Active ingredients: Fluorouracil
Fluorouracil Hospira 50 mg / ml solution for injection for intravenous use
Why is Fluorouracil used? What is it for?
Fluorouracil Hospira contains the active substance fluorouracil and belongs to the category of anticancer drugs.
Fluorouracil Hospira is used for the palliative treatment of cancer:
- breast
- of the colon
- of the rectum
- stomach
- of the pancreas
in patients carefully selected and considered intractable by surgery or other means.
Contraindications When Fluorouracil should not be used
You should NOT be given Fluorouracil Hospira
- if you are allergic to fluorouracil or any of the other ingredients of this medicine (listed in section 6).
- if you are undernourished
- if you suffer from decreased bone marrow function
- if you have severe infections
- for the treatment of non-malignant diseases
- during pregnancy and breastfeeding (see section Pregnancy, breastfeeding and fertility).
Precautions for use What you need to know before taking Fluorouracil
Talk to your doctor or nurse before you are given fluorouracil
Stop taking fluorouracil immediately
- at the first sign of mouth ulceration (stomatitis or esophagopharyngitis)
- in case of evident side effects on the gastrointestinal system (e.g. untreatable vomiting, diarrhea, ulceration, bleeding)
- in case of bleeding in any location
- if the number of platelets drops too low (less than 100,000 / mm3)
- if the number of white blood cells falls too low (less than 3,500 / mm3)
Fluorouracil will be given to you with caution
- if you suffer from impaired kidney or liver function including jaundice (yellowing of the skin)
- if you suffer from heart disease
- if you have a decrease in the number of blood cells
- if you have undergone high dose pelvic irradiation
- if being treated with alkylating drugs
- if your bone marrow has widespread metastases
Tell your doctor if
- You experience chest pain during the course of therapy Fluorouracil treatment is usually associated with a decrease in the number of white blood cells (leukopenia). You will have blood tests to check for this.
Since Fluorouracil Hospira is an anti-cancer medicine, it will be given to you in a special unit and under the supervision of a doctor qualified in the use of anti-cancer medicines (powerful antimetabolites). after treatment. This sheet can help you remember this.
Due to the possibility of severe toxic effects, he will be hospitalized at least during the first course of therapy. Your doctor will closely monitor your response to treatment and signs of toxicity and will eventually stop therapy.
The container of this medicine is made of latex rubber. It can cause severe allergic reactions.
Children
This medicine should not be used in children. The safety and efficacy of fluorouracil in children has not yet been established.
Interactions Which drugs or foods can modify the effect of Fluorouracil
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, even those not prescribed by a doctor.
Other medicines may affect the anticancer effect or toxicity of fluorouracil, including:
- methotrexate (anticancer medicine)
- metronidazole (antibiotic)
- calcium levofolinate (used as a detoxifier in cancer therapy)
- allopurinol (used to treat gout)
- cimetidine (used to treat stomach ulcers)
- cisplatin (anticancer)
- warfarin (anticoagulant)
- sorivudine (antiviral)
- phenytoin (used to control epilepsy / fits and irregular heart rhythm)
Diagnostic interference
There may be an increase in some blood test parameters such as alkaline phosphatase, transaminase, bilirubin and lactic dehydrogenase and some values in the urine (5-hydroxyindolacetic acid (5-HIAA).
A particular protein (plasma albumin) can decrease following a protein malabsorption caused by the drug
Immunosuppressants / radiation therapy
Fluorouracil may increase immunosuppressive action. Your doctor will decide if you need to reduce the dosage of these drugs, including radiation therapy.
Vaccines
Fluorouracil can reduce your normal immune defenses and decrease the effectiveness of vaccines, increasing their side effects.
Tell your doctor about concomitant use of vaccines. He will decide when is the most appropriate time to start fluorouracil therapy.
It is also important to tell your doctor if you are using fluorouracil before getting the vaccination. Tell your doctor if a family member needs to have an oral polio virus vaccine.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.
Do not use fluorouracil during pregnancy and breastfeeding.
If you are a woman of childbearing potential, do not start fluorouracil therapy until you have ruled out a possible pregnancy. Your doctor will advise you of the potential risks to the fetus if you become pregnant during treatment.
Driving and using machines
No reliable data are available, therefore it is recommended not to drive or use machines.
Fluorouracil contains sodium.
To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
Dose, Method and Time of Administration How to use Fluorouracil: Posology
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or nurse.
Administration:
- Fluorouracil Hospira should only be administered under the direct supervision of a physician experienced in the use of anticancer medicines.
- The medicine will be given intravenously as a normal injection or by infusion.
Dosage
The daily dose will be calculated by your doctor based on your actual body weight.
The dose of this medicine that you will be given depends on the type of cancer, your health condition, liver and kidney function, and whether you are being given other medicines at the same time.
Use in children
The safety and efficacy of fluorouracil in children has not yet been established.
Use in the elderly
Elderly patients more frequently have age-related decreases in renal function, requiring dose reduction in patients receiving fluorouracil therapy.
Overdose What to do if you have taken too much Fluorouracil
Overdose with fluorouracil is unlikely to occur as it will be administered by your doctor or nurse. However, the symptoms that herald an overdose are:
- Nausea
- He retched
- Diarrhea
- Gastrointestinal ulceration or bleeding
- Decreased function of the spinal cord
Fluorouracil administration should be promptly discontinued if these symptoms occur.
Treatment
No specific antidote is known. Patients in whom a fluorouracil overdose has occurred should be closely monitored for at least 4 weeks. Appropriate therapy should be adopted in case abnormalities appear.
Side Effects What are the side effects of Fluorouracil
Like all medicines, this medicine can cause side effects, although not everybody gets them
Common side effects (may affect up to 1 in 10 people)
- Dehydration, frequently associated with diarrhea and / or vomiting
- Increased heart rate (tachycardia), shortness of breath and changes in the ECG (electrocardiogram)
- Fever and generalized infection (sepsis), due to infectious complications of spinal cord toxicity and haematological toxicity
- Brain injuries and nervous system disorders (leukoencephalopathy, neuropathy)
- Stomatitis, inflammation of the esophagus and pharynx (esophagopharyngitis) with scaling and ulceration
- Diarrhea
- Anorexia, nausea and vomiting
- Inflammation of the intestine (enteritis), cramps, duodenal ulcers, watery stools, inflammation of the duodenum (duodenitis), gastritis, inflammation of the tongue (glossitis) and pharyngitis (pharyngitis)
- Decrease in the number of white blood cells in the blood (leukopenia)
- Hair loss (alopecia) and dermatitis, mainly an itchy rash localized to the extremities.
Undesirable effects with frequency not known (frequency cannot be estimated from the available data)
- Suppression of bone marrow functioning (myelosuppression)
- Decrease in blood components (pancytopenia)
- Decrease in the number of platelets in the blood (thrombocytopenia)
- Noticeable decrease in white blood cells (agranulocytosis)
- Decrease in red blood cells (anemia)
- Inflammation of superficial veins (thrombophlebitis)
- Painful seizures in the heart region (angina pectoris)
- Insufficient blood supply to the heart (myocardial ischaemia)
- Myocardial infarction
- Lesion on the inner surface of the gastric wall (gastrointestinal ulceration) and bleeding
- Liver changes (intra and extra hepatic sclerosis)
- Inflammation of the gallbladder (cholecystitis) even in the absence of stones
- Abdominal pain
- Inflammation of the rectum (proctitis)
- Allergic reactions
- Difficulty in performing movements (ataxia)
- Headache
- Deep sleep state (lethargy)
- Defective diction
- Dizziness
- Instability
- Weakness
- Malaise
- Disturbance of perception and intellectual functions such as, for example, memory loss, space-time disorientation, agitation (acute cerebellar syndrome)
- Dry skin, cracking
- Erythema or patches of the skin, sensitivity to sunlight (photosensitivity)
- Spots in the veins (pigmentation of the veins)
- Tingling in the hands and feet followed by pain, erythema and swelling (palmar-plantar erythrodysaesthesia syndrome), an unusual complication of continuous high-dose bolus or protracted fluorouracil therapy
- Light intolerance (photophobia)
- Tearing
- Reduction of visual acuity
- Rhythmic and involuntary movements of the eyes (nystagmus)
- Double vision (diplopia)
- Narrowing of the tear canal (tear duct stenosis)
- Vision alteration
- Disorientation
- Confusion
- State of excessive happiness (euphoria)
- Nosebleed (epistaxis)
- Increased levels of thyroid hormones (TT4 and TT3)
- Nail alteration (streaking or shedding of the nails)
Infusion related side effects
- Dilation of the arteries (arterial aneurysm)
- Insufficient blood supply to the arteries (arterial ischemia)
- Blood clot formation in the arteries (arterial thrombosis)
- Bleeding from the cannula used to infuse the medicine
- Obstruction of an artery or vein (embolism)
- Muscle aches
- Abscesses
- Infections at the cannula insertion site
The immunosuppressive effect of fluorouracil can lead to an increased risk of microbial infections, delayed healing and bleeding of the gums.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
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. You can also report side effects directly via the website: https://www.aifa.gov. it / content / reports-adverse-reactions
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Store below 25 ° C. Do not refrigerate or freeze.
