In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing ethyl esters of omega-3 acids (omega-3-acid ethyl esters), reached the following conclusions.
Given the available data on the risk of atrial fibrillation obtained from clinical trials, the literature and spontaneous reports, the PRAC considers that a causal relationship between the use of omega-3 acid ethyl esters and atrial fibrillation is at least a possibility. The PRAC concluded that the instructions for medical use of medicinal products containing omega-3 acid ethyl esters should be amended accordingly.
After adoption of the PRAC recommendation:
- The registration certificate holder BASF did not fully agree with the adopted PRAC recommendation and provided additional information in writing and during an oral explanation to the Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh) in support of its objections to the calculation of the frequency of atrial fibrillation as “common” based on a meta-analysis of randomized clinical trials, the need to inform through a Direct Healthcare Professional Communication (DHPC), and the change in the PSUR frequency from 3 years to 1 year.
- The registration certificate holder SPA provided written objections regarding the calculation of the frequency of atrial fibrillation as “common” based on a meta-analysis of randomized clinical trials.
Having considered the PRAC recommendation, the information provided by the holder BASF in writing and during the oral explanation, as well as the written comments provided by the holder SPA after the adoption of the PRAC recommendation, the CMDh agrees with the overall conclusions of the PRAC and the grounds for the recommendations.
Based on the scientific conclusions on ethyl esters of omega-3 acids (omega-3-acid ethyl esters), the CMDh considers that the benefit/risk balance of medicinal products containing ethyl esters of omega-3 acids (omega-3-acid ethyl esters) remains unchanged, subject to the proposed amendments being made to the instructions for medical use.
Changes to be made to the relevant sections of the instruction for medical use (new text underlined and in bold).
“Special precautions for use” section
Systematic reviews and meta-analyses of randomized controlled clinical trials have shown a dose-dependent increase in the risk of atrial fibrillation in patients with established cardiovascular disease or cardiovascular risk factors who used omega-3 acid ethyl esters compared with placebo. The risk is highest at a dose of 4 g/day (see section “Adverse reactions”). If atrial fibrillation develops, treatment should be permanently discontinued.
“Adverse reactions” section
The following adverse reaction should be added to the subsection “Cardiovascular system disorders” with the frequency “common”
Atrial fibrillation
Changes to the safety information of medicinal products containing omega-3 acid ethyl esters (omega-3-acid ethyl esters) following the results of the Pharmacovigilance Risk Assessment Committee (PRAC) meeting of 25–28 September 2023
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 25–28 September 2023. Following the meeting, a decision was made on the need to introduce safety-related changes to the registration materials/instructions for medical use of medicinal products containing omega-3-acid ethyl esters (omega-3-acid ethyl esters).
Ethyl esters of omega-3 acids (omega-3-acid ethyl esters) – PSUSA/00010312/202301
Omega-3 acid ethyl esters (omega-3-acid ethyl esters) are ethyl esters of polyunsaturated fatty acids (PUFAs), the main components of which are eicosapentaenoic acid (EPA) and (DHA), and are indicated for lowering elevated triglyceride levels (hypertriglyceridemia) when the response to diet and other non-pharmacological measures has proved insufficient.
Based on the evaluation of the PSURs, the PRAC reviewed the benefit/risk balance of medicinal products containing omega-3-acid ethyl esters (omega-3-acid ethyl esters) and made the following recommendations.
Summary of recommendations and conclusions
- Based on the analysis of safety and efficacy data, the benefit/risk balance of medicinal products containing ethyl esters of omega-3 acids (omega-3-acid ethyl esters) for the approved indications remains unchanged.
- Nevertheless, the instructions for medical use should be updated to add atrial fibrillation as a warning and as an adverse reaction with the frequency “common”. Accordingly, the existing provisions of the instructions for medical use should be amended1.
- In the next PSUR, all registration certificate holders (RCHs) must include “atrial fibrillation” as an important identified risk in the list of safety concerns and monitor any new data on this risk from any source, and also discuss the need to implement further risk minimization measures if necessary. In addition, all RCHs must monitor cases of “increased blood creatine phosphokinase” and discuss the possible contributing role of the use of omega-3 acid ethyl esters (omega-3-acid ethyl esters).
PRAC agreed on the distribution of the DHPC together with a communication plan.
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1 Update of the sections “Special warnings and precautions for use” and “Adverse reactions” of the package insert. The risk assessment report and PRAC recommendation are forwarded to the CMDh for a decision.
Decision of the Coordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh) of 10-11 October 2023 on medicinal products containing omega-3 acid ethyl esters (omega-3-acid ethyl esters)
Ethyl esters of omega-3 acids (omega-3-acid ethyl esters) – PSUSA/00010312/202301
An oral explanation was provided by one registration certificate holder (RCH), who did not fully agree with the PRAC recommendation to include atrial fibrillation as an adverse reaction with the frequency “common” in the instructions for medical use of medicinal products containing omega-3 acid ethyl esters, the proposed DHPC, and the change of the PSUR submission frequency to annual. The CMDh heard the arguments presented by the holder and discussed the issues raised.
CMDh, having considered the PSUR on the basis of the PRAC recommendation, the PRAC assessment report, and additional information provided by the holder, agreed by consensus with the PRAC recommendation without any changes.
List of medicinal products containing ethyl esters of omega-3 acids (omega-3-acid ethyl esters) and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 07.12.2023)
To analyze the published information, the applicant must use the original text available at the link:
