The symptoms and signs of overdosage are qualitatively similar to the adverse reactions and should be managed as indicated under "Special Warnings and Precautions†and "Undesirable Effects".
Patients in which an overdose of Fluorouracil Pliva is detected should be closely monitored for at least 4 weeks.
Fluorouracil Pliva is contraindicated in patients who have any known hypersensitivity to Fluorouracil Pliva, are seriously debilitated or are suffering from bone marrow depression after radiotherapy or treatment with other antineoplastic agents, or who are suffering from a potentially serious infection.
Fluorouracil Pliva is strictly contraindicated in pregnant or breast feeding women.
Fluorouracil Pliva should not be used in the management of non-malignant disease.
5-Fluorouracil Pliva is incompatible with Carboplatin, Cisplatin, Cytarabine. Diazepam, Doxorubicin, other Anthracyclines and possibly Methotrexate.
Formulated solutions are alkaline and it is recommended that admixture with acidic drugs or preparations should be avoided.
Frequencies are defined using the following convention:
Very common (>1/10),
Common (> 1/100 to < 1/10),
Uncommon (> 1/1000 to < 1/100),
Rare (> 1/10000 to < 1/1000),
Very rare (< 1/10000),
Not known (cannot be estimated from the available data).
Blood and lymphatic system disorders:
Very common: Myelosuppression (leucopenia, pancytopenia and thrombocytopenia); agranulocytosis, anaemia.
Immune system disorders:
Very common: Bronchospasm, immunosuppression with an increased risk of infection.
Rare: Hypersensitivity reactions, generalised anaphylactic and allergic reactions.
Psychiatric disorders:
Uncommon: Euphoria.
Rare:, a reversible confusional state may occur.
Very rare: Disorientation,
Eye disorders:
Systemic Fluorouracil Pliva treatment has been associated with various types of ocular toxicity.
Uncommon: Incidences of excessive lacrimation, dacryostenosis, visual changes and photophobia.
Vascular disorders:
Rare: Cerebral, intestinal and peripheral ischemia, Reynaud's syndrome, thromboembolism, thrombophlebitis
Uncommon: Hypotension
Gastrointestinal disorders:
Very common: Diarrhoea, nausea and vomiting are observed quite commonly during therapy and may be treated symptomatically. An anti-emetic may be given for nausea and vomiting. Additionally, events of anorexia, stomatitis (symptoms include soreness, erythema or ulceration of the oral cavity or dysphagia); proctitis, oesophagitis,
Uncommon: gastrointestinal ulcerations and bleeding (may result in therapy being discontinued).
Skin and subcutaneous tissue disorders:
Very common:Alopecia may be seen in a substantial number of cases particularly in females, but is reversible.
Palmar-plantar erythrodysesthesia syndrome has been reported as an unusual complication of high dose bolus or protracted continuous therapy for 5-Fluorouracil Pliva. The syndrome begins with dysaesthesia of the palms and soles that progress to pain and tenderness. There is associated symmetrical swelling and erythema of the hand and foot.
Uncommon: Other side effects include dermatitis, , pigmentation, changes in the nails (e.g. diffuse superficial blue pigmentation, hyperpigmentation, nail dystrophy, pain and thickening of the nail bed, paronychia), dry skin, fissure erosion, erythema, pruritic maculopapular rash, exanthema, photosensitivity, hyperpigmentation of the skin, streaky hyperpigmentation or depigmentation near the veins.
General disorders and administration site conditions:
Very common: Malaise, weakness,.
Not known: Fever, vein discolouration proximal to injection sites
Cardiac disorders:
Very common: ECG changes,
Common: angina pectoris-like chest pain,
Uncommon:, arrhythmia, myocardial infarction, myocardial ishchaemia, dilative cardiomyopathy.
Very rare: Cardiac arrest and sudden cardiac death.
Not known: tachycardia, breathlessness
Special attention is therefore advisable in treating patients with a history of heart disease or those who develop chest pain during treatment.
Nervous system disorders:.
Uncommon: Nystagmus, headache, dizziness, symptoms of Parkinson's disease, pyramidal signs, and somnolence.
Very rare: Cases of leucoencephalopathy have also been reported. With symptoms including ataxia, acute cerebellar syndrome, dysarthria, , myasthenia, aphasia, convulsion or coma in patients receiving high doses of 5-Fluorouracil Pliva and in patients with dihydropyrimidine dehydrogenase deficiency, kidney failure.
Not known: Peripheral neuropathy may occur
Preclinical information has not been included because the toxicity profile of Fluorouracil Pliva has been established after many years of clinical use. Please refer to section 4.
Fluorouracil Pliva may be used alone, or in combination, for the management of common malignancies particularly cancer of the colon and breast.
Fluorouracil Pliva is an analogue of uracil, a component of ribonucleic acid. The drug is believed to function as an antimetabolite. After intracellular conversion to the active deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. Fluorouracil Pliva may also interfere with RNA synthesis.