Store in the original package to protect the medicine from light.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to the last day of that month.
Do not use this medicine if you notice visible signs of deterioration or if the product has a brown or dark yellow color.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Fluorauracil Hospira contains
- The active ingredient is fluorouracil
- The other ingredients are: sodium hydroxide, water for injection, NaOH / HCl as pH correctors
What Fluorouracil Hospira looks like and contents of the pack
Clear glass vial containing a solution for injection for intravenous use. Pack sizes of 1 to 5 vials or a single vial, as follows:
5 vials Onco-Tain 250mg / 5ml
5 vials Onco-Tain 500mg / 10ml
5 vials Onco-Tain 1g / 20ml
1 Onco-Tain 1g / 20ml vial
1 Onco-Tain 2.5g / 50ml vial
1 Onco-Tain 5g / 100ml vial
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
FLUOROURACIL HOSPIRA 50 MG / 1 ML SOLUTION FOR INJECTION FOR INTRAVENOUS USE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains:
fluorouracil 50 mg.
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection for intravenous use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Fluorouracil Hospira is indicated for the palliative treatment of carcinoma of the breast, colon, rectum, stomach and pancreas in carefully selected patients considered intractable by surgery or other means.
04.2 Posology and method of administration
Drugs administered parenterally, prior to administration, must be subjected to visual inspection for the presence of particles or discolouration, whenever the solution and container allow it.
Fluorouracil can be used in combination with other cytotoxic chemotherapy drugs; however the fluorouracil solution for injection must not be mixed directly in the same container as other chemotherapy drugs or other intravenous solutions (see section 6.2).
It is recommended that patients be hospitalized during their first course of therapy.
Fluorouracil Hospira should only be administered intravenously. It is also possible to administer intra-arterial route, taking care, in both cases, to avoid extravasation.
Dosage should be customized and calculated on the patient's actual body weight, using the Lean Body Mass Index (dry weight) if the patient is obese or if weight is artificially increased due to edema, ascites or other water retention conditions. abnormal.
It is recommended that each patient be carefully evaluated before starting treatment in order to determine the optimal fluorouracil dosage with maximum precision.
Fluorouracil Hospira can be diluted with 0.9% sodium chloride for injection or 5% dextrose for injection. The solution obtained is stable for 48 hours if stored at room temperature.
INITIAL DOSAGE:
The dose is 12 mg / kg body weight once daily for 4 subsequent days. The daily dose should not exceed 800 mg. If no toxicity is noted, 6 mg / kg can be administered on the 6th, 8th, 10th, 12th day, while no administration should be given on the 5th, 7th, 9th, 11th day. Therapy should be discontinued at the end of day 12 even if no signs of toxicity appear. (see section 4.4).
At-risk and defected patients (see section 4.4) should receive 6 mg / kg per day for 3 consecutive days. If there are no manifestations of toxicity, 3 mg / kg can be administered on the 5th, 7th, 9th day, until toxicity occurs. No therapy should be administered on the 4th, 6th, 8th day. The total daily dose should not exceed 400 mg.
An intravenous administration sequence belonging to one or the other scheme constitutes a "therapy cycle".
Therapy should be discontinued immediately if signs of toxicity appear.
MAINTENANCE THERAPY:
In cases where toxicity is not a problem, therapy is continued by adopting one or the other scheme:
1. Repeat the administration with the same dosage as the previous one every 30 days from the last treatment.
2. When the signs of toxicity manifested following the initial course of therapy have diminished, administer a maintenance therapy of 10-15 mg / kg / week in a single administration. Do not exceed 1 g per week and use lower doses in the patients at risk Adjust the dosage according to the patient's reactions to previous treatment Some patients have received 9 to 45 courses of treatment over a period of 12 to 60 months.
INFUSION:
A daily dose of 15 mg / kg, but not exceeding 1 g per infusion, to be diluted in 500 ml of 5% dextrose for injection or 0.9% sodium chloride for injection and administered by intravenous infusion at the rate of 40 drops per minute in 4 hours.
Alternatively, the daily dose can be infused for 30-60 minutes, or as a continuous infusion over 24 hours. This daily dose should be administered the following days until signs of toxicity are found or until a dose of 12-15 gr is administered.
