Fluorouracil Injection USP 500mg/10 ml Taj Pharma

Name of the medicinal product

Fluorouracil 250mg/10ml Injection Taj Pharma
Fluorouracil 500mg/10ml Injection Taj Pharma

Qualitative and quantitative composition

a) Each ml contains:
Fluorouracil USP 25mg
Water for injection q.s

b) Each ml contains:
Fluorouracil USP 50mg
Water for injection q.s

Pharmaceutical form

Solution for injection.

Clear, colourless or slightly yellow solution.

Clinical particulars

4.1 Therapeutic indications

Fluorouracil may be used alone, or in combination, for the management of common malignancies particularly cancer of the colon and breast.

4.2 Posology and method of administration

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 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:

Cachexia.
Major surgery within preceding 30 days.
Reduced bone marrow function.
Impaired hepatic or renal function.

Fluorouracil 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 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 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 should be used.

Children:

No recommendations are made regarding the use of fluorouracil in children.

Elderly:

Fluorouracil 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 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-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 treatment.

4.3 Contraindications

Fluorouracil is contraindicated in patients who have any known hypersensitivity to fluorouracil, 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 is strictly contraindicated in pregnant or breast feeding women.

Fluorouracil should not be used in the management of non-malignant disease.

In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity (see section 4.4)

4.4 Special warnings and precautions for use

It is recommended that fluorouracil 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 is contraindicated in patients who have a poor nutritional state.

Adequate treatment with fluorouracil is usually followed by leucopoenia, 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 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 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 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. 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 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. If therapy is continued careful monitoring of the patient is required.

Cardiotoxicity

Cardiotoxicity has been associated with fluoropyrimidine therapy, including myocardial infarction, angina, arrhythmias, myocarditis, cardiogenic shock, sudden death and electrocardiographic changes (including very rare cases of QT prolongation). These adverse events are more common in patients receiving continuous infusion of 5-fluorouracil rather than bolus injection. Prior history of coronary artery disease may be a risk factor for cardiac adverse reactions. Care should therefore be exercised in 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.

Rarely, severe and unexpected toxic reactions (including stomatitis, diarrhoea, neutropenia and neurotoxicity) have been reported in association with fluorouracil. 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.

The most pronounced and dose-limiting toxic effects of fluorouracil are on the normal, rapidly proliferating cells of the bone marrow and the lining of the gastrointestinal tract. The immunosuppressive effect of fluorouracil 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 (see section 4.5). Therefore, an interval of at least 4 weeks between administration of fluorouracil and brivudin, sorivudin or analogues should be kept. In the case of accidental administration of nucleoside analogues to patients treated with fluorouracil, effective measures should be taken to reduce fluorouracil toxicity. Immediate hospitalisation is recommended. Any measure to prevent systemic infections and dehydration should be commenced.

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 for hyperammonaemia and hyperammonaemic encephalopathy.

Dihydropyrimidine dehydrogenase (DPD) deficiency

Rarely, unexpected, severe toxicity (e.g. stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of DPD activity.

Patients with low or absent DPD activity, an enzyme involved in fluorouracil degradation, are at increased risk for 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 variants), 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 toxicity and should not be treated with 5-fluorouracil (see 4.3). No dose 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 these alleles is recommended to identify patients at increased risk for severe toxicity. Data on the frequency of these DPYD variants in other populations than Caucasian is limited. It cannot be excluded that other rare variants may also be associated with an increased risk of severe toxicity.

Patients with partial DPD deficiency (such as those with heterozygous mutations in the DPYD gene) and where the benefits of 5-fluorouracil are considered to outweigh the risks (taking into account the suitability of an alternative non-fluoropyrimidine chemotherapeutic regimen), must be treated with extreme caution and frequent monitoring with dose adjustment according to toxicity should be conducted. A reduction of the starting dose in these patients may be considered to avoid serious 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 side 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 the patient.

The patients who are tested negative for the above-mentioned alleles may still have a risk of severe adverse events.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Various purines, pyrimidines, and antimetabolites have shown biochemical modulation of fluorouracil in in vitro test systems. Purines include inosine, guanosine, guanosine-5′-phosphate and deoxyinosine. Pyrimidines include thymidine, uridine and cytidine. Antimetabolites include methotrexate, tamoxifen, interferon, phosphonoacteyl-L-aspartate (PALA), allopurinol, hydroxyurea, dipyridamol and leucovorin (folinic acid). Synergistic cytotoxic interactions, such as those involving fluorouracil with leucovorin, have shown beneficial therapeutic effects, particularly in colon cancer. However, the drug combination may result in increased clinical toxicity (gastrointestinal side effects) of the fluorouracil component. Other drugs include metronidazole and cimetidine. Pretreatment with cimetidine prior to intravenous fluorouracil increased the fluorouracil area under the concentration versus time curve (AUC) by 27%. The total body clearance was reduced by 28%. This may lead to increased plasma concentrations of fluorouracil.