After intravenous administration, Fluorouracil Pliva is distributed through the body water and disappears from the blood within 3 hours. It is preferentially taken up by actively dividing tissues and tumours after conversion to its nucleotide. Fluorouracil Pliva readily enters the C.S.F. and brain tissue.
Following I.V. administration, the plasma elimination half-life averages about 16 minutes and is dose dependent. Following a single I.V. dose of Fluorouracil Pliva approximately 15% of the dose is excreted unchanged in the urine within 6 hours; over 90% of this is excreted in the first hour. The remainder is mostly metabolised in the liver by the usual body mechanisms for uracil.
It is recommended that Fluorouracil Pliva be given only by, or under the strict supervision of a qualified physician who is conversant with the use of potent antimetabolites.
All patients should be admitted to hospital for initial treatment.
Fluorouracil Pliva is contraindicated in patients who have a poor nutritional state.
Adequate treatment with Fluorouracil Pliva is usually followed by leucopenia, the lowest white blood cell (W.B.C.) count commonly being observed between the 7th and 14th day of the first course, but occasionally being delayed for as long as 20 days. The count usually returns to normal by the 30th day. Daily monitoring of platelet and W.B.C. Count is recommended and treatment should be stopped if platelets fall 100,000 per mm3 or the W.B.C. count falls below 3,500 per mm3. If the total count is less than 2000 per mm3, and especially if there is granulocytopenia, it is recommended that the patient be placed in protective isolation in the hospital and treated with appropriate measures to prevent systemic infection.
Treatment should also be stopped at the first sign of oral ulceration or if there is evidence of gastrointestinal side effects such as stomatitis, diarrhoea or bleeding from the gastrointestinal tract or haemorrhage at any site, oesophagopharyngitis or intractable vomiting. Fluorouracil Pliva should be resumed only when the patient has recovered from the above signs. The ratio between effective and toxic dose is small and therapeutic response is unlikely without some degree of toxicity. Care must be taken therefore, in the selection of patients and adjustment of dosage.
Fluorouracil Pliva should be used with extreme caution in poor risk patients who have recently undergone surgery, have a history of high-dose irradiation of bone marrow-bearing areas (pelvis, spine, ribs, etc.) or prior use of another chemotherapeutic agent causing myelosuppression, have a widespread involvement of bone marrow by metastatic tumours, or those with reduced renal or liver function, jaundice or who have a poor nutritional state. Fluorouracil Pliva should also be used with caution in patients with heart disease. Isolated cases of angina, ECG abnormalities and rarely, myocardial infarction have been reported following administration of Fluorouracil Pliva. Caution should therefore be exercised in treating patients who experience chest pain during courses of treatment, or patients with a history of heart disease. Careful consideration should be given to re-administration of Fluorouracil Pliva after a documented cardiovascular reaction (arrhythmia, angina, ST segment changes) as there is a risk of sudden death. Severe toxicity and fatalities are more likely in poor risk patients, but have occasionally occurred in patients who are in relatively good condition. Any form of therapy which adds to the stress of the patient, interferes with nutritional uptake or depresses the bone marrow function, will increase the toxicity of Fluorouracil Pliva. If therapy is continued careful monitoring of the patient is required.
Rarely, severe and unexpected toxic reactions (including stomatitis, diarrhoea, neutropenia and neurotoxicity) have been reported in association with Fluorouracil Pliva. These reports of increased toxicity in patients who have reduced activity/deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), which appears to cause prolonged clearance of Fluorouracil Pliva.
The most pronounced and dose-limiting toxic effects of Fluorouracil Pliva are on the normal, rapidly proliferating cells of the bone marrow and the lining of the gastrointestinal tract. The immunosuppressive effect of Fluorouracil Pliva may cause a higher incidence of microbial infections, delayed wound healing and bleeding of the gums.
Nucleoside analogues, e.g. Brivudin and sorivudin, which affect DPD activity may cause increased plasma concentrations and increased toxicity of fluoropyrimidines. Therefore, an interval of at least 4 weeks between administration of Fluorouracil Pliva and brivudin, sorivudin or analogues should be kept. In the case of accidental administration of nucleoside analogues to patients treated with Fluorouracil Pliva, effective measures should be taken to reduce Fluorouracil Pliva toxicity. Immediate hospitalisation is recommended. Any measure to prevent systemic infections and dehydration should be commenced.
No studies on the effects on the ability to drive and use machinery have been performed.
Fluorouracil Pliva may induce side effects such as nausea and vomiting. It can also produce adverse events of the nervous system and visual changes which could interfere with driving or the usage of heavy machinery.
Adults:
Selection of an appropriate dose and treatment regime depends upon the condition of the patient, the type of carcinoma being treated and whether Fluorouracil Pliva is to be administered alone or in combination with other therapy. Initial treatment should be given in hospital and the total daily dose should not exceed 0.8 - 1 gram. It is customary to calculate the dose in accordance with the patient's actual bodyweight unless there is obesity, oedema or some form of abnormal fluid retention such as ascites. Ideal weight is used as the basis for calculation in such cases. The initial dose should be reduced by one-third to one half in patients with any of the following:
1. Cachexia.
2. Major surgery within preceding 30 days.
3. Reduced bone marrow function.
4. Impaired hepatic or renal function.
Fluorouracil Pliva injection should not be mixed directly, in the same container, with other chemotherapeutic agents or intravenous additives.
The following regimens have been recommended for use as a single agent:
Initial Treatment:
This may be in the form of an infusion or an injection, the former usually being preferred because of lesser toxicity.
Intravenous infusion:
15mg/kg bodyweight, but not more than 1g per infusion, diluted in 300 - 500ml of 5% glucose or 0.9% NaCl injection and given over 4 hours. Alternatively the daily dose may be infused over 30 - 60 minutes or may be given as a continuous infusion over 24 hours. The infusion may be repeated daily until there is evidence of toxicity or a total dose of 12 - 15g has been reached.
Intravenous Injection:
12mg/kg bodyweight, but not more than the recommended 1g daily dose may be given daily for 3 days and then, if there is no evidence of toxicity, 6mg/kg on alternate days for 3 further doses.
An alternative regimen is 15mg/kg as a single intravenous injection once a week throughout the course.
Intra-arterial infusion:
5/7.5mg/kg bodyweight daily may be given by 24 hour continuous intra-arterial infusion.
Maintenance therapy:
An initial intensive course may be followed by maintenance therapy providing there are no significant toxic effects.
In all instances, toxic side effects must disappear before maintenance therapy is started. If, however, they do appear, therapy must be discontinued until the symptoms resolve.
The initial course of Fluorouracil Pliva can be repeated after an interval of 4 to 6 weeks from the last dose or, alternatively, treatment can be continued with intravenous injections of 5-15mg/kg bodyweight at weekly intervals.
This sequence constitutes a course of therapy. Some patients have received up to 30g at a maximum rate of 1 g daily.
A more recent alternative method is to give 15mg/kg IV once a week throughout the course of treatment. This obviates the need for an initial period of daily administration.
In combination with irradiation
Irradiation combined with Fluorouracil Pliva has been found to be useful in the treatment of certain types of metastatic lesions in the lungs and for the relief of pain caused by recurrent, inoperable growth. The standard dose of Fluorouracil Pliva should be used.
Children:
No recommendations are made regarding the use of Fluorouracil Pliva in children.
Elderly:
Fluorouracil Pliva should be used in the elderly with similar considerations as in younger adults, notwithstanding that incidence of concomitant medical illness is higher in the former group.
Fluorouracil Pliva should be used with caution in elderly patients. The female gender and an age of 70 years or older are reported as independent risk factors for severe toxicity from Fluorouracil Pliva-based chemotherapy. Close monitoring for multiple organ toxicities and vigorous supportive care of those with toxicity are necessary. Elderly patients more frequently manifest a decreased kidney function correlated to age, which makes a decrease in dosage necessary for those patients undergoing Fluorouracil Pliva treatment.
Cytotoxic Handling Guidelines
Should be administered only by or under the direct supervision of a qualified physician who is experienced in the use of cancer chemotherapeutic agents.
Fluorouracil Pliva Injection should only be prepared for administration by professionals who have been trained in the safe use of the preparation. Preparation should only be carried out in an aseptic cabinet or suite dedicated for the assembly of cytotoxics.
In the event of spillage, operators should put on gloves, face mask, eye protection and disposable apron and mop up the spilled material with a absorbent material kept in the area for that purpose. The area should then be cleaned and all contaminated material transferred to a cytotoxic spillage bag or bin and sealed for incineration.
Contamination
Fluorouracil Pliva is an irritant, contact with skin and mucous membranes should be avoided.
In the event of contact with the skin or eyes, the affected area should be washed with copious amounts of water or normal saline. A bland cream may be used to treat the transient stinging of the skin. Medical advice should be sought if the eyes are affected or if the preparation is inhaled or ingested.
Please refer to company for COSHH hazard datasheets.
Preparation Guidelines
a) Chemotherapeutic agents should be prepared for administration only by professionals who have been trained in the safe use of the preparation.
b) Operations such as reconstitution of powder and transfer to syringes should be carried out only under aseptic conditions in a suite or cabinet dedicated for the assembly of cytotoxics.
c) The personnel carrying out these procedures should be adequately protected with clothing, gloves and eye shield.
d) Pregnant personnel are advised not to handle chemotherapeutic agents.
Disposal
Syringes, Onco-Vials® and adaptors containing remaining solution, absorbent materials, and any other contaminated material should be placed in a thick plastic bag or other impervious container and incinerated at 700°C.
Diluents
Fluorouracil Pliva Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water for Injections immediately before parenteral use.
