Ketoprofen (Page 2 of 7)

Elimination

The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd of 0.1 L/kg after IV administration. The elimination half-life of ketoprofen has been reported to be 2.05 ± 0.58 h (Mean ± S.D.) following IV administration from 2 to 4 hours following administration of ketoprofen capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears prolonged.

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.

Special Populations

Elderly

Clearance and unbound fraction

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 Cmax increased by 60% as compared with estimates of the same parameters in young subjects (those younger than 35 years of age; see 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.

Renally Impaired

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 t1/2 was prolonged from 1.6 hours in normal subjects to approximately 3 hours in patients with mild renal impairment, and to approximately 5 to 9 hours in patients with moderately to severely impaired renal function.

Hepatically Impaired

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.

Clinical Trials

Rheumatoid Arthritis and Osteoarthritis

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.

Management of Pain

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.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of ketoprofen capsules USP and other treatment options before deciding to use ketoprofen capsules USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Ketoprofen capsules USP are indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis.

Ketoprofen capsules USP are indicated for the management of pain. Ketoprofen capsules USP are also indicated for treatment of primary dysmenorrhea.

CONTRAINDICATIONS

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 and PRECAUTIONS , Preexisting Asthma).

Ketoprofen capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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 to 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 four years of follow-up.

Avoid the use of ketoprofen capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketoprofen capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

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