Based on the evaluation of the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing carboplatin (carboplatin), the Pharmacovigilance Risk Assessment Committee (PRAC) reached the following conclusions.
Kounis syndrome is defined as any allergy-mediated acute coronary syndrome, including stent thrombosis resulting from anaphylactoid processes, and therefore it can be regarded as a coronary syndrome in the case of allergic/anaphylactic reactions. The clinical manifestations of this syndrome are always associated with subclinical, clinical, acute, or chronic allergic reactions accompanied by cardiac symptoms.
In total, 8 cases were selected from the reports submitted by registration certificate holders (RCHs) in their review (also confirmed by a query run in the Eudravigilance database) that support Kounis syndrome with the use of carboplatin.
5 of 8 cases of carboplatin-induced coronary artery vasospasm were obtained from reports documented in the published literature. In particular, two cases reported the preferred term (PT) “Kounis syndrome”, one case the PT “Arteriospasm coronary” and two cases the PT “Angina associated with hypersensitivity reaction”. Among these literature cases, two (Baroni M, et al. Journal of Cardiology Cases 4: e58-e61, No. 1, August 2011; Tambe V et al. American Journal of Therapeutics. /November/2020; 27) were well described and provided evidence of a possible causal relationship between the occurrence of Kounis syndrome and the use of carboplatin, with ECG signs suggestive of acute coronary syndrome. One case (Martin R. et al. Cancer Chemother. Pharmacol. 2002; 50:429-431) was described in combination therapy with several medicinal products, and another (Mark A. et al., American Journal of Obstetrics and Gynecology) had no ECG signs. Nevertheless, both cases had a possible association with the occurrence of Kounis syndrome related to the use of carboplatin, based on the temporal relationship and diagnostic criteria. In the fifth case (Shuichi Y et al. Journal of Japanese Circulation Journal, 1996, volume 1996, page 185-188), which was fatal, etoposide was noted as a confounding factor. However, the authors described a temporal relationship with carboplatin and diagnostic criteria plausible for Kounis syndrome.
Three case reports were received from healthcare professionals. These three less well-documented cases are considered relevant to this review.
In total, in seven cases, patients experienced cardiac symptoms in the context of hypersensitivity/anaphylaxis with a temporal relationship consistent with a diagnosis of Kounis syndrome, which was also supported by ECG data (ST-segment elevation, documented in 5 cases). Information on the results of myocardial perfusion imaging, cardiac enzymes, and coronary angiography was not reported.
In most cases, the events resolved after treatment with nitroglycerin and/or corticosteroids.
Allergic reactions/hypersensitivity are already included in the list of adverse reactions and important identified risks for carboplatin. In addition, articles on antineoplastic drugs and cardiotoxicity document that platinum-containing medicinal products such as cisplatin, carboplatin, and oxaliplatin can induce Kounis syndrome, usually type I and/or type II.
Based on a review of spontaneous reports, the literature, and biological plausibility, it was concluded that there is reasonable evidence supporting a causal relationship between the use of carboplatin and the development of Kounis syndrome. Since hypersensitivity reactions associated with carboplatin therapy have been reported, and patients with pre-existing coronary disease or with risk factors for coronary disease have a higher risk of more severe Kounis syndrome progressing to myocardial infarction, it is considered important to inform healthcare professionals and patients about signs and symptoms that require close attention.
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the scientific conclusions drawn by the PRAC.
Based on the scientific conclusions, the CMDh considers that the benefit/risk balance of medicinal products containing carboplatin remains unchanged, provided that the appropriate changes are made to the instructions for medical use.
Changes that should be included in the relevant sections of the instructions for medical use (new text underlined in bold, deleted text struck through).
Section “Special warnings and precautions for use”
The following warnings should be added:
Hypersensitivity reactions
[…]
There have been reports of hypersensitivity reactions that progressed to Kounis syndrome (acute allergic coronary artery spasm that can lead to myocardial infarction, see the “Adverse reactions” section).
“Adverse reactions” section
Cardiac disorders: frequency “not known”: Kounis syndrome
Перелік лікарських засобів, що містять карбоплатин (carboplatin) та дозволені для застосування на території України (за даними Державного реєстру лікарських засобів станом на 01.12.2022)
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