Piroxicam

Oral
Ankylosing spondylitis, Osteoarthritis, Rheumatoid arthritis

Topical/Cutaneous
Pain and inflammation

Pharmacogenomics:

Piroxicam is mainly metabolised by CYP2C9 isoenzyme via hydroxylation into the inactive major metabolite, 5'-hydroxypiroxicam. CYP2C9 polymorphisms influence the metabolism and clearance of NSAIDs, thus affecting drug exposure and potential safety. CYP2C9*2 and CYP2C9*3 are genetic polymorphisms present in individuals with reduced CYP2C9 activity. Differences in allele frequencies have been noted across many racially, geographically, and ethnically diverse groups. The frequency of the homozygous *3/*3 genotype is approx 0-1% in the general population but frequencies as high as 5.7% have been reported in certain ethnic groups. Genetic testing may be considered to identify the metaboliser status of the patient.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of March 2020:

Phenotype and Genotype	Implications	Recommendations
CYP2C9 intermediate metaboliser (activity score of 1) Patients carrying 1 normal functional allele plus 1 decreased function allele, or 1 normal functional allele plus 1 non-functional allele, or 2 decreased function alleles e.g. *1/*3, *2/*2	Moderately reduced piroxicam metabolism and higher plasma piroxicam concentrations which may increase the risk of toxicities.	Select an alternative therapy that is not metabolised by CYP2C9 (e.g. ketorolac, naproxen, sulindac) or not significantly affected by CYP2C9 genetic variants in vivo, or choose an NSAID metabolised by CYP2C9 but with a shorter half-life. Selection of therapy may depend on individual treatment goals and risks for toxicity.
CYP2C9 poor metaboliser (activity score of 0 or 0.5) Patients carrying 1 non-functional allele plus 1 decreased function allele, or 2 non-functional alleles e.g. *2/*3, *3/*3	Significantly reduced metabolism and prolonged half-life of piroxicam; higher plasma piroxicam concentrations may increase the risk and/or severity of toxicities.	Select an alternative therapy that is not metabolised by CYP2C9 (e.g. ketorolac, naproxen, sulindac) or not significantly affected by CYP2C9 genetic variants in vivo, or choose an NSAID metabolised by CYP2C9 but with a shorter half-life. Selection of therapy may depend on individual treatment goals and risks for toxicity.

In contrast, the US Food and Drug Administration drug label for piroxicam recommends dose reduction in patients who are known (based on genotyping) or suspected (based on the previous history with other CYP2C9 substrates) poor metabolisers of CYP2C9.

Should be taken with food.

Hypersensitivity (including serious allergic reaction of any type) to piroxicam; history of skin reactions (regardless of severity) to piroxicam or other NSAIDs and other drugs; history of asthma, urticaria, angioedema, or nasal polyps following aspirin or other NSAID use. Active peptic ulcer, gastrointestinal bleeding, inflammatory bowel disease; history of gastrointestinal disorders predisposing to bleeding disorders (e.g. ulcerative colitis, Crohn's disease, gastrointestinal cancer, diverticulitis); history of gastrointestinal ulceration, bleeding, or perforation; severe heart failure; history of uncontrolled hypertension, CVA, or MI. Use in the setting of CABG surgery. Pregnancy (3rd trimester). Concomitant use with anticoagulants, aspirin (at analgesic doses) and other NSAIDs including COX-2 inhibitors.

Patient with oedema, mild to moderate CHF, established ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, risk factors for CV disease (e.g. hyperlipidaemia, diabetes mellitus), hypovolaemia, bleeding diathesis, other forms of asthma or history of bronchial asthma. Dehydrated and debilitated patients. Smokers. CYP2C9 poor and intermediate metabolisers. Patient taking oral corticosteroids, SSRIs, or antiplatelet agents. Consider discontinuation of treatment in women having difficulties conceiving or who are undergoing investigation of infertility. May mask signs and symptoms of infection. Not indicated as 1st-line treatment for rheumatic conditions (oral). Renal and hepatic impairment. Elderly. Pregnancy (1st-2nd trimester) and lactation.

