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 5-fluorouracil (5-fluorouracil) (for intravenous use), PSUSA/00000007/202312, made the following conclusions.
Given the data available in the literature on hypertriglyceridemia, extravasation, colitis, enterocolitis, vitamin B1 deficiency, Wernicke's encephalopathy, and errors in diagnosing dihydropyrimidine dehydrogenase (DPD) deficiency, spontaneous reports, including in some cases a close temporal association, a case with a positive de-challenge test and/or a case with a positive re-challenge test, and also given the plausible mechanism of action, PRAC considers that a causal relationship between the use of 5-fluorouracil (5-fluorouracil) (for intravenous use) and hypertriglyceridemia, extravasation, enterocolitis, vitamin B1 deficiency, Wernicke's encephalopathy, and errors in diagnosing DPD is at least reasonably possible. PRAC concluded that the instructions for medical use of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use) 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 5-fluorouracil (5-fluorouracil) (for intravenous use), the CMDh considers that the benefit/risk balance of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use) remains unchanged, provided that the proposed amendments to the instructions for medical use are made.
Changes to be made to the relevant sections of the instructions for medical use (new text underlined and in bold, deleted text struck through).
- “Special precautions for use” section
The warning should be amended as follows:
Testing to determine DPD deficiency
It is recommended to perform phenotype and/or genotype testing before starting treatment with 5-fluorouracil, despite uncertainty regarding the optimal testing methods before the start of treatment. Relevant clinical guidelines should be taken into account.
Renal impairment may lead to increased uracil levels in the blood, which leads to an increased risk of diagnostic errors in patients with DPD deficiency who have moderate or severe renal impairment.
[…]
Phenotypic characteristics of DPD deficiency
For phenotypic characterization of DPD deficiency, measurement of the level of the endogenous DPD substrate – uracil (U) – in blood plasma before the start of treatment is recommended. Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite the uncertainty regarding uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥ 16 ng/mL and < 150 ng/mL should be considered an indicator of partial DPD deficiency and associated with an increased risk of fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/mL should be considered an indicator of complete DPD deficiency and associated with a risk of fluoropyrimidine toxicity that is life-threatening or fatal. Blood uracil levels should be interpreted with caution in patients with impaired renal function (see “Testing for DPD deficiency” above).
Encephalopathy
Cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy, posterior reversible encephalopathy syndrome (PRES), Wernicke's encephalopathy) associated with 5-fluorouracil treatment have been reported from post-registration sources. Signs or symptoms of encephalopathy are altered mental status, confusion, disorientation, coma or ataxia. If a patient develops any of these symptoms, treatment should be stopped immediately and the serum ammonia level and vitamin B1 should be checked. If serum ammonia is elevated or vitamin B1 is deficient, ammonia-lowering appropriate therapy should be started. Hyperammonemic encephalopathy often occurs together with lactic acidosis.
- “Adverse reactions” section
The following adverse reactions should be added to the subsection “Metabolism and nutrition disorders” with the frequency “not known”:
– Hypertriglyceridemia
– Vitamin B1 deficiency
The following adverse reaction should be added to the subsection “Nervous system disorders” with the frequency “not known”:
– Wernicke encephalopathy
The following adverse reactions should be added to the subsection “Gastrointestinal disorders” with the frequency “not known”:
– Enterocolitis
– Colitis (including necrotizing colitis)
The following adverse reaction should be added to the subsection “General disorders and administration site conditions” with the frequency “not known”:
– Local reaction caused by extravasation (pain, swelling, erythema)
Changes to the safety information of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use) following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 02 – 05 September 2024
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) held on 02 – 05 September 2024. Following the meeting, it was decided that safety-related changes need to be made to the registration materials/instructions for medical use of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use).
5-fluorouracil (5-fluorouracil) (for intravenous use) – PSUSA/00000007/202312
5-Fluorouracil (5-fluorouracil) is an antitumor agent indicated for the treatment of various solid tumors, including tumors of the gastrointestinal tract (for example, cancer of the colon, rectum, stomach, pancreas, esophagus), head and neck cancer, and breast cancer.
Based on the evaluation of Periodic Safety Update Reports (PSURs), the PRAC reviewed the benefit/risk balance of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use) 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 5-fluorouracil (5-fluorouracil) (for intravenous use), for the approved indications remains unchanged.
- Nevertheless, the instructions for medical use should be updated, supplementing the warning on the phenotypic characterization of DPD deficiency and encephalopathy, and adding vitamin B1 deficiency, Wernicke's encephalopathy, hypertriglyceridemia, infusion site reactions caused by extravasation, colitis (including necrotizing colitis), and enterocolitis as adverse reactions with a frequency of “not known”. Thus, the existing provisions of the instructions for medical use should be amended1.
In the next PSUR, registration certificate holders must provide a cumulative review of cases of gastrointestinal necrosis, gastrointestinal perforation, and mania, and discuss the need to update the instructions for medical use.
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1 Update of the sections “Special Precautions for Use” and “Adverse Reactions” of the instructions for medical use. The risk assessment report and the PRAC recommendation are forwarded to the CMDh for decision.
List of medicinal products containing 5-fluorouracil (5-fluorouracil) (for intravenous use) and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 24.12.2024).
TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE CORRESPONDING APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT POSTED AT THE LINKS:
