Ketoprofen Extended-release

KETOPROFEN EXTENDED-RELEASE- ketoprofen capsule, extended release
Andrx Pharmaceuticals, Inc.

Rx Only

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 extended-release 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 nonsteroidal anti-inflammatory drug. The chemical name for ketoprofen is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:

Image from Drug Label Content

Its molecular formula is C16 H14 O3 , with a molecular weight of 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.

Each ketoprofen extended-release 100 mg, 150 mg, or 200 mg capsule contains ketoprofen in the form of hundreds of coated pellets. The dissolution of the pellets is pH dependent with optimum dissolution occurring at pH 6.5-7.5. There is no dissolution at pH 1. In addition, each capsule contains the following inactive ingredients: black iron oxide, D&C Yellow 10, ethylcellulose, FD&C Blue 1, FD&C Blue 2, FD&C Red 40, gelatin, propylene glycol, shellac, starch, sucrose, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

Ketoprofen is a nonsteroidal 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 nonsteroidal 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.

PHARMACOKINETICS

General

Ketoprofen extended-release 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”).

The systemic availability (Fs) when 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 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 Table below). When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.

Administration of ketoprofen extended-release capsules 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 ketoprofen extended-release capsules.

Multiple Dosing

Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with ketoprofen extended-release capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of ketoprofen extended-release 200 mg capsules were 0.4 mg/L. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of ketoprofen extended-release capsules is minimal.

PHARMACOKINETIC PARAMETERS# FOR KETOPROFEN EXTENDED-RELEASE CAPSULES
Kinetic Parameters Ketoprofen Extended-releaseCapsules(1 x 200 mg)

#Values expressed are mean ± standard deviation

1 Absorption is slowed, intrinsic clearance is unchanged, but because the rate of elimination is dependant on absorption, the half-life is prolonged.

Extent of oral absorption (bioavailability) Fs (%) ~90
Peak plasma levels Cmax (mg/L)
Fasted 3.1 ± 1.2
Fed 3.4 ± 1.3
Time to peak concentration tmax (h)
Fasted 6.8 ± 2.1
Fed 9.2 ± 2.6
Area under plasma concentration-time curve
AUC 0-24h (mg·h/L)
Fasted 30.1 ± 7.9
Fed 31.3 ± 8.1
Oral-dose clearance CL/F (L/h) 6.8 ± 1.8
Half-life t1/2 (h) 5.4 ± 2.2
[See footnote 1]

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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