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Feldene

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Feldene

CLINICAL PHARMACOLOGY

Pharmacodynamics

FELDENE (piroxicam) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of FELDENE (piroxicam) , like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics

Absorption: FELDENE (piroxicam) is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE (piroxicam) , usually stabilize at 3-8 mcg/mL. Most patients approximate steady state plasma levels within 7-12 days. Higher levels, which approximate steady state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred.

With food there is a slight delay in the rate but not the extent of absorption following oral administration. The concomitant administration of antacids (aluminum hydroxide or aluminum hydroxide with magnesium hydroxide) have been shown to have no effect on the plasma levels of orally administered piroxicam.

Distribution: The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days). Piroxicam appeared in breast milk at about 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment.

Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. In vitro studies indicate cytochrome P4502C9 (CYP2C9) as the main enzyme involved in the formation to the 5'-hydroxy-piroxicam, the major metabolite (see Pharmacogenetics, and Special Populations, Poor Metabolizers of CYP2C9 Substrates). The biotransformation products of piroxicam metabolism are reported to not have any anti-inflammatory activity.

Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects (see Pharmacogenetics, and Special Populations, Poor Metabolizers of CYP2C9 Substrates).

Excretion: FELDENE (piroxicam) and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as in the feces. Approximately 5% of a FELDENE (piroxicam) dose is excreted unchanged. The plasma half-life (Ty2) for piroxicam is approximately 50 hours.

Pharmacogenetics: CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from one published report that included nine subjects each with heterozygous CYP2C9*l/*2 and CYP2C9*l/*3 genotypes and one subject with the homozygous CYP2C9*3/*3 genotype showed piroxicam systemic levels that were 1.7-, 1.7-and 5.3-fold, respectively, higher compared to the 17 subjects with CYP2C9*1/*1 or normal metabolizer genotype. The pharmacokinetics of piroxicam have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups.

Special Populations

Pediatric: FELDENE (piroxicam) has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Insufficiency: The effects of hepatic disease on FELDENE (piroxicam) pharmacokinetics have not been established. However, a substantial portion of FELDENE (piroxicam) elimination occurs by hepatic metabolism. Consequently, patients with hepatic disease may require reduced doses of FELDENE (piroxicam) as compared to patients with normal hepatic function.

Poor Metabolizers ofCYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Renal Insufficiency: FELDENE (piroxicam) pharmacokinetics have been investigated in patients with renal insufficiency. Studies indicate patients with mild to moderate renal impairment may not require dosing adjustments. However, the pharmacokinetic properties of FELDENE (piroxicam) in patients with severe renal insufficiency or those receiving hemodialysis are not known.

Other Information

In controlled clinical trials, the effectiveness of FELDENE (piroxicam) has been established for both acute exacerbations and long-term management of rheumatoid arthritis and osteoarthritis.

The therapeutic effects of FELDENE (piroxicam) are evident early in the treatment of both diseases with a progressive increase in response over several (8-12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation.

Doses of 20 mg/day FELDENE (piroxicam) display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus.

FELDENE (piroxicam) has been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a "steroid-sparing" effect has not been adequately studied to date.

Last reviewed on RxList: 9/14/2010
This monograph has been modified to include the generic and brand name in many instances.

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