Marked elevations of prothrombin time and INR have been reported in a few patients stabilised on warfarin therapy following initiation of fluorouracil regimes.

A clinically significant interaction between the antiviral sorivudine and fluorouracil prodrugs, resulting from inhibition of dihydropyrimidine dehydrogenase by sorivudine or chemically related analogues. Caution should be taken when using Fluorouracil in conjunction with medications which may affect dihydropyrimidine dehydrogenase activity.

Combination therapy with fluorouracil and levamisole has been associated with multifocal inflammatory leukoencephalopathy (MILE). Symptoms may include memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. The cerebrospinal fluid may show mild pleiocytosis, and computed tomography and magnetic resonance scans may show lesions in the white matter suggestive of demyelination. If this syndrome occurs, treatment should be discontinued immediately. The condition is at least partially reversible if fluorouracil and levamisole are discontinued, and corticosteroids given. The use of levamisole and fluorouracil is no longer recommended by NH&MRC ‘Clinical Practice guidelines: The prevention, early detection and management of colorectal cancer’. This combination regimen has been superseded by fluorouracil and leucovorin.

Increased phenytoin plasma concentrations have been reported during concomitant use of phenytoin with capecitabine or its metabolite fluorouracil. Formal interaction studies between phenytoin and capecitabine have not been conducted, but the mechanism of interaction is presumed to be inhibition of CYP2C9 isoenzyme system by capecitabine. Serum levels of phenytoin sustained above the optimal range may produce encephalopathy, or confusional states (delirium psychosis), or rarely irreversible cerebellar dysfunction. Therefore, patients taking phenytoin concomitantly with capecitabine or fluorouracil should be regularly monitored for increased phenytoin plasma levels.

Vaccination with a live vaccine should be avoided in patients receiving 5-fluorouracil due to the potential for serious or fatal infections. Contact should be avoided with people who have recently been treated with polio virus vaccine.

Patients with leukaemia who are in remission should not receive vaccines containing weakened viruses until three months has elapsed since their last chemotherapy session. Furthermore, immunisation with orally administered vaccines containing the poliomyelitis virus must be postponed for those persons coming into direct contact with the patient, particularly family members.

4.6 Fertility, pregnancy and lactation

Fluorouracil is strictly contraindicated in pregnant or breast-feeding women.

Women of childbearing potential should be advised to avoid becoming pregnant and use an effective method of contraception during treatment with Fluorouracil and up to 6 months afterwards (see section 4.4). If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be fully informed of the potential hazard to the foetus and genetic counselling is recommended. Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

There are no adequate and well-controlled studies in pregnant women, however, fatal defects and miscarriages have been reported.

Men treated with Fluorouracil are advised not to father a child during and for up to 6 months following cessation of treatment (see section 4.4). Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Fluorouracil.

Since it is not known whether Fluorouracil passes into breast milk, breast-feeding must be discontinued if the mother is treated with Fluorouracil.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machinery have been performed.

Fluorouracil 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.

4.8 Undesirable effects

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.

Common: Febrile neutropenia

Infections and infestations:

Very common: Infections

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 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. 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: Pericarditis, 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 leukoencephalopathy 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 and in patients with dihydropyrimidine dehydrogenase deficiency, kidney failure.

Not known: Peripheral neuropathy may occur, Hyperammonaemic encephalopathy

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

4.9 Overdose

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 is detected should be closely monitored for at least 4 weeks.

Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents; Antimetabolites; Pyrimidine analogues

Fluorouracil 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 may also interfere with RNA synthesis.

5.2 Pharmacokinetic properties

Absorption and Distribution:

After intravenous administration, fluorouracil 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 readily enters the C.S.F. and brain tissue.

Biotransformation:

5-fluorouracil is catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureido-propionase 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 section 4.3 and 4.4).

Elimination:

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 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.

5.3 Preclinical safety data

Preclinical information has not been included because the toxicity profile of fluorouracil has been established after many years of clinical use. Please refer to section 4.

Pharmaceutical particulars

6.1 List of excipients

Sodium hydroxide

Water for Injections.

6.2 Incompatibilities

5-Fluorouracil 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.

6.3 Shelf life

Before use: 24 months

In use: Chemical and physical in-use stability has been demonstrated for 5 days at 20-21°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze. Keep container in the outer carton.

The pH of fluorouracil injection is 8.9 and the drug has maximal stability over the pH range 8.6 to 9.0.

If a precipitate has formed as a result of exposure to low temperatures, redissolve by heating to 60°C accompanied by vigorous shaking. Allow to cool to body temperature prior to use.

The product should be discarded if it appears brown or dark yellow in solution.

6.5 Nature and contents of container

Type I Conventional Clear Glass Vials with rubber closures.

Type I Clear Onco-Tain Vials with rubber closures.

250 mg/10ml: Pack Size 5.

500 mg/20ml: Pack Size 10.

2.5 g/100 ml: Pack Size Singles and 10’s.

Not all presentations or pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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 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 an 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 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 Injection may be diluted with Glucose 5% Injection or Sodium Chloride 0.9% Injection or Water for Injections immediately before parenteral use.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Fluorouracil 25 mg/ml Injection

PACKAGE LEAFLET: INFORMATION FOR THE USER

Fluorouracil 25 mg/ml Injection

Read all of this leaflet carefully before you start taking this medicine.

Keep this leaflet. You may need to read it
If you have any further questions, ask your doctor or
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or

What is in this leaflet:

What Fluorouracil Injection is and what it is used for
What you need to know before you use Fluorouracil Injection
How to use Fluorouracil Injection
Possible side effects
How to store Fluorouracil Injection
Further information

WHAT FLUOROURACIL INJECTION IS AND WHAT IT IS USED FOR

Fluorouracil Injection is an anti-cancer medicine. Treatment with an anti-cancer medicine is sometimes called cancer chemotherapy.

Fluorouracil Injection is used to treat many common cancers, particularly cancers of the large bowel and breast. It may be used in combination with other anti-cancer medicines or radiotherapy.

WHAT YOU NEED TO KNOW BEFORE YOU USE FLUOROURACIL INJECTION

Do not use Fluorouracil Injection

if you have shown signs of severe allergy to fluorouracil in the past
if you are in a seriously weakened state due to long illness
if your bone marrow has been damaged by other cancer treatments (including radiotherapy)
if you know that you do not have any activity of the enzyme dihydropyrimidine dehydrogenase (DPD)
if you have a potentially serious infection
if your cancer is non-malignant
if you are pregnant or you are breast-feeding
if you are taking or have taken in the past 4 weeks brivudine, sorivudine and similar drugs (antivirals)

Tell your doctor if any of the above applies to you before this medicine is used.

Talk to your doctor or pharmacist before using Fluorouracil Injection

if your bone marrow is not producing blood cells normally (your doctor will do a blood test to check this)
if you have any problems with your kidneys
if you have any problems with your liver including jaundice (yellowing of the skin)
if you have suffered from angina (chest pain) or have a history of heart disease
if you have problems with your heart. Tell your doctor if you experience any chest pain during treatment
if you have reduced activity/deficiency of the enzyme DPD (dihydropyrimidine dehydrogenase)
if you are in generally poor health and have lost a lot of weight
if you have had surgery within the last 30 days
if you are elderly
if you know that you have a partial deficiency in the activity of the enzyme dihydropyrimidine dehydrogenase (DPD)

DPD deficiency: DPD deficiency is a rare condition present at birth that is not usually associated with health problems unless you receive certain medicines. If you have an unrecognised DPD deficiency and take 5-fluorouracil, you are at an increased risk of acute early-onset of severe forms of the side effects listed under section 4 Possible side effects. Contact your doctor immediately if you are concerned about any of the side effects or if you notice any additional side effects not listed in the leaflet (see section 4 Possible side effects).

Contact your healthcare provider immediately, if you experience the following signs or symptoms: new onset of confusion, disorientation, or otherwise altered mental status, difficulty with balance or coordination, visual disturbances. These could be signs of encephalopathy which can lead to coma and death, if left untreated.

Tell your doctor if any of the above applies to you before this medicine is used.

Taking/using other medicines

Special care is needed if you are taking/using other medicines as some could interact with Fluorouracil Injection, for example:

methotrexate, cisplatin, cytarabine, mitomycin-C, tamoxifen (anti-cancer medicines)
metronidazole (an antibiotic)
calcium leucovorin (also called calcium folinate – used to reduce the harmful effects of anti-cancer medicines)
allopurinol (used to treat gout)
cimetidine (used to treat stomach ulcers)
warfarin (used to treat blood clots)
interferon alpha 2a; brivudine, sorivudine and similar drugs (antivirals)
phenytoin (an anti-epilepsy medicine)
vaccines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding. This medicine must not be used during pregnancy and breast-feeding.

Both women of childbearing potential and men must use an effective method of contraception while taking fluorouracil and for at least 6 months afterwards.

Men are advised to seek advice on the conservation of sperm due to the possibility of irreversible infertility due to using fluorouracil.

If a pregnancy does occur during your treatment, you must inform your doctor who will advise you of the potential hazards and may recommend genetic counselling for you.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Do not drive or use machines if you experience any side effect from Fluorouracil, such as nausea and vomiting. Fluorouracil can also produce adverse events on your nervous system and cause visual changes. If you experience any of these effects, do not drive or use any tools or machines, as they may impair your ability to do so.

Important information about one of the ingredients of Fluorouracil Injection

This medicinal product contains 7 mmol (160 mg) sodium per 1 gram dose. To be taken into consideration by patients on a controlled sodium diet.

3. HOW TO USE FLUOROURACIL INJECTION

This medicine is given into a vein or an artery. If it is given into a vein, it can either be injected (using a syringe) or infused (using a drip). If it is given into an artery, it will be given as an infusion.

If it is to be given as an infusion the medicine will be diluted before use.

Dose

Your doctor will work out the correct dose of Fluorouracil Injection for you and how often it must be given.

The dose of medicine given to you will depend on your medical condition, your size, if you have had recent surgery and how well your bone marrow, liver and kidneys are working.

Your doctor will tell how well your bone marrow, liver and kidneys are working using blood tests.

The total daily dose should not exceed 1 gram.

If you are given too much or too little Fluorouracil Injection

This medicine will be given to you by a doctor or nurse. It is unlikely that you will be given too much or too little, however, tell your doctor or nurse if you have any concerns. If you have taken too much, your doctor will monitor you closely for at least 4 weeks.

4. POSSIBLE SIDE EFFECTS

Like all medicines, fluorouracil can cause side effects, although not everybody gets them.

If any of the following happen, tell your doctor immediately:

severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint
chest pains (which may be due to heart problems, including having a heart attack)
shortness of breath
your bowel motions are bloodstained or black
your mouth becomes sore or develops ulcers

symptoms of leucoencephalopathy (disease of brain) – extreme weakness and fatigue, staggering while walking, thinking or speech difficulties, seizures, coma.

These are very serious side effects. You may need urgent medical attention.

The frequency of possible side effects listed below is defined using the following convention: Very common: may affect more than 1 in 10 people

Common: may affect up to 1 in 10 people Uncommon: may affect up to 1 in 100 people Rare: may affect up to 1 in 1,000 people

Very rare: may affect up to 1 in 10,000 people

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

If you experience any of the following tell your doctor as soon as possible: Very common side effects

abnormality in the heart’s rhythm
anaemia
diarrhoea
infections
feeling or being sick
anorexia
tiredness
reddening of the palms of the hands and/or the soles of the feet
hair loss (especially in women)
increased chance of picking up infections and/or delayed wound healing due to low white blood cells
inflammation of the lining of the mouth, throat, gut, rectum or anus

Common side effects

low white blood cells accompanied by fever

Uncommon side effects

low blood pressure (you may feel faint)
watering eyes, changes in vision, sensitivity to light, side-to-side movements of the eyes
numbness, tingling or tremor in the hands or feet
feeling euphoric
symptoms of Parkinson’s disease (e.g. shaking hands)
headache
skin problems, (including dry skin, itchy weals, rash, redness, inflammation)
skin may appear lighter or darker
changes in your nails, such as changes in colour or thickening of the nails

Rare side effects

feeling confused
discolouration in your fingers and toes (Raynaud’s syndrome)
reduced circulation to the brain, intestines and extremities (ischaemia)
blood clots (pain, redness or swelling of the part affected)

Very rare side effects

muscle weakness
cardiac arrest
sudden cardiac death

Frequency unknown

quickening of your heart rate
fever
the vein where fluorouracil is administered may become painful or discoloured, which may be the sign of a blood clot
hyperammonaemic encephalopathy (brain dysfunction caused by elevated ammonia)

Fluorouracil may lead to changes in your blood cells. Your doctor will take blood samples to check for abnormalities (e.g. bone marrow depression which may result in low white cells, low red cells, low platelets, low gamma globulins).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5. HOW TO STORE FLUOROURACIL INJECTION

Keep out of the sight and reach of children

Expiry

This medicine must not be used after the expiry date which is stated on the vial label and carton after ‘EXP’. Where only a month and year is stated, the expiry date refers to the last day of that month.

Storage

Keep the vials in the outer carton, in order to protect from light and store at or below 25°C. They should not be refrigerated or frozen.

Prepared infusions should be used immediately, however, if this is not possible they can be stored for up to 5 days provided they have been prepared in a way to exclude microbial contamination.

Visible signs of deterioration

The product should be discarded if it appears brown or dark yellow in colour.

Disposal

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

FURTHER INFORMATION

What Fluorouracil Injection contains

The active substance is fluorouracil. Each millilitre (ml) of solution contains 25mg of fluorouracil.

The other ingredients are sodium hydroxide and Water for Injections.

What Fluorouracil Injection looks like and contents of the pack

Fluorouracil Injection is a clear, colourless or slightly yellow solution for injection which comes in glass containers called vials.

It may be supplied in packs containing:

5 x 250mg/10 ml vials
10 x 500mg/20 ml vials
1 or 10 x 2.5 g/100 ml vial

Not all packs may be marketed.