Ketoprofen

KETOPROFEN — ketoprofen tablet
RedPharm Drug Inc.

Cardiovascular Risk

  • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
  • Ketoprofen capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

  • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events (see WARNINGS).

DESCRIPTION

Ketoprofen is a non-steroidal anti-inflammatory drug. The chemical name for ketoprofen is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:

ketoprofen structural formula

C16 H14 O3 M.W. 254.29

It has a pKa of 5.94 in methanol: water (3:1) and an n-octanol: water partition coefficient of 0.97 (buffer pH 7.4).

Ketoprofen is a white or off-white, odorless, nonhygroscopic, fine to granular powder, melting at about 95°C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20°C.

Ketoprofen capsules contain 50 mg or 75 mg of ketoprofen for oral administration.

Inactive Ingredients

Drug Product

Lactose, magnesium stearate, and sodium starch glycolate.

Capsule Shell Constituents

Gelatin, printing ink, sodium lauryl sulfate, titanium dioxide, D&C Red #28, and FD&C Blue #1.

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 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 non-steroidal anti-inflammatory drugs, is not fully understood.

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 (ke0 ) was estimated to be 0.9 hour-1 (95% confidence limits: 0 to 2.1), and the concentration (Ce 50 ) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 mcg/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.

Pharmacokinetics

General

The systemic availability (FS ) when the 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.

Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.

Absorption

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 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.

Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from ketoprofen capsules.

Multiple Dosing

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.D.) around the mean for immediate-release ketoprofen capsules.

KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS
(click image for full-size original)

KETOPROFEN PLASMA CONCENTRATIONS IN SUBJECTS RECEIVING KETOPROFEN CAPSULES 50 MG EVERY 4 HOURS FOR 16 HOURS

PHARMACOKINETIC PARAMETERS FOR IMMEDIATE-RELEASE KETOPROFEN CAPSULES
Kinetic Parameters Ketoprofen Capsules (4 x 50 mg)
Extent of oral absorption (bioavailability) Fs (%)~90
Peak plasma levels Cm ax (mg/L) Fasted Fed3.9 ± 1.3 2.4 ± 1.0
Time to peak concentration tm ax (h) Fasted Fed1.2 ± 0.6 2.0 ± 0.8
Area under plasma concentration-time curve AUC0 - 24h (mg•h/L) Fasted Fed32.1 ± 7.2 36.6 ± 8.1
Oral-dose clearance CL/F (L/h)6.9 ± 0.8
Half-life t1/2 (h)2.1 ± 1.2

Metabolism

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.

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