Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Ranbaxy Pharmaceuticals (Pty) Ltd, 14 Lautre Road, Stormill, Ext. 1, Roodepoort, 1724, South Africa
PYROCAPS is a non-steroidal anti-inflammatory agent which also possesses analgesic and antipyretic properties. Oedema, erythema, tissue proliferation, fever and pain can all be inhibited in laboratory animals by the administration of piroxicam. It is effective regardless of the aetiology of the inflammation. While its mode of action is not fully understood, independent studies reported in vitro as well as in vivo have shown that piroxicam interacts at several steps in the immune and inflammation responses through:
Inhibition of prostanoid synthesis, including prostaglandins, through a reversible inhibition of the cyclo-oxygenase enzyme.
Inhibition of neutrophil aggregation.
Inhibition of polymorphonuclear cell and monocyte migration to the area of inflammation. Inhibition of lyosomal enzyme release from stimulated leucocytes.
Reduction of both systemic and synovial fluid rheumatoid factor production in patients with seropositive rheumatoid arthritis.
It is established that piroxicam does not act by pituitary-adrenal axis stimulation. In vitro studies have not revealed any negative effects on cartilage metabolism.
Piroxicam is well absorbed following oral or rectal administration. With food there is a slight delay in the rate but not the extent of absorption following administration. The plasma half-life is approximately 50 hours in man and stable plasma concentrations are maintained throughout the day on once-daily dosage. Continuous treatment with 20mg/day for periods of 1 year produces similar blood levels to those seen once steady state is first achieved.
Drug plasma concentrations are proportional for 10 and 20mg doses and generally peak within 3 to 5 hours after medication. A single 20mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/ml while maximum plasma concentrations, after repeated daily ingestion of 20mg piroxicam, usually stabilise at 3 to 8 mcg/ml. Most patients approximate steady state plasma levels within 7 to 12 days.
Treatment with a loading dose regimen of 40mg daily for the first 2 days followed by 20mg daily thereafter allows a high percentage (approximately 76%) of steady state levels to be achieved immediately following the second dose. Steady state levels, area under the curves and elimination half-life are similar to that following a 20mg daily dose regimen.
A multiple dose comparative study of the bioavailability of the injectable forms with the oral capsule has shown that after intramuscular administration of piroxicam, plasma levels are significantly higher than those obtained after ingestion of capsules during the 45 minutes following administration the first day, during 30 minutes the second day and 15 minutes the seventh day. Bioequivalence exists between the two dosage forms.
A multiple dose comparative study reported the pharmacokinetics and the bioavailability of Piroxicam FDDF with the oral capsule has shown that after once daily administration for 14 days, the mean plasma piroxicam concentration time profiles for capsules and Piroxicam FDDF were nearly superimposable. There were no significant differences between the mean steady state Cmax values, Cmin values, T½, or Tmax values. This study concluded that Piroxicam FDDF (Fast Dissolving Dosage Form) is bioequivalent to the capsule after once daily dosing. Single dose studies have demonstrated bioequivalence as well when the tablet is taken with or without water.
Piroxicam is extensively metabolised and less than 5% of the daily dose is excreted unchanged in urine and faeces. Piroxicam metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. One important metabolic pathway is hydroxylation of the pyridyl ring of the piroxicam side-chain, followed by conjugation with glucuronic acid and urinary elimination.
Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with otherCYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance (see section 4.4).
CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3polymorphisms. 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-foldhigher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of an oral single dose. The mean elimination half life values of piroxicam for subjects withCYP2C9*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 5.7% in various ethnic groups.
Not applicable.
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