Adjuvant or palliative treatment of

 

-       advanced colorectal cancer

-       advanced gastric cancer

-       advanced pancreatic cancer

-       advanced and/or metastatic breast cancer

-       advanced tumours of the head and neck area

-       advanced cervical cancer

 

5-Fluorouracil Ebewe 50 mg/ml – Concentration for solution for infusion is used in adults.

Treatment with 5-fluorouracil should be administered only by doctors with experience in tumour therapy. In the initial phase, hospitalisation of the patient should be considered.

 

5-fluorouracil is used in mono-chemotherapy and as a component of poly-chemotherapy. Since the method of application and dose recommendation for 5-fluorouracil vary widely, only general reference values can be given.

 

The exact dosage should be taken from treatment protocols that have proved effective in the particular disease.

 

Posology

Initial therapy in daily use:

-        as IV infusion

15 mg/kg or 600 mg/m² over 4 hours daily – until the onset of undesirable effects.

 

-        as IV injection

slow IV administration of 12 mg/kg or 480 mg/m² (2 to 3 minutes) on days 1, 2 and 3 ;

if no signs of toxicity are evident – administration of 6 mg/kg or 240 mg/m² on day 5, 7 and 9. .

 

Initial therapy in weekly use:

Slow IV administration of 15 mg/kg or 600 mg/m² once weekly.

 

Maintenance therapy:

Once remission has been achieved or rather after the abatement of undesirable effects and further increase in leukocytes up to 3,000 to 4,000/µl, in thrombocytes up to 80,000 to 100,000/µl: 5–10 mg/kg or 200–400 mg/m² IV once weekly.

 

The maximum daily dose of 1 g must not be exceeded.

 

All dosage information applies to normal weight, i.e. in obesity, ascites or oedema, dosages must be standardised accordingly.

 

The duration of treatment depends on the nature and progress of the disease and is determined by an experienced specialist or in accordance with the treatment protocol.

 

When 5‑Fluorouracil is combined with other cytostatic agents with a similar safety profile or with radiotherapy, the dose must be reduced accordingly. It can be administered in the form of a 24-hour continuous drip infusion.

 

Method of administration

For intravenous use.

5-fluorouracil must be applied strictly into the vein. It can be injected or infused after dilution with 0.9% NaCl solution or 5% glucose.

 

Extravascular application must be avoided.

 

Special dosage instructions:

The recommended doses should be reduced by one third to one half in patients with poor nutritional condition, after a major surgical intervention, in myelosuppression (leucocytes < 4,000/µl, thrombocytes < 100,000/µl) and severe hepatic and renal impairment.

 

Renal or hepatic dysfunction:

In patients with renal or hepatic dysfunction, caution should be exercised and the dose reduced if necessary. 

                                                                                  

Elderly persons (aged 65 or more):

No initial dose adjustment is required. Careful monitoring of elderly patients is recommended.

5-fluorouracil is contraindicated in: - hypersensitivity to the active substance or any of the excipients listed in section 6.1 - significant changes in the blood count - bone marrow depression - haemorrhagia - severe hepatic and/or renal impairment - acute, severe infections (e.g. herpes zoster, varicella) - stomatitis - oral and gastrointestinal tract ulcerations - pseudomembranous enteritis - patients in poor general condition - during pregnancy and breast-feeding (see section 4.6) - patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see section 4.4) - recent or concomitant treatment with brivudine (see sections 4.4 and 4.5 for interactions) Brivudine is a potent inhibitor of the enzyme dihydropyrimidine dehydrogenase (DPD), which breaks down 5-fluorouracil. In patients who have dihydropyrimidine dehydrogenase deficiency, normal 5-flourouracil doses can provoke intensified undesirable effects. If serious undesirable effects occur, a DPD activity screening may be indicated. Patients with dihydropyrimidine dehydrogenase deficiency must not be treated with 5-flourouracil. Vaccination with a live vaccine must not be administered concomitantly with a 5-fluorouracil therapy. All contact with poliomyelitis vaccines should be avoided.

Precautions for handling and use of 5-fluorouracil

Due to the possible mutagenic and carcinogenic effects, enhanced safety precautions for hospital staff and physicians apply. While handling 5-fluorouracil, any contact with skin and mucosa should be avoided. Failing this, immediately wash with soap and water. In the event of eye contamination, rinse immediately with water and seek medical advice. All provisions must be made to allow for completely aseptic work. The use of a workspace with laminar flow is recommended. Protective clothing must be worn while handling 5-fluorouracil.

