Adverse reactions : תופעות לוואי

4.8 Undesirable effects

The most common and significant side effects of fluorouracil are bone marrow toxicity and gastrointestinal symptoms.

The frequency of adverse reactions is defined using the following convention:  very common        ≥ 1/10 common             ≥ 1/100 to < 1/10 uncommon           ≥ 1/1,000 to < 1/100 rare               ≥ 1/10,000 to < 1/1,000 very rare          < 1/10,000 not known          Frequency cannot be estimated from available data

Infections and infestations
Very common: Infections
Common:          Immunosuppression with an increased infection rate. Rare:      Sepsis.
Blood and lymphatic system disorders
Common:         Myelosuppression, neutropenia, thrombocytopenia and anemia, febrile neutropenia. Rare:   Agranulocytosis, pancytopenia.

Myelosuppression is common and is one of the dose-limiting adverse events (see Sections 4.2 and 4.4). Mild to extremely severe cases of neutropenia and thrombocytopenia, as well as agranulocytosis,
anemia and pancytopenia have all been reported.
The degree of myelosuppression (NCI grades 1 to 4) depends on the method of administration (I.V. bolus injection or continuous intravenous infusion) and the dosage regimen.
Neutropenia occurs after each course of treatment as I.V. bolus injections in adequate doses (nadir: 9th to 14th [to 20th] day of treatment; normal values usually achieved after the 30th day).

Immune system disorders
Rare:         Generalized allergic reactions including anaphylactic shock.

Endocrine disorders
Not known:     Increases in serum levels of total thyroxine (T4) and total triiodothyronine (T3), with no increase in free T4 and TSH, and no clinical signs of hyperthyroidism.

Metabolism and nutrition disorders
Common:       Hyperuricemia.
Not known:    Lactic acidosis, tumor lysis syndrome.

Nervous system disorders
Rare:         Nystagmus, headache, dizziness, Parkinson's symptoms, pyramidal signs and euphoria.
Peripheral neuropathy (in combination regimens with radiation therapy).
Very rare:    Dysgeusia.
(Leuko-)encephalopathy with symptoms such as ataxia, speech disorders, confusion, disorientation, muscle weakness, aphasia, seizures or coma.
Not known:    Hyperammonemic encephalopathy, posterior reversible encephalopathy syndrome (PRES).

Eye disorders
Rare:         Excessive flow of tears, blurred vision, disorders of ocular motility, optic neuritis, diplopia, loss of vision, photophobia, conjunctivitis, blepharitis, scar-related ectropion, and tear-duct fibrosis.

Cardiac disorders
Common:        Ischemic changes in ECG.
Uncommon:      Chest pain resembling angina pectoris.
Rare:          Arrhythmias, myocardial infarction, myocarditis, heart failure, dilated cardiomyopathy and cardiogenic shock.
Very rare:        Cardiac arrest and sudden cardiac death.
Not known:     Pericarditis, stress cardiomyopathy (Takotsubo syndrome).

Cardiotoxic side effects usually occur during or a few hours after the first administration cycle.
Patients with pre-existing coronary artery disease or cardiomyopathy are at an increased risk of developing cardiotoxic side effects.

Vascular disorders
Rare:          The occurrence of thrombophlebitis has been reported.
Not known:     Cerebral, intestinal and peripheral ischemia, Raynaud's syndrome and thromboembolism.

Respiratory, thoracic and mediastinal disorders
Common:         Bronchospasm, epistaxis.

Gastrointestinal disorders
Common:         Mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea and vomiting.
Rare:           Dehydration as well as ulcers and bleeding in the gastrointestinal tract.
Not known:      Pneumatosis intestinalis.
Gastrointestinal side effects are common and may be life-threatening.
Mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea and vomiting (ranging from mild to severe), and a calculous cholecystitis have been reported (see also Section 4.4). The severity (NCI grades 1 through 4) of gastrointestinal adverse effects depends on the dosage regimen and method of administration. In administration by continuous intravenous infusion, stomatitis rather than myelosuppression is the dose-limiting factor.

As long as inflammations, ulcers or diarrhea persist, the use of fluorouracil should be avoided.

Hepatobiliary disorders
Rarely, liver cell damage and, in isolated cases, liver necrosis were observed, some of which were lethal.

Skin and subcutaneous tissue disorders
The so-called "hand-foot syndrome" with dysesthesia as well as redness, swelling, pain and peeling of the skin on the palms and soles occurs more frequently after administration as a continuous I.V.
infusion than after I.V. bolus injections.
Common:          Alopecia (usually reversible).
Rare:            Exanthema, dry skin with fissures, dermatitis, urticaria, photosensitivity, hyperpigmentation of the skin and streaky hyperpigmentation or pigment loss along the vein course.
Nail changes (e.g., diffuse superficial bluish pigmentation, hyperpigmentation, nail dystrophy, pain and thickening of the nail bed, paronychia) and onycholysis.
Not known:       Cutaneous lupus erythematosus (CLE).

General disorders and administration site conditions
Common:        Delayed wound healing, exhaustion, general weakness, fatigue and listlessness.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il