The anti-inflammatory, analgesic, and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other nonsteroidal anti-inflammatory drugs, is not fully understood.
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 Orudis (ketoprofen) . The effect-site rate constant (ke0) was estimated to be 0.9 hour-1 (95% confidence limits: 0 to 2.1), and the concentration (Ce50) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 m g/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68% of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.
Orudis and Oruvail capsules both contain ketoprofen. They differ only in their release characteristics. Orudis (ketoprofen) capsules release drug in the stomach whereas the pellets in Oruvail capsules are designed to resist dissolution in the low pH of gastric fluid but release drug at a controlled rate in the higher pH environment of the small intestine (see DESCRIPTION).
Irrespective of the pattern of release, the systemic availability (Fs) when either oral formulation is compared with IV administration is approximately 90% in humans. For 75 to 200 mg single doses, the area under the curve has been shown to be dose proportional. The figure depicts the plasma time curves associated with both products.
Separate sections follow which delineate differences between Orudis (ketoprofen) and Oruvail capsules.
Orudis capsules - Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
Oruvail capsules - Ketoprofen is also well-absorbed from this dosage form, although an observable increase in plasma levels does not occur until approximately 2 to 3 hours after taking the formulation. Peak plasma levels are usually reached 6 to 7 hours after dosing. (See Figure and Table, below).
When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption from e ither dosage form is slowed.
Orudis (ketoprofen) capsules - Food intake reduces Cmax by approximately one-half and increases the mean time to peak concentration (tmax) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process.
Oruvail capsules - Administration of Oruvail with a high-fat meal causes a delay of about 2 hours in reaching the Cmax; neither the total bioavailability (AUC) nor the Cmax is affected. Circadian changes in the absorption process have not been studied.
The administration of antacids or other drugs which may raise stomach pH would not be expected to change the rate or extent of absorption of ketoprofen from Oruvail capsules.
Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with Orudis (ketoprofen) or Oruvail capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of Oruvail 200 mg capsules were 0.4 mg/L compared with 0.07 mg/L at 24 hours following administration of Orudis (ketoprofen) 50 mg capsules QID (12 hours), or 0.13 mg/L following administration of Orudis (ketoprofen) 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of Oruvail or Orudis (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.D.) around the mean for Orudis or Oruvail.
KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING 200 MG OF ORUVAIL ONCE A DAY (QD), OR ORUDIS (ketoprofen) 50 MG EVERY 4 HOURS FOR 16 HOURS
COMPARISON OF PHARMACOKINETIC PARAMETERS# FOR ORUDIS (ketoprofen) AND ORUVAIL
|Kinetic Parameters||Orudis (4 x 50 mg)||Oruvail (1 x 200 mg)|
|Extent of oral absorption (bioavailability) Fs (%)||~90||~90|
|Peak plasma levels Cmax (mg/L)|
|Fasted||3.9 ± 1.3||3.1 ± 1.2|
|Fed||2.4 ± 1.0||3.4 ± 1.3|
|Time to peak concentration tmax (h)|
|Fasted||1.2 ± 0.6||6.8 ± 2.1|
|Fed||2.0 ± 0.8||9.2 ± 2.6|
|Area under plasma concentration-time curve|
|Fasted||32.1 ± 7.2||30.1 ± 7.9|
|Fed||36.6 ± 8.1||31.3 ± 8.1|
|Oral-dose clearance CL/F (L/h)||6.9 ± 0.8||6.8 ± 1.8|
|Half-life t½ (h)
[See footnote 1]
|2.1 ± 1.2||5.4 ± 2.2|
# Values expressed are mean ± standard deviation
1 In the case of Oruvail, absorption is slowed, intrinsic clearance is unchanged, but because the rate of elimination is dependent on absorption, the half-life is prolonged.
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: Renally impaired"). The conjugates are reported to appear only in trace amounts in plasma in healthy adults, but are higher in elderly subjects - presumably because of reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses (50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively, for the S & R enantiomers.
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 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 h following administration of Orudis (ketoprofen) capsules, and 5.4 ± 2.2 h after administration of Oruvail 200 mg capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t½ relative to an IV dose appears prolonged.
After a single 200 mg dose of Oruvail, the plasma levels decline slowly, and average 0.4 mg/L after 24 hours (see Figure above).
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.
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).
Orudis (ketoprofen) capsules - 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.
Oruvail (ketoprofen) capsules - The effects of age and gender on ketoprofen disposition were investigated in 2 small studies in which elderly male and female subjects received Oruvail 200 mg capsules. The results were compared with those from another study conducted in healthy young men.
Compared to the younger subject group, the elimination half-life in the elderly was prolonged by 54% and total drug Cmax and AUC were 40% and 70% higher, respectively. Plasma concentrations in the elderly after single doses and at steady state were essentially the same. Thus, no drug accumulation occurs.
In comparison to younger subjects taking the immediate-release formulation (Orudis (ketoprofen) ), there was a decrease of 16% and 25% in total drug Cmax and AUC, respectively, among the elderly. Free drug data are not available for Oruvail.
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 t½ 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.
No studies have been conducted in patients with renal impairment taking Oruvail capsules (see DOSAGE AND ADMINISTRATION).
For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of Orudis (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.
No studies have been conducted in patients with hepatic impairment taking Oruvail capsules (see DOSAGE AND ADMINISTRATION).
Rheumatoid Arthritis and Osteoarthritis
The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. Using standard assessments of therapeutic response, there were no detectable differences in effectiveness or in the incidence of adverse events in crossover comparison of Orudis (ketoprofen) and Oruvail (ketoprofen). 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 nonsteroidal drugs.
Management of Pain
The effectiveness of Orudis (ketoprofen) 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 Orudis (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.
The use of Oruvail in patients with acute pain is not recommended, since, in comparison to Orudis (ketoprofen) , Oruvail would be expected to have a delayed analgesic response due to its extended-release characteristics.
Last reviewed on RxList: 2/21/2006
This monograph has been modified to include the generic and brand name in many instances.
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