 

Pregnant staff must not work with 5-fluorouracil.

 

Cardiotoxicity

Treatment with fluoropyrimidines has been associated with cardiotoxicity, including myocardial infarction, angina pectoris, arrhythmias, myocarditis, cardiogenic shock, sudden death, and ECG changes (including QT interval prolongation in very rare cases). These undesirable effects appear more frequently in patients receiving a continuous infusion with 5-flourouracil than in patients receiving a bolus injection. A history of coronary heart disease may be a risk factor for cardiac undesirable effects. Caution is therefore indicated when treating patients who experienced chest pain during courses of treatment, or patients with a history of heart disease. Cardiac function should be regularly monitored during treatment with fluorouracil. In case of severe cardiotoxicity, the treatment should be discontinued.

 

Encephalopathy

Cases of encephalopathies (including hyperammonaemic encephalopathy, leukoencephalopathy) associated with 5-fluorouracil treatment have been reported from post-marketing sources. Signs or symptoms of encephalopathy are altered mental status, confusion, disorientation, coma or ataxia. If a patient develops any of these symptoms, withhold treatment and test serum ammonia levels immediately. In case of elevated serum ammonia levels initiate ammonia-lowering therapy.

 

Caution is necessary when administering fluorouracil to patients with renal and/or hepatic impairment. Patients with impaired renal and/or hepatic function may have an increased risk of hyperammonaemia and hyperammonaemic encephalopathy.

 

Dihydropyrimidine dehydrogenase (DPD) deficiency

The enzyme dihydropyrimidine dehydrogenase (DPD) plays an important role in breaking down 5-fluorouracil. Nucleoside analogues, e.g. brivudine and sorivudine, may cause increased plasma concentrations of 5‑fluorouracil and other fluoropyrimidines and thus to an associated increase in toxicity. Therefore, an interval of at least 4 weeks between administration of 5-fluorouracil and brivudine, sorivudine, or analogues should be maintained.

 

Brivudine must not be administered concomitantly with 5-fluorouracil. Fatalities have been reported following this drug interaction. There must be at least a 4-week waiting period between end of treatment with brivudine and start of 5-fluorouracil therapy. Treatment with brivudine can be started 24 hours after the last dose of 5-fluorouracil (see sections 4.3 and 4.5). If applicable, determination of DPD enzyme activity is indicated prior to the treatment with 5-fluorouracil.

 

In case of an inadvertent administration of brivudine to patients receiving 5-fluorouracil, effective measures should be taken to reduce the 5-fluorouracil toxicity. Immediate hospitalisation is recommended. All measures should be initiated to prevent systemic infections and dehydration.

 

Rare, unexpected and severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-FU has been attributed to limited DPD activity. Patients with low or absent activity of DPD, an enzyme involved in fluorouracil elimination, are at increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Although DPD deficiency cannot be precisely defined, it is known that patients with certain homozygous or certain compound heterozygous mutations in the DPYD gene locus (e.g. DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3), which can cause complete or near complete absence of DPD enzymatic activity (as determined from laboratory assays), have the highest risk of life-threatening or fatal adverse reaction and should not be treated with 5-fluorouracil (see section 4.3). No dosage has been proven safe for patients with complete absence of DPD activity.

Patients with certain heterozygous DPYD variants (including DPYD*2A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3 variants) have been shown to have increased risk of severe toxicity when treated with fluoropyrimidines.

 

The frequency of the heterozygous DPYD*2A 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. Genotyping for this allele is recommended to identify patients at increased risk of severe toxicity. Data on the frequency of these DPYD variants in populations other than Caucasian is limited. It cannot be ruled out that other rare variants may also be associated with an increased risk of severe toxicity.

 

For patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of 5-flourouracil are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), these individuals must be treated with extreme caution and frequent monitoring with dose adjustment according to toxicity. In such patients a reduction of the starting dose should be considered to prevent severe toxicity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by specific test. It has been reported that the DPYD*2A, c.1679T>G variants lead to a greater reduction in enzymatic activity compared to other variants with a higher risk of undesirable effects. The consequences of a reduced dose on the efficacy are currently uncertain. Therefore, in the absence of serious toxicity the dose could be increased while carefully monitoring of the patient. The patients who are tested negative for the above-mentioned allele may still have a risk of severe undesirable effects.

