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.
Changes to the safety information for medicinal products containing piretanide / ramipril, piretanide, based on the results of the meeting of the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) of 24 – 25 March 2026
Piretanide / ramipril, piretanide – PSUSA/00002434/202508
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), having considered the Periodic Safety Update Reports (PSURs) on the basis of the recommendations and report of the Pharmacovigilance Risk Assessment Committee (PRAC), agreed by consensus to amend the registration materials / instructions for medical use of medicinal products containing piretanide / ramipril, piretanide.
PRAC noted that angioedema may also develop a long time after the start of treatment with angiotensin-converting enzyme (ACE) inhibitors. In addition, available data indicate that angioedema caused by ACE inhibitors is mediated by bradykinin, and epinephrine may be ineffective in treating angioedema caused by ACE inhibitors. This information should be added to the existing warning on angioedema in the section “Special warnings and precautions for use” of the instructions for medical use of ACE inhibitors.
It should be noted that the sections “Special warnings and precautions for use” and/or “Overdose” of the instructions for medical use of some ACE inhibitors contain incorrect recommendations, according to which treatment of angioedema caused by ACE inhibitors involves the immediate administration of epinephrine. This incorrect information should be removed.
The PRAC concluded that this updated information applies to all medicinal products containing ACE inhibitors, including fixed-dose combinations, and therefore should be appropriately reflected in the instructions for medical use of these medicinal products.
The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing piretanide / ramipril, piretanide, PSUSA/00002434/202508, reached the following conclusions.
In view of the available literature data on life-threatening angioedema, which indicate the need for specific emergency therapy instead of the therapy used to treat histamine-mediated anaphylaxis (such as epinephrine, corticosteroids, antihistamines or H2-receptor antagonists), and in view of the available data on cases of angioedema that occurred after several months or years of treatment, it is recommended to amend the existing warning regarding the measures to be taken when this adverse reaction develops. The instructions for medical use of medicinal products containing piretanide / ramipril 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 on piretanide / ramipril, piretanide, the CMDh considers that the benefit/risk ratio of medicinal products containing piretanide / ramipril, piretanide remains unchanged, provided the proposed changes are 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, deleted text struck through).
“Special precautions for use” section
The precaution should be amended as follows:
Angioedema — of the head, neck, or extremities
If angioedema occurs during treatment, [name of medicinal product] must be discontinued immediately. Angioedema of the face, extremities, lips, tongue, glottis, or larynx was observed may occur at any time during therapy with ACE inhibitors.
Emergency treatment In case of life-threatening angioedema, caused by ACE inhibitors, the use of epinephrine may be ineffective involves immediate administration of epinephrine (by subcutaneous injection or slow intravenous administration) under ECG control and blood pressure monitoring. The patient should be hospitalized, kept under medical supervision for at least 12–24 hours, and discharged only after complete resolution of symptoms.
“Overdose” section
Recommendations on measures in case of overdose should be removed:
Emergency treatment of angioedema
In cases of life-threatening angioedema involving the tongue, glottis and/or larynx, the following emergency measures are recommended: immediate subcutaneous administration of 0,3–0,5 mg of epinephrine or slow intravenous administration of 0,1 mg of epinephrine (follow the dilution instructions!) under ECG and blood pressure monitoring, followed by systemic administration of glucocorticoids. Intravenous administration of antihistamines and H2-receptor antagonists is also recommended. In addition to epinephrine, in cases of known C1 inhibitor deficiency, administration of C1 inhibitor may be considered. The patient should be hospitalized and observed for at least 12–24 hours. The patient should not be discharged until the symptoms have completely resolved.
Changes to the safety information for medicinal products containing piretanide / ramipril, piretanide following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of March 09 – 12, 2026
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 09 – 12 March 2026. 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 piretanide / ramipril, piretanide.
Piretanide / ramipril, piretanide – PSUSA/00002434/202508
Piretanide is a diuretic indicated for the treatment of arterial hypertension. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of arterial hypertension. The piretanide/ramipril combination is indicated for the treatment of essential hypertension in patients in whom sufficient reduction of blood pressure could not be achieved with ramipril monotherapy.
Based on the evaluation of periodic safety update reports (PSURs), the PRAC reviewed the benefit/risk balance of medicinal products containing piretanide / ramipril, piretanide, and gave 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 piretanide/ramipril and piretanide for the approved indications remains unchanged.
- At the same time, the instructions for medical use should be updated by amending the warning on angioedema, in particular by clarifying that in the case of angioedema caused by angiotensin-converting enzyme inhibitors, the use of epinephrine may be ineffective, and by removing the existing wording on emergency therapy for angioedema. Thus, the existing provisions of the instructions for medical use of medicinal products for systemic use should be amended1.
- In the next PSUR, the registration certificate holder Zentiva must continue to carefully monitor and analyze any new cases of drug-induced eosinophilia with systemic symptoms (DRESS). The registration certificate holder Sanofi must review the list of safety concerns for the next PSUR in order to remove from it the safety concerns that belong to important identified risks.
_______________________________________________________________________________
1 Update of the sections “Special warnings and precautions for use” and “Overdose” of the instructions for medical use. The PRAC assessment report and recommendations are forwarded to the CMDh for adoption of a position.
List of medicinal products containing angiotensin-converting enzyme (ACE) inhibitors and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 23.06.2026). (65 KB) (Downloaded: 30.06.2026 05:13:35)
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:
