The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing 5-fluorouracil (5-fluorouracil) [for intravenous use], made the following conclusions.
Given the available data from literature and spontaneous reports, including cases with a positive test on re-administration and repeated withdrawal (de-challenge) and/or a positive test on re-prescription (re-challenge), PRAC considers a causal relationship between the use of medicinal products containing 5-fluorouracil (5-fluorouracil) [IV use] and the occurrence of cutaneous lupus erythematosus to be at least possible. PRAC concluded that the instructions for medical use should be changed accordingly.
Given the available data from the literature and spontaneous reports, including cases with a close temporal relationship, with a positive test on repeated use and repeated withdrawal (de-challenge) and/or a positive test on re-prescription (re-challenge), PRAC considers that a causal relationship between the use of medicinal products containing 5-fluorouracil (5-fluorouracil) [IV use] and the occurrence of stress cardiomyopathy (takotsubo syndrome) and intestinal pneumatosis is at least possible. PRAC concluded that the instructions for medical use should be amended accordingly.
Given the available data from literature and spontaneous reports, including a close temporal relationship and a case with a positive test on re-administration and repeated withdrawal (de-challenge), PRAC considers that a causal relationship between the use of medicinal products containing 5-fluorouracil (5-fluorouracil) [IV use] and the occurrence of posterior reversible encephalopathy syndrome and lactic acidosis is at least possible. PRAC concluded that the instructions for medical use should be changed accordingly.
In view of the available data from the literature and spontaneous reports, including cases with a close temporal relationship, as well as a plausible mechanism of action, the PRAC considers that a causal relationship between the use of medicinal products containing 5-fluorouracil (5-fluorouracil) [IV use] and the occurrence of tumor lysis syndrome is at least possible; therefore, appropriate changes must be made to the instructions for medical use.
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the PRAC scientific conclusions.
The CMDh considers that the benefit/risk balance of medicinal products containing fluorouracil (5-fluorouracil) [IV use] remains unchanged, provided that changes are made to the instructions for medical use.
Amendments to be included in the relevant sections of the package insert (new text underlined in bold, deleted text struck through).
Section “Special warnings and precautions for use”
Cardiotoxicity
Cardiotoxicity is associated with fluoropyrimidine therapy, including myocardial infarction, angina pectoris, arrhythmias, myocarditis, cardiogenic shock, sudden death, stress cardiomyopathy (takotsubo syndrome), and electrocardiographic changes (including very rare cases of QT prolongation). These adverse events occur more often in patients receiving continuous infusion of 5-fluorouracil than bolus injections. A history of coronary heart disease may be a risk factor for the occurrence of some cardiovascular adverse reactions. Therefore, attention should be paid to patients who complained of chest pain during the course of treatment, or patients with a history of heart disease. Cardiac function should be monitored regularly during treatment with fluorouracil. In case of severe cardiotoxicity, treatment should be discontinued.
Encephalopathy
From postmarketing experience, cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy, posterior reversible encephalopathy syndrome)) associated with 5-fluorouracil treatment are known. Symptoms of encephalopathy are altered mental status, confusion, disorientation, coma, or ataxia. If a patient develops any of these symptoms, treatment should be suspended immediately and the serum ammonia level checked. In case of elevated serum ammonia, measures to lower it should be taken. Hyperammonemic encephalopathy often occurs simultaneously with lactic acidosis.
Tumor lysis syndrome
Post-marketing experience includes known cases of tumor lysis syndrome associated with the use of fluorouracil. Patients at increased risk of developing tumor lysis syndrome (e.g., patients with renal failure, hyperuricemia, high tumor burden, or rapid disease progression) should be closely monitored. Preventive measures should be considered (e.g., hydration, correction of high uric acid levels).
“Adverse reactions” section
Add the adverse reaction “Cutaneous lupus erythematosus” to the section “Skin and subcutaneous tissue disorders” with the frequency “Not known”.
Add the adverse reaction “Stress cardiomyopathy (Takotsubo syndrome)” to the section “Cardiac disorders” with the frequency “Not known.”
Add the adverse reaction “Intestinal pneumatosis” to the section “Gastrointestinal disorders” with the frequency “Not known”.
Add the adverse reaction “Posterior reversible encephalopathy syndrome” to the section “Nervous system disorders” with the frequency “Not known.”
Add the adverse reactions “Lactic acidosis” and “Tumor lysis syndrome” to the section “Metabolic disorders” with the frequency “Not known”.
Перелік лікарських засобів, що містять 5-фторурацил (5-fluorouracil) і дозволені до медичного застосування в Україні (за даними Державного реєстру лікарських засобів України станом на 05.11.2021).
To analyze the published information, the applicant must use the original text available at the link https://www.ema.europa.eu/en/documents/psusa/5-fluorouracil-iv-application-scientific-conclusions-grounds-variation-terms-marketing-authorisation_en.pdf
