and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another. An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with immediate-release ketoprofen capsules. The effect-site rate constant (k e0 -1 e50 The systemic availability (F S Ketoprofen is > 99% bound to plasma proteins, mainly to albumin. Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0. 5 to 2 hours. When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed. Food intake reduces C max max Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from ketoprofen capsules. Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with immediate-release ketoprofen capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of immediate-release ketoprofen 50 mg capsules QID for 12 hours were 0. 07 mg/L and 0. 13 mg/L at 24 hours following administration of immediate-release ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of immediate-release ketoprofen capsules is minimal. The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area. The shaded area represents +/- 1 standard deviation (S. ) around the mean for immediate-release ketoprofen capsules. KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS PHARMACOKINETIC PARAMETERS Values expressed are mean +/- standard deviation Kinetic Parameters Ketoprofen Capsules (4 x 50 mg) Extent of oral absorption (bioavailability) Fs (%) ~90 Peak plasma levels C max 3. 0 Time to peak concentration t max 1. 8 Area under plasma concentration-time curve AUC 0-24h 32. 1 Oral-dose clearance CL/F (L/h) 6. 8 Half-life t 1/2 2. 2 KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug (see Special Populations There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes. The plasma clearance of ketoprofen is approximately 0. 08 L/kg/h with a V d 1/2 In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite. Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this. The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC increase with increasing age. In addition, there is a corresponding increase in unbound fraction with increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not been determined whether age-related changes in absorption among the elderly contribute to the changes in bioavailability of ketoprofen (see Geriatric Use In a study conducted with young and elderly men and women, results for subjects older than 75 years of age showed that free drug AUC increased by 40% and C max DOSAGE AND ADMINISTRATION Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction associated with aging. Studies of the effects of renal-function impairment have been small. They indicate a decrease in clearance in patients with impaired renal function. In 23 patients with renal impairment, free ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function, and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination t 1/2 For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of immediate-release ketoprofen capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was 0. 07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that observed for normal subjects. However, the unbound (biologically active) fraction was approximately doubled, probably due to hypoalbuminemia and high variability which was observed in the pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect. The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac, and indomethacin. In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs. In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs. The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg. Doses of 25 mg were superior to placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen in doses of 25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen.
Pharmacodynamics
Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another. An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with immediate-release ketoprofen capsules. The effect-site rate constant (k e0 -1 e50
Pharmacokinetics
The systemic availability (F S Ketoprofen is > 99% bound to plasma proteins, mainly to albumin. Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0. 5 to 2 hours. When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed. Food intake reduces C max max Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from ketoprofen capsules. Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with immediate-release ketoprofen capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of immediate-release ketoprofen 50 mg capsules QID for 12 hours were 0. 07 mg/L and 0. 13 mg/L at 24 hours following administration of immediate-release ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of immediate-release ketoprofen capsules is minimal. The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area. The shaded area represents +/- 1 standard deviation (S. ) around the mean for immediate-release ketoprofen capsules. KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS PHARMACOKINETIC PARAMETERS Values expressed are mean +/- standard deviation Kinetic Parameters Ketoprofen Capsules (4 x 50 mg) Extent of oral absorption (bioavailability) Fs (%) ~90 Peak plasma levels C max 3. 0 Time to peak concentration t max 1. 8 Area under plasma concentration-time curve AUC 0-24h 32. 1 Oral-dose clearance CL/F (L/h) 6. 8 Half-life t 1/2 2. 2 KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug (see Special Populations There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes. The plasma clearance of ketoprofen is approximately 0. 08 L/kg/h with a V d 1/2 In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite. Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this.

Excipients: Lactose, magnesium stearate, and sodium starch glycolate. Gelatin, printing ink, sodium lauryl sulfate, titanium dioxide, D&C Red #28, and FD&C Blue #1.