 

In patients with unrecognised DPD deficiency treated with 5-fluoruracil as well as in those patients who test negative for specific DPYD variations, life-threatening toxicities manifesting as acute overdose may occur (see section 4.9). In the event of grade 2-4 acute toxicity, treatment must be discontinued immediately. Permanent discontinuation should be considered based on clinical assessment of the onset, duration and severity of the observed toxicities.

 

Due to the possibility of anaphylactic reaction, the usual anti-shock measures should be provided prior to the use of 5-fluorouracil.

 

Patients taking phenytoin concomitantly with 5-fluorouracil should undergo regular testing because of the possibility of an elevated phenytoin plasma level.

 

Damage to the intestinal wall requires symptomatic treatment depending on severity, for example fluid substitution. Mild diarrhoea can be treated with antidiarrhoeal agents. However, these are not sufficient in moderate to severe diarrhoea.

 

Prior to and during treatment with 5-fluorouracil, the following investigations are recommended:

-       daily inspection of the oral cavity and pharynx for changes in the mucosa

-       Blood count including differential blood count and thrombocytes prior to each administration of 5-fluorouracil, and every 2‒3 days at the beginning of treatment

-       retention values at regular intervals

-       liver parameters at regular intervals

-       determination of uric acid levels

-       stool tests for occult blood

 

Patients should be informed that stomatitis/mucositis, diarrhoea and bleeding (especially from the gastrointestinal tract) may occur. They should be instructed to consult their doctor at the first signs. Immediate discontinuation of treatment is required with the following symptoms: gastrointestinal reactions (stomatitis, mucositis, severe diarrhoea, severe vomiting, ulcers, bleeding), leukocytes < 3,000/µl, thrombocytes < 80,000/µl, central undesirable effects (including ataxia and tremor) and cardiac undesirable effects.

 

The treatment can be continued only after abatement of the undesirable effects and if the patient’s general condition allows. In severe gastrointestinal, cardiac or neurological toxicity symptoms, resuming therapy is generally not recommended.

 

In concomitant administration of 5-fluorouracil and oral anticoagulants, the Quick value must be closely monitored.

 

Special caution is advised in high-risk patients who have had high-dose pelvic radiation, after therapy with alkylating substances, in extensive bone metastases and extensive hepatic metastases (reduced elimination!) and in cachectic patients.

 

In combination with methotrexate, methotrexate must be applied up to 24 hours prior to 5-fluorouracil (not vice-versa!) to achieve optimum effect.

 

5-fluorouracil can be mutagenic. Male patients treated with 5-fluorouracil are therefore advised not to father a child during and up to 6 months following treatment, and to seek advice on sperm preservation before the start of therapy due to the possibility of severe spermatogenesis impairment. Female patients must not get pregnant during therapy with 5-fluorouracil and must use effective contraceptive measures.

When planning a child after treatment discontinuation, genetic counselling is recommended.

 

Paediatric population:

There is insufficient experience of the use of 5-fluorouracil in children and adolescents.

 

5-Fluorouracil Ebewe contains sodium

This medicine contains up to 9.31 mg sodium per ml, or 186.20 mg per maximum daily dose. This is equivalent to 9.31% of the WHO-recommended daily dietary intake of sodium, which is 2 g.

Please note that the following information can also apply to recently administered medicinal products.

 

Brivudine

A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine, has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially fatal. Therefore, brivudine must not be administered concomitantly with 5-fluorouracil (see section 4.3 and 4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and start of 5-fluorouracil therapy. Treatment with brivudine can be started 24 hours after the last dose of 5-fluorouracil. If applicable, determination of DPD enzyme activity is indicated prior to the treatment with 5-fluorouracil.

 

All therapeutic measures that worsen the patient’s physical condition or that have myeloid effects (e.g. other cytostatic agents) can increase 5-fluorouracil toxicity.

 

Fluorouracil can enhance skin toxicity of radiotherapy.

 

Calcium folinate can enhance the effect of 5-fluorouracil. The clinical consequence of this interaction can be severe, sometimes fatal diarrhoea. An increased number of such fatalities was reported particularly in connection with an administration schedule of an IV bolus injection of 600 mg of 5-fluorouracil per m² body surface once per week combined with calcium folinate.

