PIROXICAM — piroxicam capsule
H.J. Harkins Company, Inc.
- NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, 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).
- Piroxicam capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
- 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 events (see WARNINGS).
Piroxicam capsules USP contain piroxicam which is a member of the oxicam group of non-steroidal anti-inflammatory drugs (NSAIDs). Each dark green and olive capsule contains 10 mg piroxicam, each dark green capsule contains 20 mg piroxicam for oral administration. The chemical name for piroxicam is 4-hydroxy-2-methyl-N -2-pyridinyl-2H -1,2-benzothiazine-3-carboxamide 1,1-dioxide. Members of the oxicam family are not carboxylic acids, but they are acidic by virtue of the enolic 4-hydroxy substituent. Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous alkaline solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). It has the following structural formula:
C15 H13 N3 O4 S M.W. 331.35
Each capsule, for oral administration, contains 10 mg or 20 mg piroxicam. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, corn starch, D&C Yellow No. 10, FD&C Green No. 3, gelatin, lactose, magnesium stearate, povidone, shellac, sodium lauryl sulfate, and titanium dioxide. The imprinting ink may contain antifoam DC 1510, 2-ethoxyethanol, lecithin, poly(dimethylsiloxane), propylene glycol, silicon dioxide, and sodium hydroxide.
Piroxicam capsules USP, 10 mg also contain: black iron oxide, FD&C Blue No. 1, and yellow iron oxide.
Piroxicam capsules are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of piroxicam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
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 piroxicam capsules, 20 mg, usually stabilize at 3 to 8 mcg/mL. 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.
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.
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 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).
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 (T½ ) for piroxicam is approximately 50 hours.
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* 1/* 2 and CYP2C9* 1/* 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.
Piroxicam capsules have not been investigated in pediatric patients.
Pharmacokinetic differences due to race have not been identified.
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.
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.
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.
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