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 captopril, PSUSA/00000535/202504, reached the following conclusions.
In view of the data available in the literature on autoimmune insulin syndrome, spontaneous reports, including isolated cases with a positive de-challenge, and the plausible mechanism of action, the PRAC considers that a causal relationship between the use of captopril and autoimmune insulin syndrome is at least reasonably possible. The PRAC concluded that the instructions for medical use of medicinal products containing captopril should be amended accordingly.
Given the data available in the literature on angioedema with delayed onset and bradykinin-mediated angioedema, as well as spontaneous reports, including individual cases with a positive de-challenge, PRAC considers that the development of delayed-onset angioedema associated with the use of captopril is at least reasonably possible. PRAC concluded that the instructions for medical use of medicinal products containing captopril should be amended accordingly.
Having considered the PRAC recommendations, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the overall conclusions of the PRAC and the grounds for the recommendations.
Based on the scientific conclusions regarding captopril, the CMDh considers that the benefit/risk balance of medicinal products containing captopril remains unchanged, subject to the proposed changes 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
The following warning should be added:
Hypersensitivity / angioedema:
In patients receiving ACE inhibitors, especially during the first week of treatment, angioedema of the extremities, face, lips, mucous membranes, tongue, glottis, and/or larynx may occur. However, in rare cases severe angioedema may develop after months or years of long-term treatment with an ACE inhibitor. In such cases, treatment should be discontinued immediately. Angioedema extending to the tongue, glottis, or larynx can be fatal. Emergency therapy should be initiated.
The warning should be supplemented as follows:
Autoimmune insulin syndrome (AIS):
During treatment with captopril, cases of autoimmune insulin syndrome (AIS), including severe hypoglycemic events, have been reported (see the section “Adverse reactions”). If AIS is suspected, captopril should be discontinued and appropriate treatment initiated.
Cough:
…
“Adverse reactions” section
The following adverse reaction should be added to the System Organ Class (SOC) “Immune system disorders” (with the frequency “not known”):
Insulin autoimmune syndrome
Changes to the safety information of medicinal products containing captopril, following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 24 – 27 November 2025
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) held on November 24 – 27, 2025. Following the meeting, a decision was made that safety-related changes need to be introduced to the registration materials/ instructions for medical use of medicinal products containing captopril.
Captopril – PSUSA/00000535/202504
Captopril is an angiotensin-converting enzyme (ACE) inhibitor indicated for the treatment of arterial hypertension, myocardial infarction and macroproteinuric diabetic nephropathy in patients with type I diabetes mellitus, as well as for the treatment of chronic heart failure with reduced ventricular systolic function in combination with diuretics and, if necessary, medicinal products containing digitalis, and beta-blockers.
Based on the evaluation of periodic safety update reports (PSURs), PRAC reviewed the benefit/risk balance of medicinal products containing captopril and provided the relevant recommendations.
Summary of recommendations and conclusions
- Based on the analysis of safety and efficacy data, the benefit / risk balance of medicinal products containing captopril for the approved indications remains unchanged.
- At the same time, the instructions for medical use should be updated to amend the warning on angioedema, stating that severe angioedema may develop after several months or years of long-term treatment with an ACE inhibitor. In addition, the instructions for medical use should be updated by adding warnings on autoimmune insulin syndrome and angioedema, and by adding autoimmune insulin syndrome as an adverse reaction with a frequency of “unknown”. Thus, the existing provisions of the instructions for medical use should be amended1.
- In the next PSUR, if any new important safety information regarding angioedema is identified, all registration certificate holders (RCHs) should assess the appropriateness of introducing additional regulatory actions. In addition, all RCHs should provide cumulative reviews of cases of psoriasis, lax skin syndrome (cutis laxa), and malignant neoplasms associated with the use of captopril, based on relevant data sources, and assess any new important information on this issue. Furthermore, RCHs should monitor cases of drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), and linear IgA dermatosis and analyze any new safety information identified.
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1Update of the “Special warnings and precautions for use” and “Adverse reactions” sections of the instructions for medical use. The risk assessment report and the PRAC recommendation are forwarded to CMDh for decision.
List of medicinal products containing captopril and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 13.04.2026). (13 KB) (Downloaded: 28.04.2026 07:51:32)
TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE RELEVANT APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT AVAILABLE AT THE FOLLOWING LINKS:
