PIROXICAM (Page 5 of 7)

11 DESCRIPTION

Piroxicam capsule USP, is a nonsteroidal anti-inflammatory drug, each maroon and blue capsule contains 10 mg piroxicam USP, each maroon capsule contains 20 mg piroxicam USP for oral administration. The chemical name is 4-hydroxyl-2-methyl- N -2­pyridinyl-2 H -1,2,-benzothiazine-3-carboxamide1,1-dioxide. The molecular weight is 331.35. Its molecular formula is C 15 H 13 N 3 O 4 S, and it has the following chemical structure.

structure
(click image for full-size original)

Piroxicam USP occurs as an off white to light tan or light yellow, odourless crystalline powder, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8).

The inactive ingredients in piroxicam capsules USP include: lactose monohydrate, magnesium stearate, maize starch pregelatinised, and sodium lauryl sulfate. The empty hard gelatin capsule shell consists of FD & C Blue 1, FD & C Red 40, FD & C Red 3, gelatin, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Piroxicam has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of piroxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Piroxicam is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Piroxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because piroxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics

General pharmacokinetic characteristics

The pharmacokinetics of piroxicam have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of piroxicam are linear. Proportional increase in exposure is observed with increasing doses. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and significant accumulation upon multiple dosing. Most patients approximate steady state plasma levels within 7 to 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.

Absorption

Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 mg and 20 mg doses and generally peak within three to five hours after administration. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 mcg/mL to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily administration of 20 mg piroxicam, usually stabilize at 3 mcg/mL to 8 mcg/mL.

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 approximately 1% to 3% of the maternal concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment.

Elimination

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 Clinical Pharmacology (12.5)] . 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 Clinical Pharmacology (12.5)] .

Excretion

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 piroxicam dose is excreted unchanged. The plasma half-life (t ½ ) for piroxicam is approximately 50 hours.

Specific Populations

Pediatric

Piroxicam has not been investigated in pediatric patients.

Race

Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment

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

Renal Impairment

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 piroxicam in patients with severe renal insufficiency or those receiving hemodialysis are not known.

Drug Interaction Studies

Antacids

Concomitant administration of antacids had no effect on piroxicam plasma levels.

Aspirin

When piroxicam was administered with aspirin, its protein binding was reduced, although the clearance of free piroxicam was not altered. Plasma levels of piroxicam were decreased to approximately 80% of their normal values when piroxicam capsule was administered (20 mg/day) in conjunction with aspirin (3900 mg/day). The clinical significance of this interaction is not known [see Drug Interactions (7)].

12.5 Pharmacogenomics

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been reported in certain ethnic groups.

Poor Metabolizers of CYP2C9 Substrates: In 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) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis

Long-term animal studies have not been conducted to characterize the carcinogenic potential of piroxicam.

Mutagenesis

Piroxicam was not mutagenic in an Ames bacterial reverse mutation assay, or in a dominant lethal mutation assay in mice, and was not clastogenic in an in vivo chromosome aberration assay in mice.

Impairment of Fertility

Reproductive studies in which rats were administered piroxicam at doses of 2, 5, or 10 mg/kg/day (up to 5 times the MRHD of 20 mg based on mg/m 2 body surface area [BSA]) revealed no impairment of male or female fertility.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.