Omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000mg capsules): dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors

Systematic reviews and meta-analyses of randomised controlled trials have highlighted a dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors treated with omega-3-acid ethyl ester medicines compared to placebo.

From:
Medicines and Healthcare products Regulatory Agency
Published
22 January 2024
Therapeutic area:
Cardiovascular disease and lipidology and Nutrition and dietetics

Advice for healthcare professionals:

  • atrial fibrillation is now listed as an adverse drug reaction with a “common” frequency (may affect up to 1 in 10 people) for medicines containing omega-3-acid ethyl esters licensed for the treatment of hypertriglyceridaemia
  • the observed risk was found to be highest with a dose of 4 g/day
  • advise patients taking omega-3-acid ethyl ester medicines for the treatment of hypertriglyceridaemia to seek medical attention if they develop symptoms of atrial fibrillation
  • if a patient develops atrial fibrillation whilst taking these medicines for the treatment of hypertriglyceridaemia then the medicine should be discontinued permanently
  • report suspected adverse drug reactions associated with omega-3-acid ethyl ester medicines on a Yellow Card

Advice for healthcare professionals to give to patients and carers:

  • medicinal products containing omega-3 ethyl esters are licensed for the reduction of high triglyceride levels (hypertriglyceridaemia) after changes to diet have not worked
  • very high levels of triglycerides in the blood can cause problems such as increasing the risk of coronary heart disease and causing inflammation of the pancreas (pancreatitis)
  • before taking an omega-3-acid ethyl ester medicine, inform your doctor or pharmacist if you are currently experiencing heart problems or have a history of heart problems
  • talk to your doctor if you experience palpitations, dizziness, shortness of breath and tiredness as these may be symptoms of an irregular and often very rapid heart rhythm (atrial fibrillation)
  • do not stop your hypertriglyceridaemia treatment without first discussing this with your doctor

Review of atrial fibrillation associated with omega-3-acid ethyl ester medicines

A recent European regulatory review recommended “atrial fibrillation” should be listed as a common adverse reaction (may affect up to 1 in 10 people) in the product information of medicines containing omega-3-acid ethyl esters. The review of safety and efficacy data for omega-3 acid ethyl ester medicines licensed for the treatment of hypertriglyceridaemia considered a dose-dependent increased risk of atrial fibrillation which had been identified by several meta-analyses of large randomised controlled trials (RCTs). These trials investigated the effect on cardiovascular outcomes compared with placebo enrolling more than 80,000 patients, mostly with cardiovascular diseases or cardiovascular risk factors. [footnote 1][footnote 2][footnote 3] The frequency of atrial fibrillation was determined as “common” since, from this data, the incidence would be 3.9%.

The findings of this review were considered by the Pharmacovigilance Expert Advisory Committee (PEAG) of the Commission on Human Medicines (CHM), which agreed with the recommendations of European regulators to update the product information. A letter has been sent to UK healthcare professionals. The PEAG also recommended issuing a Drug Safety Update to inform healthcare professionals and patients about the new information.

The product information recommends permanent discontinuation of treatment for patients who develop atrial fibrillation whilst taking these medicines for hypertriglyceridaemia. Clinical judgment and assessment of the individual benefits and risks to the patient should be taken into consideration before any decision to stop treatment.

The PEAG noted that, in the case of patients with a previous or current diagnosis of atrial fibrillation, the Product Information does not provide specific advice or contraindicate use of these medicines.

Omega-3 dietary sources and supplements

The MHRA does not regulate food or dietary supplements that are marketed without reference to a medicinal effect/claim. Neither the randomised controlled trials or the review evaluated dietary consumption of fish and other foods rich in omega-3 nor supplements, and we are unable to give advice on the risk in individuals who consume dietary omega-3 supplements without a known history of cardiovascular disease or significant cardiovascular risk factors.

Reports of atrial fibrillation with omega-3-containing products

Up to 13 November 2023, the MHRA has not received any Yellow Card reports describing atrial fibrillation in association with a medicinal product containing omega-3 acids as the active substance. Atrial fibrillation is an abnormal heart rhythm characterised by a fast irregularly irregular heart rate. Symptoms of atrial fibrillation include palpitations, dizziness, shortness of breath and tiredness. If untreated it can cause formation of blood clots in the heart which may travel to the brain (embolise), leading to a stroke.

Other omega 3 ethyl ester medicines

Vazkepa (icosapent ethyl) authorised in 2021 is indicated to reduce the risk of cardiovascular events in adult statin-treated patients at high cardiovascular risk with elevated triglycerides (≥ 150 mg/dL [≥ 1.7 mmol/L]) and established cardiovascular disease, or diabetes, and at least one other cardiovascular risk factor. Icosapent ethyl is a stable ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). At time of initial authorisation of this medicinal product, atrial fibrillation/flutter was listed as a common adverse drug reaction. The incidence of atrial fibrillation/flutter was 5.8% of subjects receiving icosapent ethyl in a placebo-controlled cardiovascular outcomes trial compared with 4.5% in subjects receiving placebo.

Several parenteral infusion products that contain omega 3 acid triglycerides or omega-3 fish oil are licensed as prescription only medicines in the UK. These products do not currently list atrial fibrillation as a recognised adverse drug reaction. At this time they are not directly impacted by the regulatory action that has been taken.

Report suspected drug reactions on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme. Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Article citation: Drug Safety Update volume 17, issue 6, January 2024: 3.

  1. Lombardi M, and others. Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials. European Heart Journal Cardiovascular Pharmacotherapy. 2021 Jul 23;7(4):e69-e70. ↩

  2. Gencer B, and others. Omega-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021 Dec 21;144(25):1981-1990. ↩

  3. Yan J and others. The most important safety risk of fish oil from the latest meta-analysis?, European Journal of Preventive Cardiology. Volume 29, Issue Supplement_1, May 2022, zwac056.186, ↩

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Published 22 January 2024
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