This sequence of injections constitutes a "cycle" of therapy. Some patients received up to 30 gr. with a maximum daily dose of up to 1 gr. The interval between two cycles should be 4/6 weeks.
Use in pediatrics:
The safety and efficacy of fluorouracil in children has not yet been established.
Use in the elderly:
Elderly patients more frequently have age-related decreases in renal function, requiring dose reduction in patients receiving fluorouracil therapy.
Combined therapy:
Any therapy that increases patient stress, interferes with nutrition or depresses bone marrow functions may increase the toxicity of fluorouracil (see section 4.5).
04.3 Contraindications
The medicine is contraindicated in patients with hypersensitivity to fluorouracil or its excipients.
Fluorouracil therapy is contraindicated in undernourished patients, in those with decreased bone marrow function or with severe infections.
Fluorouracil should not be used for the treatment of non-malignant diseases.
Flurouracil is contraindicated in pregnancy and lactation (see section 4.6).
04.4 Special warnings and appropriate precautions for use
The container of this medicine is made of latex rubber. It can cause severe allergic reactions.
Fluorouracil treatment is generally associated with leukopenia. The lowest white blood cell count is usually seen between the 7th and 14th day after the first course of treatment, although the depression can extraordinarily last until the 20th day. The count usually returns to normal levels by the 30th day. Daily monitoring of platelets and white blood cells is recommended and treatment should be stopped if platelets fall below 100,000 / mm3 or leukocytes fall below 3,500 / mm3. When the total value falls below 2000 / mm3, in particular in the presence of granulocytopenia, and to prevent systemic infections, it is recommended to transfer the patient to isolated and protected areas of the hospital and to treat him with appropriate medical aids. .
Treatment should also be stopped at the first sign of oral ulceration or in case of obvious adverse effects on the gastrointestinal system such as stomatitis, diarrhea, bleeding from the gastrointestinal tract or haemorrhage anywhere else in the body, oesophagopharyngitis or intractable vomiting. Fluorouracil therapy can only be resumed when the patient recovers from this symptomatology. The relationship between effective dose and toxic dose is very modest and the therapeutic response is unlikely to occur without any signs of toxicity. Therefore, great care is needed in patient selection and dose adjustment.
Fluorouracil should be used with caution in patients with impaired renal or hepatic function or with jaundice.
Fluorouracil should be used with caution in patients with heart disease. Isolated cases of angina pectoris, ECG abnormalities and rarely myocardial infarction have been reported following administration of fluorouracil. Care should therefore be exercised when treating both patients who complain of chest pain during the course of therapy and patients with history of heart disease
. Due to the risk of sudden death, fluorouracil treatment should not be resumed following a documented cardiovascular reaction (arrhythmia, angina, changes in the ST interval).
It is recommended that fluorouracil be used only by, or under the supervision of, a physician specialized in the use of chemotherapeutic agents and in particular in the use of potent antimetabolites.
Due to the possibility of severe toxic effects, it is recommended that patients be hospitalized at least during the initial course of therapy.
Particular caution should be exercised in patients at risk already undergoing high dose pelvic irradiation, or treatment with alkylating drugs, in patients whose bone marrow has widespread metastases, or with reduced renal or hepatic function.
Any therapy that increases patient stress, interferes with nutritional status, or depresses bone marrow function increases drug toxicity.
Fluorouracil is not an adjuvant therapy to be combined with surgical therapy.
Fluorouracil is a drug that possesses high toxicity with a low safety margin. Patients should be carefully monitored, as the therapeutic response is unlikely to occur without some signs of toxicity.
Severe haematological toxicity, gastrointestinal bleeding and even death can occur with the use of fluorouracil, despite careful patient selection and precise dosage adjustment. Although severe toxic effects may more readily occur in at-risk patients, occasionally it does occur. they can also occur in patients in relatively good condition.
Therapy should be discontinued whenever any of the following signs of toxicity occur:
- stomatitis or esophagopharyngitis, at the first visible sign;
- leukopenia (white blood cell count - WBC less than 3,500) or a rapid fall in white blood cell count;
- untreatable vomiting;
- diarrhea, frequent bowel movements and watery stools;
- gastrointestinal ulceration and bleeding from the gastrointestinal tract;
- thrombocytopenia (platelet count less than 100,000);
- bleeding.
In all cases, the toxic effects must resolve before instituting maintenance therapy. Toxic symptoms often occur during maintenance therapy. However, in the event that they occur, therapy must be interrupted until they are resolved.
Administration of fluorouracil has been associated with the onset of palm-to-palm erythrodysaesthesia syndrome
plantar, also known as "hand-foot syndrome" (see section 4.8) reported as an unusual complication of long-term high-dose bolus fluorouracil therapy.