 

In concomitant administration of phenytoin and 5-fluorouracil, an increase of phenytoin plasma concentration has been reported, resulting in symptoms of phenytoin intoxication.

 

Cimetidine, metronidazole, allopurinol, and interferons can increase the plasma levels of 5-flourouracil. This can increase the toxic effects of 5-fluorouracil.

 

In female patients receiving thiazide-type diuretics in addition to cyclophosphamide, methotrexate and 5-fluorouracil, the decrease in the number of granulocytes was more pronounced when compared to an equal number of cytostatic cycles without thiazide.

 

In concomitant administration of 5-fluorouracil and warfarin, prothrombin time may be prolonged, so this should be closely monitored. There were isolated cases of patients treated with warfarin and adjuvant 5-fluorouracil alone or in combination with levamisole, in whom a decrease in the Quick value was observed.

 

Hepatotoxicity (increase in alkaline phosphatases, transaminases or bilirubin) has been observed commonly in concomitant treatment with 5-fluorouracil and levamisole.

 

In patients with breast cancer, combination therapy with cyclophosphamide, methotrexate, 5-fluorouracil and tamoxifen has been reported to increase the risk of thromboembolic events.

 

Severe, potentially fatal mucositis can occur in concomitant administration of vinorelbine and 5-fluorouracil/folinic acid.

 

Assay techniques for bilirubin and 5-hydroxyindolacetic acid can yield increased or false positive values.

 

Aminophenazones, phenylbutazones and sulphonamides should not be given prior to and during treatment.

 

Chlordiazepoxide, disulfiram, griseofulvin and isoniazid can enhance the effect of 5‑Fluorouracil.

 

The onset of haemolytic uremic syndrome has been reported after long-term administration of 5-fluorouracil in combination with mitomycin.

 

Incidents of cerebral infarction has been very rarely reported in conjunction with 5-fluorouracil therapy in combination with other chemotherapeutic agents (mitomycin C or cisplatin).

 

General information

Cytostatic agents can reduce antibody formation following influenza vaccination.

Cytostatic agents can increase the risk of serious infection following the administration of live vaccines.

 

Incompatibilities

5-fluorouracil may be diluted only with normal saline solution or 5% glucose solution.

5-fluorouracil must not be mixed in the same infusion as the other substances.

 

Incompatibilities with the following substances have been reported:

cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, leucovorin, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition solutions, vinorelbine.

Pregnancy

5-fluorouracil can be mutagenic and must not be administered during pregnancy (see section 4.3). Women of childbearing age must ensure effective contraception during treatment and up to six months afterwards. If the patient becomes pregnant during treatment, genetic counselling should be taken into consideration.

 

Animal studies revealed teratogenic reactions in foetuses.

 

5-fluorouracil is suspected of causing severe damage to the unborn child if used during pregnancy.

 

Breast-feeding

Since it is not known whether 5-fluorouracil passes into breast milk, women receiving this medicinal product must not breast-feed.If use during breast-feeding is essential, breast-feeding must be discontinued first (see section 4.3).

 

Fertility

5-fluorouracil may cause genetic damage. Men treated with 5-fluorouracil are advised not to father a child during and for up to 6 months after the end of treatment. Advice on sperm conservation is recommended prior to treatment, because of the possibility of irreversible infertility due to therapy with 5-fluorouracil.

5‑Fluorouracil may induce nausea, vomiting, undesirable reactions of the nervous system and visual changes which could indirectly interfere ability to drive or use machines. Therefore, do not drive or use machines during the treatment with 5‑Fluorouracil.

The most common and serious undesirable effects of 5-fluorouracil are bone marrow toxicity and gastrointestinal symptoms.

 

The following criteria are used for the frequency of undesirable effects:

 

Very common (≥ 1/10)

Common (≥1/100, <1/10)

Uncommon (≥1/1,000, <1/100)

Rare (≥1/10,000, <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data).

 

Blood and lymphatic system disorders

Very common: myelosuppression (leukopenia, neutropenia, thrombopenia), anaemia

Common: febrile neutropenia

Very rare: agranulocytosis, pancytopenia

 

Infections and infestations:

Very common: infections

Common: immunosuppression with increased risk of infection

Rare: sepsis

 

Immune system disorders

Rare: general allergic reactions, anaphylaxis, anaphylactic shock

 

Endocrine disorders

Not known: total thyroxin (T₄) and total triiodothyronine (T₃) in the serum can increase, without increase of free T₄ and TSH, and without clinical signs of hyperthyroidism (patient thyroid levels remain clinically normal)

 

Metabolism and nutrition disorders

Very common: Hyperuricaemia

 

Psychiatric disorders

Rare: Confusion

 

Nervous system disorders

Uncommon: nystagmus, headache, dizziness, symptoms of Parkinson’s disease, pyramidal signs, euphoria, somnolence

Rare: peripheral neuropathy (in combination with radiotherapy)

Very rare: dysgeusia, (leuko)encephalopathy with ataxia, acute cerebellar syndrome, speech disorders, dysarthria, confusion, disorientation, myasthenia, aphasia, convulsions, or coma

Not known: hyperammonaemic encephalopathy

 

Eye disorders

Uncommon: excessive lacrimation and lacrimal duct stenosis, blurred vision, eye movement disturbance, optic neuritis, double vision, decrease in visual acuity, photophobia, conjunctivitis, eyelid inflammation, ectropion due to scar formation and lacrimal gland fibroses

 

Cardiac disorders

Very common: ischaemic ECG abnormalities

Common: angina pectoris-like chest pain

Uncommon: arrhythmia, myocardial infarction, myocardial ischemia, myocarditis, cardiac insufficiency, dilative cardiomyopathy, cardiogenic shock

Very rare: cardiac arrest, sudden cardiac death;

Not known: pericarditis

 

Vascular disorders

Uncommon: hypotension

Rare: thrombophlebitis

Not known: cerebral, intestinal and peripheral ischaemia, Raynaud's syndrome, thromboembolism

 

Respiratory, thoracic and mediastinal disorders

Very common: bronchial spasm, epistaxis

 

Gastrointestinal disorders

Very common: gastrointestinal tract disorders (partially life-threatening), such as mucositis (stomatitis, pharyngitis, oesophagitis, proctitis), anorexia, (watery) diarrhoea, nausea, vomiting (see also section 4.4)

Uncommon: dehydration, gastrointestinal ulceration and bleeding, sloughing

 

Hepatobiliary disorders

Uncommon: hepatic cell damage, non-calculous cholecystitis

Very rare: infection (including fatal outcome)

 

Skin and subcutaneous tissue disorders

Very common: alopecia, palmar-plantar erythrodysaesthesia syndrome (“hand-foot syndrome) with dysaesthesia, reddening, swelling, pain and scaling of the skin on palms and soles

Uncommon: dermatitis, skin alterations (dry skin, erosion/cracks, erythema, pruritic maculopapular rash), exanthema, urticaria, photosensitivity, hyperpigmentation of the skin, streaky hyperpigmentation or depigmentation in the vein area, changes in nails (e.g. diffuse superficial blue pigmentation, hyperpigmentation, nail dystrophy, pain and thickening of the nail bed paronychia) and onycholysis.

 

Reproductive system and breast disorders

Uncommon: spermatogenesis and ovulation disorders

 

General disorders and administration site conditions

Very common: delayed wound healing, fatigue, general asthaenia, tiredness, listlessness, fever

 

Description of selected undesirable effects

Blood and lymphatic system disorders

Myelosuppression is one of the dose-limiting undesirable effects (see also Section 4.2). The degree of severity (NCI grades I–IV) of myelosuppression depends on the method of administration (IV bolus injection or IV continuous infusion) and posology. Neutropenia occurs following each treatment cycle with an IV bolus injection with adequate doses (nadir: Days 9 – 14 – (20) of treatment; normal value: usually after day 30).

 

Cardiac disorders

Cardiotoxic effects mostly occur during or within few hours of the first treatment cycle. There is an increased risk of cardiotoxicity in patients with previous coronary heart disease or cardiomyopathy.

 

Gastrointestinal disorders

The degree of severity (NCI grade I–IV) of gastrointestinal undesirable effects depends on the posology and method of administration. In a continuous IV infusion, stomatitis is more likely than myelosuppression to be the dose limiting factor.

 

Skin and subcutaneous tissue disorders

The hand-foot syndrome begins with dysaesthesia of the palms and soles that progress to reddening, swelling, pain, desquamation of the skin. It is very common after continuous IV administration and common after IV bolus injection.

 

Symptoms of an overdose

The symptoms of overdose are increased occurrence of those symptoms mentioned under undesirable effects, such as nausea, vomiting, diarrhoea, severe mucositis, gastrointestinal ulcers and bleeding, bone marrow depression (thrombocytopenia, leukopenia, agranulocytosis).

 

Acute:

psychotic reactions, somnolence, enhanced action of sedative drugs, increased alcohol toxicity.

 

Should sedation be required, small doses (e.g. starting with 5 mg) of diazepam can be administered by IV, whilst monitoring the circulatory and respiratory system.

 

Chronic:

bone marrow depression up to agranulocytosis and critical thrombopenia, bleeding tendency, gastrointestinal ulceration, diarrhoea and hair loss.

 

Therapeutic measures

If symptoms of intoxication occur, 5-fluorouracil administration should be discontinued immediately. Measures for symptomatic treatment must be taken.

Infusions of leukocyte or platelet concentrate, infection prophylaxis. Forced diuresis to restore volume and mineral balance can be beneficial. In general, haemodialysis is not necessary. Careful monitoring to detect late-onset haematological and gastrointestinal complications on time.

Long-term myelosuppression must be treated under inpatient conditions. This includes, if necessary, substitution of missing blood components and antibiotic therapy. Transfer of the patient to an aseptic room might be necessary.

 

Patients should be haematologically monitored for up to 4 weeks after an overdose.

 

Should the therapy with 5-fluorouracil be continued despite the onset of cardiac undesirable effects, administration of vasodilators is indicated to prevent coronary artery spasms.

Pharmacotherapeutic group: Antineoplastic agents, Antimetabolites, Pyrimidine analogues, ATC code: L01BC02

 

The antimetabolite 5-fluorouracil constitutes a fluorinated pyrimidine. 5-fluorouracil is enzymatically activated to deoxy-fluorouracil monophosphate. It inhibits the activity of thymidylate synthase and thus deoxythymidine monophosphate synthesis through complex formation. This results in phase-specific DNA-synthesis inhibition. Furthermore, deoxy-fluoro nucleotides inhibit de novo synthesis of pyrimidine nucleotides.

 

Calcium folinate with 5-fluorouracil and thymidylate synthase forms a relatively stable ternary complex and thus prolongs the inhibiting action of 5-fluorouracil on thymidylate synthase. The result is the enhanced cytotoxic effect of 5-fluorouracil.

 

5-fluorouracil has a phase-specific action in the cell cycle, particularly on the S-phase. The effect of the substance in rapidly proliferating tissue (bone marrow, skin and mucosa) is particularly pronounced.

5-FU is further catabolised by the enzyme DPD to the much less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureidopropionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of 5-fluorouracil (see sections 4.3 and 4.4).

 

5-fluorouracil is only partially absorbed orally (0–80%).

 

The substance exhibits a distribution of 0.12 l/kg BW (following 15 mg/kg BW IV) and can be found especially in rapidly proliferating tissue such as bone marrow, intestinal mucosa and neoplasia; 5-fluorouracil passes the blood-brain barrier.

 

Metabolism takes place in the liver and is similar to uracil metabolisation. 5-fluorouracil is rapidly transformed enzymatically into the active metabolite dihydro-5-fluorouracil, which has a substantially longer half-life than 5-fluorouracil. Other non-toxic metabolites are carbon dioxide and urea.

 

The plasma half-life (alpha phase) is between 8 and 22 minutes. The elimination half-life (beta phase) reaches approx. 20 hours due to the active metabolites in the tissue and is dose-dependent.

 

5-fluorouracil (60–80%) is primarily exhaled by the lungs as carbon dioxide. 5‑Fluorouracil is secondarily excreted unchanged by the renal system (approx. 7–20%), approx. 90% of which is excreted within the first hour. The renal clearance is approximately 170–180 ml/min. In impaired renal function, the substance is eliminated slowly.

 

Maximum concentration in the cerebrospinal fluid is reached after approximately 1.5–2 hours and accounts for approx. 50% of plasma concentration.

 

Kinetics in special clinical situations: despite the low proportion (approx. 15%) eliminated renally, an adequate dose adjustment is indicated depending on the degree of renal insufficiency and the reaction of the individual patient is indicated due to bone marrow impairment in azotaemia (due to renal insufficiency) and potential interference with the thrombocytes. A dose adjustment should also be taken into consideration in hepatic impairment.

Toxicity

The mitosis-inhibiting effect of 5-fluorouracil mainly affects rapidly proliferating tissues – both tumourigenic and healthy tissues. Accordingly, the toxicities are revealed particularly in bone marrow, with leukopenia, thrombocytopenia, gastrointestinal bleeding and secondarily in infections.

 

Reproduction toxicity/mutagenicity/carcinogenicity

In different in-vitro cultures, fluorouracil shows mutagenic potential (various strains of salmonella typhimurium, micronucleus test on mice, at high concentrations chromosome strand damage in hamster fibroblasts). In vivo in male rats, chromosomal aberrations and altered spermatogenesis and even infertility were observed. In female rats, fluorouracil reduced fertility and induced chromosome aberrations in the embryos. The effects in rabbits were less substantial.

 

Antimetabolites in animal studies showed carcinogenic properties. However, the risk of secondary tumours in humans seems to be lower than with alkylating substances.

Water for injections and sodium hydroxide (for pH adjustment)

5-Fluorouracil Ebewe may be diluted only with normal saline solution or 5% glucose solution.

5-fluorouracil must not be mixed in the same infusion as the other substances.

 

5-fluorouracil must not be diluted with strongly buffered solutions with pH <8, since 5-fluorouracil precipitates in this environment. Do not mix with other chemotherapeutic solutions.

 

Incompatibilities with the following active substances have been reported:

Fluorouracil is incompatible with folinic acid, carboplatin, cisplatin, cytarabine, diazepam, doxorubicin, droperidol, filgrastim, gallium nitrate, methotrexate, metoclopramide, morphine, ondansetron, parenteral nutrition, vinorelbine and other anthracyclines.

 

Calcium folinate

Calcium folinate must not be mixed in the same infusion as 5-fluorouracil, because a precipitate may form. 5-fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without 5% dextrose in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C or 32°C in polyvinyl chloride containers.

 

5-Fluorouracil Ebewe solution for injection/infusion must not be mixed with other medicinal products, including oxaliplatin or irinotecan.

18 months

Store below 25°C.

Do not refrigerate or freeze.

Store in the original packaging to protect the contents from light.

 

For single use only.

Use only clear and colourless to pale yellowish solutions.

 

If precipitates have formed as a result of exposure to low temperatures, they can be dissolved by careful heating to 60°C and shaking. Allow to cool before use.

 

Shelf life after dilution

The product can be diluted with 0.9% sodium chloride solution or 5% glucose solution. Stability data in concentrations of 0.35 mg/ml and 15 mg/ml have shown that the maximum shelf life of ready-to-use 5-fluorouracil infusion solution is 28 days.

This shelf life refers both to refrigerator storage (2°C–8°C) including protection from light and storage at ambient temperature (20°C–25°C) with or without protection from light.

The chemical and physical stability of the prepared solution for infusion has been demonstrated for over 28 days. From a microbiological point of view, however, the ready-to-use solution for infusion should be used immediately. If it is not used immediately, the storage conditions for the ready-to-use solution for infusion before administration are the responsibility of the user and are normally no longer than 24 hours at 2–8°C, except if the dilution is performed under controlled and validated aseptic conditions.

1 / 5 vials with 5 ml

1 / 5 vials with 10 ml

1 / 5 vials with 20 ml

1 vial with 100 ml

 

Type I amber glass vials with/without transparent PVC container (Onco-Safe).

 

Not all pack sizes may be marketed.

Due to the possible mutagenic and carcinogenic effects, enhanced safety precautions for hospital staff and physicians apply. While handling 5-fluorouracil, any contact with skin and mucosa should be avoided. Failing this, immediately wash with soap and water. In the event of eye contamination, rinse immediately with water and seek medical advice.All provisions must be made to allow for completely aseptic work. The use of a workspace with laminar flow is recommended. Protective clothing must be worn while handling 5-fluorouracil.

 

Pregnant staff must not work with fluorouracil.

 

Inactivation:       *      700°C

                           *      Sodium hypochlorite (bleach) diluted with 10 parts of water

                          *      Concentrated sodium hydroxide (NaOH) over several hours.

 

The prepared solution should be used immediately after preparation.

Precipitates formed as a result of exposure to low temperatures can be dissolved by shaking and careful heating to 60°C. Allow to cool prior to use.

 

Loss of efficacy due to the adsorption of 5-fluorouracil in the glass infusion container has been described in the literature.

 

The handling and disposal regulations for cytostatics must be observed.

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.