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Piroxicam response

MedGen UID:
941224
Concept ID:
CN258188
Sign or Symptom
Synonym: Feldene response
Drug:
piroxicam
MedGen UID:
18487
Concept ID:
C0031990
Pharmacologic Substance
A nonsteroidal oxicam derivative with anti-inflammatory, antipyretic and analgesic properties. As a non-selective, nonsteroidal anti-inflammatory drug (NSAID), piroxicam binds and chelates both isoforms of cyclooxygenases (COX1 and COX2), thereby stalling phospholipase A2 activity and conversion of arachidonic acid into prostaglandin precursors at the rate limiting cyclooxygenase enzyme step. This results in inhibition of prostaglandin biosynthesis. As a second, independent effect, piroxicam inhibits the activation of neutrophils thereby contributing to its overall anti-inflammatory effects. [from NCI]
 
Gene (location): CYP2C9 (10q23.33)

Definition

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are among the most commonly prescribed drugs to treat pain, fever and inflammation. The main therapeutic effect of NSAIDs occurs via blocking the production of prostaglandin that cause inflammation. Hepatic metabolism by cytochrome P450 isoforms CYP2C9, 1A2, and 3A4, and renal excretion are the principal routes of clearance of the majority of NSAIDs. Genetic variants in CYP2C9 (e.g., CYP2C9*2 and *3), along with other genetics and clinical factors, have been shown to affect systemic plasma concentrations of NSAIDs and potentially safety. Patients with CYP2C9 decreased or no function alleles may have elevated exposure and at increased risk for adverse effects. Guidelines regarding the use of pharmacogenomic tests in dosing for NSAIDs have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and PharmGKB websites. The CPIC guideline provides specific therapeutic recommendations for a number of NSAIDs (celecoxib, flurbiprofen, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam) based on CYP2C9 genotype. [from PharmGKB]

Additional description

From Medical Genetics Summaries
Piroxicam (brand name Feldene) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis and rheumatoid arthritis. Piroxicam provides pain relief and reduces inflammation. Piroxicam is primarily metabolized by CYP2C9. Individuals who lack CYP2C9 activity ("CYP2C9 poor metabolizers") have an increased exposure to piroxicam, and an increased risk of side effects. Like all NSAIDs, piroxicam increases the risk of serious cardiovascular events, including myocardial infarction and stroke, and serious gastrointestinal (GI) adverse events such as bleeding, ulceration, and perforation. The standard dose of piroxicam for osteoarthritis and rheumatoid arthritis in adults is 20 mg once daily. But for all patients, the lowest effective dose of piroxicam should be used for the shortest length of time, consistent with the treatment goals of each individual. The FDA-approved drug label for piroxicam states that a dose reduction should be considered 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)". Dose reductions should be considered because these patients may have abnormally high plasma levels of piroxicam caused by reduced metabolic clearance. However, specific dose reductions based on CYP2C9 phenotype are not provided. As for all NSAIDs, piroxicam is contraindicated in patients with a known hypersensitivity, a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or another NSAID, and following coronary artery bypass graft (CABG) surgery. Piroxicam should also be avoided by pregnant women starting at 30 weeks gestation.  https://www.ncbi.nlm.nih.gov/books/NBK537367

Professional guidelines

PubMed

Aggarwal I, Puyana C, Chandan N, Jetter N, Tsoukas M
Am J Clin Dermatol 2024 May;25(3):391-405. Epub 2024 Feb 13 doi: 10.1007/s40257-023-00839-8. PMID: 38351246
Pazin C, de Souza Mitidieri AM, Silva AP, Gurian MB, Poli-Neto OB, Rosa-E-Silva JC
Int Urogynecol J 2016 May;27(5):697-708. Epub 2015 Aug 14 doi: 10.1007/s00192-015-2815-5. PMID: 26272202
Chou CM
Rheum Dis Clin North Am 1999 Aug;25(3):521-37. doi: 10.1016/s0889-857x(05)70085-5. PMID: 10467627

Curated

DailyMed Drug Label, PIROXICAM, 2018

DailyMed Drug Label, piroxicam, 2008

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted 1 information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2018 Statement from the US Food and Drug Administration (FDA)

Higher systemic exposure of piroxicam has been noted in subjects with CYP2C9 polymorphisms compared to normal metabolizer type subjects.

[...]

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.

Please review the complete therapeutic recommendations that are located here: (1).

1 The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.

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