COX-2 selective inhibitors

NSAIDS with preferential cyclo-oxygenase 2 inhibitions have been developed. These include:

• celecoxib
• etoricoxib

Meloxicam and etodolac inhibit COX-2 up to 50 times more than COX-1. However they may still inhibit COX-1 at therapeutic doses (1).

Advice for Prescribers in light of concerns about cardiovascular safety of COX-2 inhibitors (2)

• evidence suggests that selective COX-2 inhibitors, as a class, may cause an increased risk of thrombotic events (e.g. MI and stroke) compared with placebo and some NSAIDs and the risk may increase with dose and duration of exposure. It is not possible to quantify the risk precisely, but it is considered unlikely to exceed one extra serious thrombotic event per 100 patient years, over the rate for no treatment. The Medicines and Health Regulatory Agency (MRHA) advice is as follows (2):
  • patients with established ischaemic heart disease or cerebrovascular disease should be switched to alternative treatment. In addition, the existing contraindication for severe heart failure is now extended to include moderate heart failure (NHYA class II-IV).
  • for all patients the balance of GI and cardiovascular risk should be considered before prescribing a COX-2 inhibitor, particularly for those with risk factors for heart disease (such as hypertension, hyperlipidaemia, diabetes and smoking, as well as for patients with peripheral arterial disease) and those taking low dose aspirin, for whom GI benefit has not been clearly demonstrated.
  • the lowest effective dose of COX-2 inhibitor should be used for the shortest necessary period. Periodic re-evaluation is recommended, especially for osteoarthritis patients who may only require intermittent treatment.
  • gastroprotective agents should be considered for patients switched to non-selective NSAIDs, e.g. omperazole 20mg
  • the European Medicines Agency has concluded its action on COX-II inhibitors (3) and has strengthened the following contraindications and precautions for the COX-2 inhibitors:
    • COX-II inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease, and also in patients with peripheral arterial disease.
    • caution should be exercised when prescribing COX-II inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia, diabetes and smoking.
    • given the association between cardiovascular risk and exposure to COX-II inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment.
    • hypersensitivity reactions and rare, but serious and sometimes fatal, skin reactions can occur with all COX-II inhibitors. In the majority of cases these occur in the first month of use, and prescribers are warned that patients with a history of drug allergies may be at greater risk.
    • the Committee concluded that "when prescribed in accordance with these additional contraindications and precautions, the balance of benefits and risks remains positive for these COX-II inhibitors used in their target patient populations"
  • there has been advice regarding etoricoxib as follows (2):
    • etoricoxib may be associated with more frequent and severe effects on BP than some other COX-2 inhibitors and NSAIDs, particularly at high doses.
    • etoricoxib treatment should not be initiated in patients whose hypertension is not under control.
    • eareful monitoring of BP is advised for patients taking etoricoxib.
  • the following reminder has also been issued by the MRHA concerning parecoxib (2):
    • parecoxib may be associated with higher rates of serious skin reactions (e.g. Stevens-Johnson syndrome, Toxic Epidermal Necrolysis) than other COX-2 inhibitors. Treatment should be stopped at the first signs of skin rash or hypersensitivity react

A review stated (4):

• there are few, if any, situations in which a COX-2 inhibitor is unequivocally indicated
• all NSAIDs, including COX-2 inhibitors, should be avoided, wherever possible, in patients at high risk of gastrointestinal complications
• there are potential hazards in prescribing a COX-2 inhibitor to a patient who is at risk from cardiovascular disease, and no advantage for patients taking low-dose aspirin for cardiovascular prophylaxis

Pfizer Ltd have voluntarily suspended the marketing and sales of valdecoxib (April 8th 2005).

Reference

• (1) Warner TD et al (1999). Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA, 96, 7563-8.
• (2) Medicines and Healthcare products Regulatory Agency (February 2005). COX-2 inhibitors - guidance by both the Medicines and Health Regulatory Agency (MHRA) and the European Medicines Agency (EMA)
• (3) European Medicines Agency (EMA) (June 2005). COX-2 inhibitors.
• (4) Drug and Therapeutics Bulletin (2005); 43(1):1-5.