This syndrome is characterized by a tingling sensation in the hands and feet that can degenerate in a few days into pain when grasping objects or walking. The soles of the feet and hands
they become erythematous and swollen symmetrically, with accentuated sensitivity of the distal phalanges, sometimes with desquamation. Discontinuation of therapy leads to gradual resolution in 5-7 days. Although pyridoxine has been shown to improve this condition, its safety and efficacy have not yet been established.
Coronary vasospasm with episodes of angina pectoris may occur in patients receiving fluorouracil (see section 4.8). Attacks of angina appear to occur approximately 6 hours (range, minutes up to 7 days) after the third dose (range 1-13 doses). The risk is greater in patients with pre-existing coronary artery disease. Nitrates or morphine appear to be effective in relieving pain; preventive treatment with calcium channel blockers may also be effective.
The most pronounced and dose-limiting toxic effects of fluorouracil occur on normal, rapidly proliferating bone marrow cells and the inner lining of the gastrointestinal tract. The immunosuppressive effect of fluorouracil can cause an increased incidence of microbial infections, delayed wound healing and gum bleeding.
Rarely, severe and unexpected toxic reactions (including stomatitis, diarrhea, neutropenia and neurotoxicity) have been reported associated with fluorouracil. These reactions have been related to the deficiency of dihydropyrimidine dehydrogenase activity which appears to cause a delayed clearance of fluorouracil.
Less than one percent of patients treated with fluorouracil present with ataxia or other manifestations of acute cerebellar syndrome secondary to drug neurotoxicity (see section 4.8). Associated with neurotoxicity, oculomotor disorders have been reported, manifesting mainly as weakness of convergence and divergence.
04.5 Interactions with other medicinal products and other forms of interaction
Several substances have been reported to modulate the biochemistry of the anticancer effect or toxicity of fluorouracil, among the most frequently reported are methotrexate, metronidazole, levofolinate as well as allopurinol and cimetidine which influence the bioavailability of the active drug. Pretreatment with cimetidine prior to intravenous infusion of fluorouracil increased its area under the concentration / time curve (AUC) by 27%. Total body clearance was reduced by 28%. This can cause an increase in plasma concentrations of fluorouracil.
A higher incidence of cerebral infarction has been reported in patients with oropharyngeal tumors treated with fluorouracil and cisplatin.
Significant increases in prothrombin time and INR have been reported in some patients stabilized with warfarin after initiation of fluorouracil-based regimens.
A "clinically significant interaction" between the antiviral sorivudine and fluorouracil prodrugs has been described as a consequence of sorivudine inhibition of dihydropyrimidine dehydrogenase. Fluorouracil should not be administered with sorivudine or chemically related analogues. Care should be taken when treating uses fluorouracil in combination with drugs that can affect the activity of dihydropyrimidine dehydrogenase.
Increased plasma concentrations of phenytoin have been reported after concomitant use of phenytoin with capecitabine or its fluorouracil metabolite. Interaction studies have been conducted between phenytoin and capecitabine, however the mechanism of interaction appears to be inhibition of the CYP2C9 isoenzymatic system by capecitabine.
Fluorouracil / Calcium folinate
Calcium folinate can increase the toxicity of fluorouracil.
Fluorouracil / Immunosuppressants / Radiation Therapy
An increase in immunosuppressive action may occur; the dosage may need to be reduced when one or more immunosuppressive drugs, including radiation therapy, are used simultaneously or consecutively.
Fluorouracil / Vaccines, Viruses killed
Depending on the fact that fluorouracil therapy can decrease normal immune defenses, the subject's antibody response may be decreased. The interval between stopping the therapy causing immunosuppression and restoring the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression that the drug causes, the underlying disease and other factors; approximately a period is calculated. between 3 months and 1 year.
Fluorouracil / Vaccines, Live attenuated viruses
Due to the fact that fluorouracil therapy can decrease normal immune defenses, the concomitant use of live attenuated virus vaccines can lead to increased replication of the virus, with consequent increase in the side effects of the vaccine, and / or can decrease the antibody response of the subject to the vaccine; vaccination of these patients should be carried out with extreme caution and only after careful evaluation of the patient's haematological parameters and only with the consent of the physician in charge of fluorouracil therapy. The interval between the interruption of the therapy that causes immunosuppression and the restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression that the drug causes, the pathology and other factors; a period between 3 months and 1 year is estimated approximately.