Significant: Anaphylactoid reactions, new-onset or exacerbation of hypertension; fixed drug eruption, Na and fluid retention, oedema, impaired female fertility, may decrease platelet adhesion and aggregation, anaemia, elevated transaminase, hyperkalaemia. Rarely, interstitial nephritis, glomerulitis, papillary necrosis, nephrotic syndrome; serum sickness-like reaction.
Blood and lymphatic system disorders: Leucopenia, eosinophilia, thrombocytopenia.
Ear and labyrinth disorders: Tinnitus, vertigo.
Eye disorders: Blurred vision, eye irritations, swollen eyes.
Gastrointestinal disorders: Nausea, vomiting, constipation, abdominal pain or discomfort, diarrhoea, epigastric distress, indigestion, flatulence.
General disorders and administration site conditions: Mild to moderate local irritation, erythema, pruritus, and dermatitis at the application site (topical).
Investigations: Weight increase.
Metabolism and nutrition disorders: Anorexia, hyperglycaemia.
Nervous system disorders: Headache, dizziness, somnolence.
Skin and subcutaneous tissue disorders: Rash, pruritus; photosensitivity reaction, eczema (topical).
Potentially Fatal: Gastrointestinal inflammation, bleeding, ulceration, and perforation; increased risk of serious CV thrombotic events (e.g. MI, stroke); drug reaction with eosinophilia and systemic symptoms, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis. Rarely, severe hepatic reactions (e.g. fulminant hepatitis, hepatic failure, hepatic necrosis).

Parenteral/PO: Z (NSAIDs caused foetal ductus arteriosus premature closure, foetal renal impairment and persistent pulmonary hypertension. Avoid near term, else use lowest dose for shortest time.)

This drug may cause drowsiness, dizziness, or visual disturbances, if affected, do not drive or operate machinery.

Monitor Hb, haematocrit, occult blood loss, electrolytes; renal and hepatic function tests (periodically); blood pressure (at the initiation of treatment and periodically during use). Periodic ophthalmologic evaluations during long-term use.

Symptoms: Lethargy, nausea, vomiting, epigastric pain, drowsiness, gastrointestinal bleeding. Rarely, hypertension, acute renal failure, respiratory depression, and coma. Management: Symptomatic and supportive treatment. Consider inducing emesis and/or administering activated charcoal (60-100 g in adults and 1-2 g/kg in children) and/or osmotic cathartic in symptomatic patients within 4 hours of ingestion or during a large overdose (5-10 times the usual dosage). Gastric lavage may also be performed if appropriate.

Increased risk of gastrointestinal ulceration or bleeding with oral corticosteroids, SSRIs, or antiplatelet agents (e.g. low-dose aspirin). May enhance the nephrotoxic effect of ciclosporin and tacrolimus. May reduce the efficacy of diuretics and antihypertensive agents (e.g. ACE inhibitors, β-blockers, ARBs). May increase plasma levels of lithium, methotrexate, and digoxin. May increase the risk of convulsion with quinolones. May interfere with mifepristone-mediated termination of pregnancy.
Potentially Fatal: May enhance effects of anticoagulants (e.g. warfarin). Increased risk of serious gastrointestinal events with aspirin and other NSAIDs.

Increased risk of gastrointestinal bleeding with excessive alcohol ingestion. May slightly delay the rate, but not the extent of absorption with food.

May result in false-positive aldosterone/renin ratio (ARR).

Description:
Mechanism of Action: Piroxicam is an oxicam derivative NSAID that reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, resulting in decreased formation of prostaglandin precursors. It has analgesic, anti-inflammatory, and antipyretic properties.
Onset: Analgesia: Within 1 hour (Max: 3-5 hours).
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract. Slightly delayed rate of absorption with food. Time to peak plasma concentration: 3-5 hours.
Distribution: Enters breast milk (small amounts). Volume of distribution: 0.14 L/kg. Plasma protein binding: 99%.
Metabolism: Extensively metabolised in the liver mainly by CYP2C9 isoenzyme via hydroxylation and conjugation with glucuronic acid into inactive metabolites.
Excretion: Via urine and faeces (<5% as unchanged drug). Elimination half-life: Approx 50 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54676228, Piroxicam. https://pubchem.ncbi.nlm.nih.gov/compound/Piroxicam. Accessed Nov. 24, 2022.

Store between 15-30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M02AA07 - piroxicam ; Belongs to the class of non-steroidal antiinflammatory preparations for topical use. Used in the treatment of joint and muscular pains.
M01AC01 - piroxicam ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, oxicams.

Theken KN, Lee CR, Gong L et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clinical Pharmacology and Therapeutics. 2020 Aug;108(2):191-200. doi: 10.1002/cpt.1830. Accessed 02/11/2022

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