INDICATIONS AND USAGE
Carefully consider the potential benefits and risks of ketoprofen capsules and other treatment options before deciding to use ketoprofen capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS Ketoprofen capsules are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Ketoprofen capsules are indicated for the management of pain. Ketoprofen capsules are also indicated for treatment of primary dysmenorrhea.
Rheumatoid Arthritis and Osteoarthritis
The recommended starting dose of ketoprofen capsules in otherwise healthy patients is 75 mg three times or 50 mg four times a day. Smaller doses of ketoprofen capsules should be utilized initially in small individuals or in debilitated or elderly patients. The recommended maximum daily dose of ketoprofen capsules is 300 mg/day. Dosages higher than 300 mg/day of ketoprofen capsules are not recommended because they have not been studied. Concomitant use of ketoprofen capsules and ketoprofen extended-release capsules is not recommended. Relatively smaller people may need smaller doses. As with other non-steroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen capsules be taken with antacids, food, or milk. Although food delays the absorption of ketoprofen capsules (see CLINICAL PHARMACOLOGY Physicians may want to make specific recommendations to patients about when they should take ketoprofen capsules in relation to food and/or what patients should do if they experience minor GI symptoms associated with ketoprofen capsules.

DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of ketoprofen capsules and other treatment options before deciding to use ketoprofen 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 capsules, the dose and frequency should be adjusted to suit an individual patient''s needs. Concomitant use of ketoprofen capsules and 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 capsules is 150 mg. In patients with a more severe renal impairment (GFR less than 25 mL/min/1. 73 m 2 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 capsules should be reduced for patients over 75 years of age (see 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 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 capsules and closely monitored. The recommended starting dose of ketoprofen capsules in otherwise healthy patients is 75 mg three times or 50 mg four times a day. Smaller doses of ketoprofen capsules should be utilized initially in small individuals or in debilitated or elderly patients. The recommended maximum daily dose of ketoprofen capsules is 300 mg/day. Dosages higher than 300 mg/day of ketoprofen capsules are not recommended because they have not been studied. Relatively smaller people may need smaller doses. As with other non-steroidal anti-inflammatory drugs, the predominant adverse effects of ketoprofen are gastrointestinal. To attempt to minimize these effects, physicians may wish to prescribe that ketoprofen capsules be taken with antacids, food, or milk. Although food delays the absorption of ketoprofen capsules (see CLINICAL PHARMACOLOGY Physicians may want to make specific recommendations to patients about when they should take ketoprofen capsules in relation to food and/or what patients should do if they experience minor GI symptoms associated with ketoprofen capsules. The usual dose of ketoprofen capsules recommended for mild-to-moderate pain and dysmenorrhea is 25 to 50 mg every 6 to 8 hours as necessary. A smaller dose should be utilized initially in small individuals, in debilitated or elderly patients, or in patients with renal or liver disease (see PRECAUTIONS WARNINGS ADVERSE REACTIONS.
Management of Pain and Dysmenorrhea
The usual dose of ketoprofen capsules recommended for mild-to-moderate pain and dysmenorrhea is 25 to 50 mg every 6 to 8 hours as necessary. A smaller dose should be utilized initially in small individuals, in debilitated or elderly patients, or in patients with renal or liver disease (see PRECAUTIONS WARNINGS ADVERSE REACTIONS

Gastrointestinal Effects - Risk of Ulceration,Bleeding, and Perforation
NSAIDs, including ketoprofen capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules. Ketoprofen capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS PRECAUTIONS Preexisting Asthma
Skin Reactions
NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including ketoprofen capsules. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. 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 a more severe hepatic reaction while on therapy with ketoprofen capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketoprofen capsules should be discontinued. In patients with chronic liver disease with reduced serum albumin levels, ketoprofen’s pharmacokinetics are altered (see CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including ketoprofen capsules. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketoprofen capsules, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketoprofen capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
ADVERSE REACTIONS
The incidence of common adverse reactions (above 1%) was obtained from a population of 835 ketoprofen-treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 patients treated with ketoprofen extended-release capsules 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 immediate-release capsules TID (255 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 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: * * * * * Nervous System: * * Special Senses: Skin and Appendages: Urogenital: * * Incidence Less Than 1% (Probable Causal Relationship) Body as a Whole: Cardiovascular: Digestive: Hemic: Metabolic and Nutritional: Musculoskeletal: Nervous System: Respiratory: Skin and Appendages: Special Senses: Urogenital: Incidence Less Than 1% (Causal Relationship Unknown) The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being listed to serve as alerting information to the physician. Body as a Whole: Cardiovascular: Digestive: Endocrine: Nervous System: Urogenital:

Ketoprofen capsules are contraindicated in patients who have shown hypersensitivity to ketoprofen. Ketoprofen 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 PRECAUTIONS Preexisting Asthma Ketoprofen capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS

Special Populations
The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC increase with increasing age. In addition, there is a corresponding increase in unbound fraction with increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not been determined whether age-related changes in absorption among the elderly contribute to the changes in bioavailability of ketoprofen (see Geriatric Use In a study conducted with young and elderly men and women, results for subjects older than 75 years of age showed that free drug AUC increased by 40% and C max DOSAGE AND ADMINISTRATION Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction associated with aging. Studies of the effects of renal-function impairment have been small. They indicate a decrease in clearance in patients with impaired renal function. In 23 patients with renal impairment, free ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function, and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination t 1/2 For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of immediate-release ketoprofen capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was 0. 07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that observed for normal subjects. However, the unbound (biologically active) fraction was approximately doubled, probably due to hypoalbuminemia and high variability which was observed in the pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease. If ketoprofen capsule therapy must be initiated, close monitoring of the patient''s renal function is advisable.
Pregnancy
In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.
Pregnancy
In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m 2 2 2 Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
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
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 18 have not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving ketoprofen capsules, compared with younger patients. Peak ketoprofen concentrations and free drug AUC were increased in older patients (see Special Populations DOSAGE AND ADMINISTRATION WARNINGS PRECAUTIONS DOSAGE AND ADMINISTRATION In ketoprofen capsule clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369 (24%) were >= 65 years of age, and 92 (6%) were >= 75 years of age. For ketoprofen capsule acute pain studies, 23 (5%) of 484 patients were >= 60 years of age. No overall differences in effectiveness were observed between these patients and younger patients.

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 capsule doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs. 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. Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as ketoprofen capsules. 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. NSAIDs can reduce the natriuretic 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 WARNINGS Renal Effects 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. 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. 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 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. 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 Drug/Laboratory Test Interactions Effect on Blood Coagulation.
Drug/Laboratory Test Interactions
Ketoprofen decreases platelet adhesion and aggregation. Therefore, it can prolong bleeding time by approximately 3 to 4 minutes from baseline values. There is no significant change in platelet count, prothrombin time, partial thromboplastin time, or thrombin time.

Clinical Trials
The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac, and indomethacin. In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs. In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs. The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg. Doses of 25 mg were superior to placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen in doses of 25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen.
WARNINGS
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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS NSAIDs, including ketoprofen capsules, can lead to onset of new hypertension or worsening of preexisting 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 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. Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Ketoprofen capsules should be used with caution in patients with fluid retention or heart failure. NSAIDs, including ketoprofen capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease. If ketoprofen capsule therapy must be initiated, close monitoring of the patient''s renal function is advisable. As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules. Ketoprofen capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS PRECAUTIONS Preexisting Asthma NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Chronic oral toxicity studies in mice (up to 32 mg/kg/day; 96 mg/m 2 2 2 A 2 year carcinogenicity study in rats, using doses up to 6.0 mg/kg/day (36 mg/m 2 2 2 2 2 2 2 Abnormal spermatogenesis or inhibition of spermatogenesis developed in rats and dogs at high doses, and a decrease in the weight of the testes occurred in dogs and baboons at high doses.
Labor and Delivery
The effects of ketoprofen on labor and delivery in pregnant women are unknown. Studies in rats have shown ketoprofen at doses of 6 mg/kg (36 mg/m 2
OVERDOSAGE
Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Respiratory depression, coma, or convulsions have occurred following large ketoprofen overdoses. Gastrointestinal bleeding, hypotension, hypertension, or acute renal failure may occur, but are rare. Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients with symptoms seen within 4 hours or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose. Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to ketoprofen’s high protein binding. Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults. Five of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child). A 12-year-old girl had tonic-clonic convulsions 1 to 2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets of acetaminophen with hydrocodone. Her ketoprofen level was 1128 mg/L (56 times the upper therapeutic level of 20 mg/L) 3 to 4 hours post ingestion. Full recovery ensued 18 hours after ingestion following management with intubation, diazepam, and activated charcoal. A 45-year-old woman ingested twelve 200 mg extended-release ketoprofen capsules and 375 mL vodka, was treated with emesis and supportive measures 2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.

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