Patients with leukemia in remission should not receive live attenuated virus vaccines for three months after their last chemotherapy session. In addition, immunization with oral polio virus vaccines should be postponed in people in direct contact with the patient, especially family members.
Diagnostic interference
An increase in alkaline phosphatase, transaminases, bilirubin and lactic dehydrogenase may occur.
An increase in 5-hydroxyindolacetic acid (5-HIAA) may occur in the urine. Plasma albumin may decrease due to protein malabsorption caused by the drug.
04.6 Pregnancy and lactation
Fluorouracil is contraindicated in pregnancy and breastfeeding women.
Women of childbearing potential should not begin fluorouracil therapy until pregnancy has been ruled out and should also be informed of the potential risks to the fetus if pregnancy occurs during treatment (see section 5.3).
04.7 Effects on ability to drive and use machines
No reliable data are available; therefore, it is not recommended to drive or use machines.
04.8 Undesirable effects
The following are the effects of fluorouracil, organized according to the MedDRA system organ class. Insufficient data are available to establish the frequency of the individual effects listed.
Metabolism and nutrition disorders
Dehydration (frequently associated with diarrhea and / or vomiting)
Gastrointestinal disorders
Diarrhea, vomiting, stomatitis, esophagus-pharyngitis (which can lead to desquamation and ulceration), anorexia, nausea, enteritis, cramps, duodenal ulcers, watery stools, duodenitis, gastritis, glossitis, and pharyngitis.
Gastrointestinal ulceration and bleeding, abdominal pain, proctitis.
Cardiac pathologies
Tachycardia, angina, myocardial ischaemia, cardiotoxicity.
Cases of myocardial infarction have been reported. There have been reports of sudden death.
Respiratory, thoracic and mediastinal disorders
Dyspnea, epistaxis
Disorders of the blood and lymphatic system
Hematotoxicity
Leukopenia (the lowest white blood cell count is usually seen between the 7th and 14th day after the first course of treatment, although the maximum depression can be extraordinarily prolonged until the 20th day. The count usually returns to normal levels by the 30th day).
Myelosuppression, pancytopenia, thrombocytopenia, agranulocytosis, anemia, thrombophlebitis.
Infections and infestations
Fever and sepsis (due to infectious complications of spinal cord and haematological toxicity)
Disorders of the immune system
Hypersensitivity reactions: Anaphylaxis and generalized allergic reactions.
Psychiatric disorders
Disorientation, confusion, euphoria.
Nervous system disorders
Leukoencephalopathy, neuropathy,
Ataxia, headache, lethargy, defective diction, dizziness, instability, acute cerebellar syndrome. These symptoms may persist after discontinuation of therapy.
Eye disorders
Photophobia, lacrimation, reduced visual acuity, nystagmus, diplopia, tear duct stenosis, visual changes.
Hepatobiliary disorders
Intra and extra hepatic sclerosis, cholecystitis in the absence of stones
Skin and subcutaneous tissue disorders
Alopecia and dermatitis have been observed in a large number of cases. The most frequently occurring dermatitis is an itchy maculopapular rash usually localized to the extremities and less frequently to the trunk. It is generally reversible and usually responds to symptomatic treatment.
Dry skin, cracking, photosensitivity, manifesting as erythema or increased skin pigmentation, vein pigmentation, palmar-plantar erythrodysaesthesia syndrome, manifesting as tingling in the hands and feet followed by pain, erythema and swelling, alteration of the nails (includes streaking or loosening of the nails).
Diagnostic tests
Modification of the electrocardiogram
Increased levels of total serum thyroxine (TT4) and total serum triiodothyronine (TT3).
General disorders and administration site conditions
Malaise, weakness
Infusion complications at the level of the regional arteries: Arterial aneurysm, arterial ischemia, arterial thrombosis, bleeding at the level of the cannula, obstruction of the cannula, removal of the cannula from the venous vessel or leakage of the infusional fluid on site; embolism, fibromyositis, abscesses, infections at the site where the cannula is inserted, thrombophlebitis.
"Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse".
04.9 Overdose
Events:
The possibility of an overdose with fluorouracil is difficult due to the conditions of administration. However, symptoms that herald an overdose are nausea, vomiting, diarrhea, gastrointestinal ulceration or bleeding, decreased bone marrow function (including the occurrence of thrombocytopenia, leukopenia and agranulocytosis). The administration of fluorouracil should be promptly discontinued upon the onset of these symptoms.
