Piroxicam Genfar

Piroxicam 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 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.

Pharmacotherapeutic group: Anti-inflammatory preparations, non-steroids for topical use (ATC code M02AA07).

Piroxicam Genfar inhibits the enzyme cyclo-oxygenase. This is a basic characteristic of non-steroidal anti-inflammatory drugs, which allows them to influence many physiological processes.

Depending on the site of action, NSAID may;

- reduce the vascular phase of inflammation,

- decrease sensitisation of nociceptors to stimulation,

- act as an antipyretic,

- inhibit the secondary phase of platelet aggregation,

- affect the motility of bronchi and of the uterus,

- cause a dose dependent decrease in renal blood flow particularly in patients with renal impairment,

- lead to the activation of free radicals by neutrophils,

- affect the permeability of the foetal umbilical arterial canal,

- interfere with the renal resorption of uric acid,

- affect the gastric mucosa leading to ulceration of the muscularis mucosa.

Piroxicam Genfar's pharmacological profile is based on the inhibition of prostaglandin synthesis from arachidonic acid in vitro, of collagen-induced aggregation of human and animal platelets in vitro, of the release of lysosomal enzymes, of the generation of the reactive superoxide anion, of chemostaxis/migration of neurophils, macrophages, monocytes, platelets, of the carrageenin-induced foot oedema in rats, of the benzoquinone-induced writhing in mice, of E.coli-induced fever in rats and of urate crystal-induced synovitis.

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 of the pharmacokinetics and the bioavailability of Piroxicam Genfar 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 Genfar FDDF were nearly superimposable. There were no significant differences between the mean steady state C_max values, C_min values, T½, or T_max values. This study concluded that Piroxicam Genfar 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 other CYP2C9 substrates should be administered piroxicam with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Pharmacogenetics:

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 an oral single 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 5.7% in various ethnic groups.

A study in man examining skin biopsies following Piroxicam Genfar gel administration concluded that Piroxicam Genfar rapidly permeates through the stratum corneum into the epidermis/dermis after application of the gel with plasma levels being low.

A separate study in man demonstrated mean plasma concentrations of Piroxicam Genfar gel to be approximately 5% of those observed after equivalent doses of oral or intramuscular Piroxicam Genfar. In healthy subjects or patients following the administration of a single oral dose, the pharmacokinetics of Piroxicam Genfar are linear, with maximum plasma concentration usually being obtained in about 2 h, but this can vary from 1-6 h in different subjects. It has a low clearance rate of approximately 45 h, but the half-life can vary from 30-60 h. After repeated doses of 20 mg daily, steady - state concentrations are generally achieved in 7-12 days; with a peak plasma concentration ranging from 4.5-2.2 mg/l.

In humans it penetrates into the synovial fluid of patients with rheumatoid arthritis, osteoarthritis, and reactive synovitis where mean concentrations are approximately 40% of those in plasma; it is also demonstrable in synovial tissues. Concentrations of Piroxicam Genfar in breast milk are about 1% of those in the maternal plasma at the same time. Overall, Piroxicam Genfar is 99% bound to plasma protein. Pharmacokinetics of the drug do not appear to be age related, and renal function has only a limited influence on its elimination, but plasma concentrations are increased in patients with severe liver dysfunction.

Piroxicam Genfar is eliminated by biotransformation in the liver. The major route is by hydroxylation, with the resultant products being excreted alone or as a glucuronide in urine and faeces. The metabolites of Piroxicam Genfar have little or no anti-inflammatory activity in animal models. Approximately 10% of an oral dose is excreted as unchanged drug in 10 days.

None stated.

There are no preclinical data of relevance to the prescriber which are additional to those included elsewhere in the SPC.

None stated.

The metabolism of Piroxicam Genfar is inhibited by cimetidine and it itself can inhibit antipyrine metabolism.

No special requirements.

Pierce the tube by reversing the cap and screwing down to break the seal on the tube. Apply 3cm (1¼” approximately) of the gel on the affected area. Rub the gel into the skin until the gel disappears. Do this three or four times a day. For muscle sprains and strains, you should start to feel better within one week. If the pain has not got any less after a week, tell your pharmacist or doctor. Replace the cap after use.

Wash hands after each application unless it is the hand that is being treated.