Piroxicam
Long acting oxicam NSAID with restricted indication
Piroxicam is a non steroidal anti inflammatory drug from the oxicam group. Pfizer introduced the compound in 1980 under the trade name Feldene; in Germany Feldene, Brexidol and numerous generics are available. Analgesic and anti inflammatory activity is comparable to other NSAIDs, but the half life of 30 to 60 hours is considerably longer. This makes piroxicam a long acting NSAID with once daily dosing, though also with a prolonged adverse effect profile.
In 2007 the EMA restricted the indication because of the increased gastrointestinal risk and dermatological reactions such as Stevens Johnson syndrome. Piroxicam may now only be used as a second line NSAID in chronic rheumatic conditions. For acute pain syndromes and mild inflammation other NSAIDs such as ibuprofen, diclofenac or naproxen are preferred. Treatment is initiated only by specialists experienced in the indication.
Mechanism of Action
Piroxicam non selectively inhibits the enzymes cyclooxygenase 1 (COX 1) and cyclooxygenase 2 (COX 2). These isoenzymes catalyse the conversion of arachidonic acid into prostaglandins, thromboxanes and prostacyclin. Inhibition of COX 2 mediates the anti inflammatory, analgesic and antipyretic effect, while COX 1 inhibition is responsible for the majority of the gastrointestinal, renal and platelet related adverse effects.
Piroxicam differs from shorter acting NSAIDs by its long half life, which allows once daily administration. Steady state concentration is reached after about seven days. The substance binds to plasma albumin at over 99 percent, which can become clinically relevant in hypoalbuminaemia or when other strongly protein bound drugs displace it.
Metabolism is predominantly hepatic through CYP2C9, and the metabolites are excreted renally. Piroxicam and its derivatives can also be eliminated unchanged in small amounts through the kidneys. Polymorphisms in CYP2C9 influence plasma concentrations individually, which may increase the likelihood of bleeding complications in certain genotypes.
Indications
- Symptomatic treatment of activated osteoarthritis in adults
- Rheumatoid arthritis as symptomatic therapy in combination with disease modifying treatment
- Ankylosing spondylitis (Bechterew's disease) to reduce pain and morning stiffness
In the European Union piroxicam is no longer approved for acute pain, colds, menstrual pain, postoperative analgesia or as monotherapy in acute gouty arthritis. For these indications alternatives with a more favourable benefit risk profile such as ibuprofen, naproxen or diclofenac are available.
Dosage and Administration
Adults: 20 mg once daily. In particularly sensitive patients therapy can be started at 10 mg once daily. The dose must not exceed 20 mg per day. The duration of therapy should be kept to the minimum necessary, and a reassessment after 14 days is mandatory.
The medicine is preferably taken with a meal to improve gastrointestinal tolerability. Capsules or tablets should be swallowed whole with fluid. Effervescent tablets are dissolved in a glass of water. With Brexidol (piroxicam β cyclodextrin) absorption is accelerated and tolerability is comparable.
Renal impairment: contraindicated in moderate to severe impairment, the lowest effective dose in mild impairment. Hepatic impairment: contraindicated in severe hepatic dysfunction. Elderly patients: a low starting dose because of the increased risk of gastrointestinal and renal complications. Children and adolescents under 18 years of age: not approved.
Side Effects
Common: gastrointestinal complaints such as dyspepsia, nausea, heartburn, abdominal pain, diarrhoea or constipation, rash, pruritus, tinnitus, headache, dizziness, oedema.
Uncommon to rare: gastrointestinal ulcers and bleeding (piroxicam carries one of the highest risks within the NSAID class), blood count changes (thrombocytopenia, anaemia, leukopenia), elevated liver enzymes up to hepatitis, bronchospasm, hypertension, exacerbation of heart failure, renal dysfunction.
