New contraindication on the use of high-dose diclofenac for more than four weeks in selected groups of patients

HSA would like to inform healthcare professionals that the use of high-dose systemic diclofenac (150mg/day via oral, rectal or parenteral routes) for more than four weeks is contraindicated in patients with established cardiovascular (CV) disease or uncontrolled hypertension. This regulatory decision was made following HSA's benefit-risk assessment, in consultation with its Product Vigilance Advisory Committee (PVAC) and several other clinical experts.

Background

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) that has been licensed in Singapore since February 1991 for the treatment of pain and inflammation for a wide range of conditions including rheumatism, post-traumatic pain and post-operative pain. There are more than 30 different brands of diclofenac registered locally. 

HSA has been closely monitoring the CV safety of NSAIDs since 2005. A Dear Healthcare Professional Letter was issued on 28 April 2005 following HSA's benefit-risk assessment and the conclusion that there was a small but increased CV risk with NSAIDs.1 Healthcare professionals were recommended to prescribe NSAIDs at the lowest effective dose and for the shortest possible duration required for treatment.In addition, it was advised that all NSAIDs should not be prescribed in patients who have undergone recent coronary artery bypass surgery and revascularisation procedures.

Benefit-risk assessment of systemic diclofenac

In recent years, there has been a growing body of scientific evidence to suggest that high doses of diclofenac used over a long duration is associated with increased CV risks.2-5 In a meta-analysis conducted by the Coxib and traditional NSAID Trialists' Collaboration, the risk of major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) was reported to have increased by about a third in patients receiving a selective COX-2 inhibitor (rate ratio [RR] 1.37; 95%CI 1.14, 1.66; p=0.0009) or diclofenac (RR 1.41; 95%CI 1.12, 1.78; p=0.0036), when compared with placebo.2 This was mainly due to an increase in major coronary events such as non-fatal myocardial infarction or coronary death (selective COX-2 inhibitor: RR 1.76; 95%CI 1.31, 2.37; p=0.0001; diclofenac: RR 1.70; 95%CI 1.19, 2.41; p=0.0032).

International regulatory actions 

The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) completed a safety assessment in June 2013, which concluded that benefits of systemic diclofenac still outweigh the risks but there is an increase in CV risk in patients taking systemic diclofenac at high doses over a long period. PRAC recommended that the precautions already in place in the European Union to minimise the risk of arterial thromboembolic events with selective COX-2 inhibitors should also be applied to diclofenac. These precautions include a contraindication in patients with established congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. The Committee also recommended that patients with significant risk factors for CV events be treated with diclofenac only after careful consideration.6

In July 2013, the New Zealand Medicines and Medical Device Safety Authority's benefit-risk assessment concluded that there is a small increase in CV risk with the use of high-dose diclofenac when given over a long duration. The New Zealand authority reminded its healthcare professionals to prescribe diclofenac at the lowest effective dose for the shortest possible duration and advised against using diclofenac in patients who have had a recent myocardial infarction (within the last 6 to 12 months).7

HSA’s advisory

Taking into consideration the currently available scientific evidence, expert opinions from local clinicians and HSA's PVAC, as well as the regulatory developments in other international jurisdictions, HSA is advising healthcare professionals on the following:

  • The use of high-dose systemic diclofenac (150mg/day) for more than four weeks is contraindicated in patients with established CV disease (congestive heart failure, established ischaemic heart disease, peripheral arterial disease) or uncontrolled hypertension.
  • If systemic diclofenac treatment is needed, patients with established CV disease, uncontrolled hypertension or significant CV risk factors (e.g., hypertension, hyperlipidaemia, diabetes mellitus and smoking) should be treated only after careful consideration and at doses ≤100mg daily if the treatment is for more than 4 weeks.
  • As the CV risks of systemic diclofenac may increase with dose and duration of exposure, diclofenac should always be prescribed at the lowest effective daily dose and for the shortest duration possible.

A Dear Healthcare Professional Letter was issued on 27 February 2014 to healthcare professionals to inform them on the new contraindication and updated advisories.8 The local package inserts for systemic diclofenac-containing products will be strengthened to reflect these recommendations.

Healthcare professionals are encouraged to take into consideration the above recommendations when prescribing diclofenac. They are also encouraged to report any suspected serious adverse reactions related to diclofenac to the Vigilance Branch of HSA.

References

  1. HSA Dear Healthcare Professional Letter: HSA’S Expert Advisory Committee’s recommendations on Cyclo-Oxygenase-2 (Cox-2) Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDS). 28 Apr 2005. No. 12. 
  2. Lancet 2013; 382: 769-79
  3. Cir Cardiovasc Qual Outcomes 2010; 3: 395-405
  4. Pharmacoepidemiol Drug Saf 2013; 22: 559-70
  5. PLoS ONE 2013; 8: e54309
  6. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Diclofenac-containing_medicinal_products/European_Commission_final_decision/WC500155819.pdf
  7. http://www.medsafe.govt.nz/Projects/B2/2013/diclofenac-cardio.asp
  8. HSA Dear Healthcare Professional Letter: New contraindication on the use of high dose diclofenac for more than four weeks in selected groups of patients. 27 Feb 2014. No. 54
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