Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Precautions to be taken when handling and using fluorouracil
Because of the potentially mutagenic and carcinogenic effects, increased safety regulations apply to nursing staff and physicians. When handling fluorouracil, any contact with the skin and mucous membranes should be avoided. The preparation must be carried out by means of an absolutely aseptic procedure. The use of a vertical laminar airflow workbench (LAF) is recommended. Protective clothing should be worn when handling fluorouracil. Pregnant personnel should not handle fluorouracil.

Cardiotoxicity
Treatment with fluoropyrimidines has been associated with cardiotoxicity, including myocardial infarction, angina pectoris, arrhythmias, myocarditis, cardiogenic shock, sudden death, stress cardiomyopathy (Takotsubo syndrome) and ECG changes (including, in very rare cases, prolongation of the QT interval). These adverse events are more common in patients who receive a continuous infusion of fluorouracil than in the recipients of a bolus injection. A history of coronary artery disease may be a risk factor for some cardiac side effects. Caution should therefore be exercised in the treatment of patients who experienced chest pain during treatment cycles, and in patients with known heart disease. During the treatment with fluorouracil, heart function should be monitored regularly. In the case of severe cardiotoxicity, therapy should be discontinued.


Encephalopathy
During post-marketing surveillance, there have been reports of cases of encephalopathy (including hyperammonemic encephalopathy, leukoencephalopathy and posterior reversible encephalopathy syndrome [PRES]) associated with 5-fluorouracil treatment. Signs and symptoms of encephalopathy include mental state changes, confusion, disorientation, coma and ataxia. If any of these symptoms occur, treatment should be discontinued immediately, and serum ammonia levels should be determined. If serum ammonia levels are elevated, ammonia-lowering treatment should be initiated.
Hyperammonemic encephalopathy often occurs concurrently with lactic acidosis.
Caution should be exercised when administering fluorouracil to patients with impaired renal and/or hepatic function. Patients with impaired renal and/or hepatic function may be at increased risk for hyperammonemia and hyperammonemic encephalopathy.

Tumor lysis syndrome
During post-marketing surveillance, there have been reports of cases of tumor lysis syndrome associated with fluorouracil therapy. Patients at increased risk of tumor lysis syndrome (e.g., patients with renal impairment, hyperuricemia, high tumor burden, rapid disease progression) should be closely monitored. Preventive measures (e.g., hydration, correction of high uric acid levels) should be considered.

Dihydropyrimidine dehydrogenase (DPD) deficiency
DPD activity is rate limiting in the catabolism of fluorouracil (see Section 5.2). Patients with DPD deficiency are therefore at increased risk of fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.
DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.

Complete DPD deficiency
Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with Fluorouracil (see section 4.3).

Partial DPD deficiency
Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered to limit this toxicity. DPD deficiency should be considered as a parameter to be taken into account in conjunction with other routine measures for dose reduction.
Initial dose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

Testing for DPD deficiency
Phenotype and/or genotype testing prior to the initiation of treatment with Fluorouracil “EBEWE” is recommended despite uncertainties regarding optimal pre-treatment testing methodologies.
Consideration should be given to applicable clinical guidelines.

Genotypic characterisation of DPD deficiency
Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.
The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13], c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymatic activity. Other rare variants may also be associated with an increased risk of severe or life-threatening toxicity.
Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g.
combinations of the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause complete or near complete absence of DPD enzymatic activity.
Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated with fluoropyrimidines.
The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients is around 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% for c.1679T>G.
Data on the frequency of the four DPYD variants in other populations than Caucasian are limited. At the present, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) are considered virtually absent in populations of African (-American) or Asian origin.

Phenotypic characterisation of DPD deficiency
For phenotypic characterisation of DPD deficiency, the measurement of pre-therapeutic blood levels of the endogenous DPD substrate uracil (U) in plasma is recommended.
Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despite uncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥ 16 ng/ml and < 150 ng/ml should be considered indicative of partial DPD deficiency and associated with an increased risk for fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/ml should be considered indicative of complete DPD deficiency and associated with a risk for life- threatening or fatal fluoropyrimidine toxicity.

Fluorouracil Therapeutic drug monitoring (TDM)
TDM of fluorouracil may improve clinical outcomes in patients receiving continuous 5-fluorouracil infusions by reducing toxicities and improving efficacy. AUC is supposed to be between 20 and 30mg x h/L.

Other notes
Brivudine should not be used together with fluorouracil. Deaths due to this drug interaction have been reported. After the end of treatment with brivudine and before the start of therapy with fluorouracil, an interval of at least 4 weeks is required. Brivudine treatment may be initiated 24 hours after the last dose of fluorouracil (see Sections 4.3 and 4.5).

In the case of an accidental administration of brivudine to patients treated with fluorouracil, effective measures must be taken to reduce the toxicity of fluorouracil. Immediate hospitalization is recommended. All measures should be taken to prevent systemic infections and dehydration.

Patients taking phenytoin concomitantly with fluorouracil should be regularly evaluated for a possible increase in phenytoin plasma levels.

Damage to the intestinal wall requires symptomatic treatment commensurate with the severity, e.g.
fluid replacement. Mild diarrhea may respond to antidiarrheal agents. In moderate to severe diarrhea, however, such agents do not suffice.

Before and during therapy with fluorouracil, the following follow-up examinations are recommended: -     Daily inspection of the oral cavity and pharynx for mucosal changes -     Blood count including the differential count, and platelet count, before each fluorouracil administration
-     Kidney parameters
-     Liver function tests (LFTs)

When co-administering fluorouracil and oral anticoagulants, the prothrombin time (Quick test) should be monitored closely.

Patients should be specifically alerted to the possibility of experiencing stomatitis/mucositis, diarrhea and bleeding (especially from the gastrointestinal tract). Patients should be instructed to consult their attending physician as soon as they have the first symptoms.

Patients should also be alerted to the possibility of experiencing hair loss, which is usually reversible, and skin changes (see also Section 4.8).

Pediatric population
There is insufficient experience on the efficacy and safety of fluorouracil in children.

Effects on Driving

4.7 Effects on ability to drive and use machines

Fluorouracil may indirectly affect the ability to drive or use machines by causing nausea and vomiting. Therefore, during treatment with fluorouracil, driving a car and using machines should be avoided.