Treatment:
No specific antidote is known. Patients in whom a fluorouracil overdose has occurred should be closely monitored for at least 4 weeks. Appropriate therapy should be used if abnormalities appear.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Fluorouracil is a fluorinated pyrimidine belonging to the category of antimetabolites, structurally similar to uracil. The exact mechanism (s) of action has not yet been clarified, but it is assumed that the drug acts as an antimetabolite in three different ways. The drug's deoxyribonucleotide, 5-fluoro-2 "-deoxyuridine-5" - phosphate, inhibits thymidylate synthetase, thereby inhibiting the methylation of deoxyuridyl acid to thymidyl acid and thereby interfering with DNA synthesis. Furthermore, fluorouracil is incorporated, for a small fraction, into the RNA, producing an abnormal RNA; finally, it inhibits the use of presynthesized uracil in the synthesis of RNA, blocking uracil phosphatase. Since DNA and RNA are essential for cell division and growth, fluorouracil can cause unbalanced growth and cell death.
Parenteral administration of fluorouracil has been shown to inhibit the growth of neoplasms in humans and that the therapeutic effects are best when used for bone marrow tumors, intestinal mucosal tumors, and certain breast, rectal, and breast cancers. colon.
05.2 "Pharmacokinetic properties
Absorption and distribution
Following i.v.administration, fluorouracil is distributed to tumor tissue, intestinal mucosa, bone marrow, liver, and other tissues. Despite its poor fat solubility, the drug quickly crosses the blood-brain barrier and is distributed in the cerebrospinal fluid and brain tissue. Distribution studies in animals and humans have shown a higher concentration of the drug, or its metabolites, in tumor tissue than in other tissues. Fluorouracil has also been shown to persist longer in some tumor tissues than in normal tissues. of the host perhaps due to a reduction in uracil catabolism.
Half-life
The mean elimination half-life from plasma is approximately 16 minutes, with a range of 8-20 minutes, and is dose dependent. Three hours after intravenous infusion, no non-metabolised drug is found in the plasma.
Excretion
The drug is excreted unchanged in the urine in 6 hours for about 7-20%; of this, more than 90% is excreted during the first hour. The remainder of the administered dose is metabolised, mainly in the liver. The catabolic metabolism of fluorouracil leads to inactive products (CO2, urea, alpha-fluoro-beta-alanine). Inactive metabolites are excreted in the urine over the next 3-4 hours.
05.3 Preclinical safety data
The LD50 of fluorouracil for i.p. was found to be 101 mg / kg in mice and 237 mg / kg in rats. The hematopoietic system is very sensitive to 5-FU and many of the toxic manifestations occur at this level. The administration of 23 mg / kg / day i.p. for six days causes a total change in bone marrow cells and in the number of endogenous colony-forming units (CFU) in mice. UFC count returns to normal 10 days after last administration. 5-FU induces qualitative and structural changes compared to normal karyocyte cells when tested for mutagenic effects on human cell chromosomes (Strain CA-1). Like many other chemotherapeutic cytotoxic agents, 5-FU has shown teratogenic action in laboratory animals.The types of malformations included deformation of the palate, legs and tail.
Mutagenic potential
A positive micronucleus test result was observed on mouse bone marrow cells, and fluorouracil at high concentrations causes chromosomal breakdown in hamster fibroblasts in vitro. Fluorouracil has been shown to be mutagenic in several Salmonella typhimurium strains, including TA 1535, TA 1537, and TA 1538 and in Saccharomyces cerevisiae but not in Salmonella typhymurium strains TA 92, TA 98, and TA 100.
Teratogenicity
Fluorouracil can cause fetal harm when administered to pregnant women. Fluorouracil was teratogenic in laboratory animals. The dosage that proves to be teratogenic is 1 to 3 times greater than the maximum recommended therapeutic dose. Fetal deformations include cleft palate, skeletal defects, appendages, leg and tail deformations.
Carcinogenicity
Long-term animal studies have not been conducted to determine the carcinogenic potential of fluorouracil, however in several animal studies lasting up to one year, with oral or i.v. administration, no evidence of carcinogenicity was observed. The risk of carcinogenicity in humans has not been established.
Effects on peri-post natal development
Fluorouracil has not been tested in animals for its effects on peri- and postnatal development. However, fluorouracil has been shown to cross the placenta and enter the fetal circulation of the rat. Administration of fluorouracil has been shown to increase abortions and embryo lethality in rats. In monkeys, doses greater than 40 mg / kg administered to the mother resulted in the death of all fetuses exposed to fluorouracil. Substances that inhibit the synthesis of DNA, RNA, and proteins can interfere with peri and postnatal development.
Effects on fertility and reproduction
Fluorouracil has not been sufficiently tested in animals to determine its effects on fertility and reproductive capacity in general. Following the intraperitoneal administration of 125 or 250 mg / kg, chromosomal aberration and modification in the chromosomal organization of spermatogonia are determined: spermatogonial differentiation is also inhibited, this determines a temporary loss of fertility. Following the intraperitoneal administration of doses of 25 o 50 mg / kg per week for 3 weeks during the preovulatory phases of oogenesis in female rats, the incidence of fertile mating is substantially reduced. Limited studies conducted in rabbits have shown that administration of single doses of 25 mg / kg or a daily dose of 5 mg / kg for 5 days has no effect on ovulation.
It is expected that compounds similar to fluorouracil, which inhibit the synthesis of DNA, RNA, and proteins, can cause toxic effects on gametogenesis. The use of a non-hormonal contraceptive is recommended during cytotoxic therapy.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium hydroxide - Water for injections - NaOH / HCl as pH correctors
06.2 Incompatibility
5-fluorouracil is incompatible with carboplatin, cisplatin, cytarabine, diazepam, doxorubicin and other anthracyclines and probably also with methotrexate.
Fluorouracil solutions are alkaline and therefore it is recommended to avoid adding acidic drugs or preparations to these solutions.
Fluorouracil solution for injection should not be mixed directly in the same container as other chemotherapy drugs or other intravenous solutions.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store in the original package at a temperature below 25 ° C, away from light. Do not refrigerate or freeze.
ATTENTION: The product does not contain preservatives. After use, it must be thrown away even if used only partially. If diluted with aseptic technique with suitable perfusion solutions, the resulting solutions can be stored for up to 24 hours between 2 ° C and 8 ° C. The user is therefore responsible for both modalities and the shelf life of the diluted drug.
The pH of the injectable fluorouracil BP is 8.9 and the product is stable at a pH between 8.5-9.1.
If a precipitate forms as a result of exposure to low temperatures, it can be returned to solution by shaking and heating the solution to 60 ° C. Before use, allow to cool to body temperature.
The product should not be used if its color is brown or dark yellow.
06.5 Nature of the immediate packaging and contents of the package
Type I clear glass vial, Onco-Tain, consisting of an outer shrink plastic anti-spreading in case of breakage of the vial with an elastomeric closure. Aluminum seal with flip-off plastic cap.
Packs of 1 or 5 vials + package leaflet.
Pack size of one vial + leaflet.
06.6 Instructions for use and handling
The Chemo-Dispensing Pin device or similar piercing devices which could cause the stopper to fall inside the vial, with consequent loss of sterility of the product, should not be used.
Guidelines for handling cytotoxic drugs
Administration
It should only be administered under the direct supervision of a physician experienced in the use of cytostatic drugs.
Preparation
1) Fluorouracil should only be prepared for use by professionals experienced in its handling.
2) Operations such as reconstitution of powders and transfer to syringes should only be conducted in suitable specially designated areas (preferably under a laminar flow hood suitable for handling cytotoxic compounds).
3) The personnel carrying out these operations must be adequately protected by gowns, gloves and safety glasses.
4) Pregnant female staff should not handle these substances.
Contamination
a) In case of accidental contact with the skin or eyes, the area should be washed with plenty of water or normal saline. A mild cream can be used to treat temporary skin irritation. Consult a specialist in case of accidental eye contact or if the drug is inhaled or ingested.
b) In case of spillage, operators should wear gloves and collect the solution with a sponge held in the work area specifically for this purpose. Wash the surface twice with water. Place the solution, the sponge and the contaminated material in a plastic bag and seal it.
Elimination
The syringes, container, absorbent material, solution and other contaminated material should be placed in a double plastic bag or other impermeable container and then incinerated at 700 ° C.
07.0 MARKETING AUTHORIZATION HOLDER
Hospira Italia S.r.l.
Via Orazio, 20/22 - 80122 Naples
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. no. 034316012 5 vials Onco-Tain 250 mg / 5 ml
A.I.C. no. 034316024 5 vials Onco-Tain 500 mg / 10 ml
A.I.C. no. 034316087 5 vials Onco-Tain 1 g / 20 ml
A.I.C. no. 034316036 1 vial Onco-Tain 1 g / 20 ml
A.I.C. no. 034316048 1 vial Onco-Tain 2.5 g / 50 ml
A.I.C. no. 034316051 1 vial Onco-Tain 5 g / 100 ml
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
A.I.C renewal: 02.11.2011
10.0 DATE OF REVISION OF THE TEXT
09/2015