Rare but serious dermatological reactions: Stevens Johnson syndrome and toxic epidermal necrolysis. Piroxicam belongs to the NSAIDs with an elevated risk of these serious reactions. At the first signs (fever, mucosal involvement, skin pain, blistering rash) therapy must be stopped immediately and emergency evaluation initiated.
Cardiovascular risk: as with other NSAIDs, prolonged use at high dose is associated with an increased risk of myocardial infarction and stroke. In patients with coronary artery disease, prior infarction or heart failure piroxicam is contraindicated.
Interactions
- Other NSAIDs, acetylsalicylic acid: additive gastrointestinal bleeding risk, avoid the combination
- Anticoagulants (warfarin, phenprocoumon, DOACs), heparins: substantially increased bleeding risk, combine only on a clear indication
- SSRIs, SNRIs: increased gastrointestinal bleeding risk
- Corticosteroids: additive ulcer and bleeding risk
- Antihypertensives (ACE inhibitors, ARBs, diuretics, β blockers): attenuation of blood pressure lowering
- Lithium, methotrexate, digoxin: elevated plasma concentrations through reduction of renal elimination, with a risk of toxicity
- CYP2C9 inhibitors (fluconazole, amiodarone, voriconazole): increased plasma concentrations of piroxicam
- Ciclosporin, tacrolimus: increased risk of nephrotoxic effects
Special Notes
Contraindications: active or previous peptic ulcer, gastrointestinal bleeding, severe heart failure, ischaemic heart disease, peripheral arterial occlusive disease, cerebrovascular disease, severe renal or hepatic impairment, third trimester of pregnancy, children under 18 years of age, known severe skin reaction in the history.
Gastric protection: in patients over 60 years of age, with a history of ulcer, on concomitant anticoagulants, SSRIs or corticosteroids a proton pump inhibitor (pantoprazole, omeprazole) should be co prescribed. Alternatively misoprostol can be used.
Pregnancy: only on a compelling indication in the first and second trimester, contraindicated in the third trimester because of the risk of premature closure of the ductus arteriosus and renal damage to the fetus. Breastfeeding: piroxicam passes into breast milk; brief single doses are possible, but prolonged therapy is not recommended.
Monitoring: blood pressure, renal and hepatic parameters before starting treatment and then every three months, full blood count in patients with bleeding risk factors. Patients should be informed of warning signs such as black stools, vomiting of blood or coffee ground material, severe abdominal pain and skin changes.
Treatment break: stop at least one week before planned operations because of the bleeding risk; for dental extractions or minor procedures decide individually.
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- Methotrexate, the basis therapy in rheumatoid arthritis
- Esomeprazole, a proton pump inhibitor for gastric protection
Frequently Asked Questions
Why is piroxicam no longer first line for pain?
The long half life produces prolonged exposure to potential adverse effects. The risk of gastrointestinal ulcer and bleeding ranks among the highest within the NSAID class and the risk of serious skin reactions is also increased. The EMA therefore restricted the indication in 2007, and piroxicam is now approved only as second line therapy in chronic rheumatic conditions.
Do I always need gastric protection?
In patients over 60 years of age, with a history of ulcer, or on combined therapy with anticoagulants, SSRIs or corticosteroids a proton pump inhibitor is the standard accompanying treatment. In younger patients without risk factors and with short term therapy gastric protection can be omitted. The decision is made individually by the prescribing doctor.
How quickly does piroxicam act?
The analgesic effect begins one to two hours after the first dose. The full anti inflammatory effect develops over several days because steady state plasma levels are only reached after about one week. Efficacy should therefore not be assessed prematurely, as a rule after 14 days.
Can I take piroxicam and blood thinners at the same time?
The combination considerably increases the bleeding risk and is justified only on a clear indication and with close monitoring. Alternatives such as paracetamol or topical NSAIDs are usually preferred in patients on anticoagulation. When the combination is compulsory a proton pump inhibitor is mandatory.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline on Rheumatoid Arthritis and Osteoarthritis
- Gelbe Liste, Piroxicam active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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