Active ingredients: Folic acid (Calcium folinate)
LEDERFOLIN 7.5 mg tablets
LEDERFOLIN 2.5 mg granules for oral solution
LEDERFOLIN 25 mg powder for solution for injection for intravenous use
Why is Lederfolin used? What is it for?
Lederfolin contains the active substance calcium levo-folinate, which belongs to a group of medicines called 'detoxifying agents for cytostatic treatments'. Calcium folinate derives from folic acid and is essential for the synthesis of DNA, containing all the genetic information necessary for the functioning of cells.
Lederfolin is used:
- as an antidote to drugs that prevent the action of folic acid and to combat the side effects of two anticancer drugs: aminopterin and methotrexate.
- to treat folate deficiency anemias.
Contraindications When Lederfolin should not be used
Do not take Lederfolin:
- if you are allergic to calcium folinate or any of the other ingredients of this medicine (listed in section 6);
- if you have anemia due to vitamin B12 deficiency. Lederfolin should not be used for this type of anemia because it can cause an apparent improvement in the disease, hiding the progression of damage to the central nervous system.
If the patient is a neonate (≤ 28 days of age) Lederfolin 25 mg powder for solution for injection for intravenous use (or other calcium-containing solutions) should not be administered concomitantly with ceftriaxone (an antibiotic), even when using lines. of separate infusions. There is a fatal risk of particle formation in the infant's bloodstream.
Precautions for use What you need to know before taking Lederfolin
Talk to your doctor or pharmacist before taking Lederfolin
Only use this medicine in combination with methotrexate (an anticancer medicine) under the direct supervision of a doctor who has experience in the use of medicines to treat cancer. This medicine must not be given to you by injection into the lumbar region of the spine (intrathecal administration) Intrathecal administration of Lederfolin, performed to counter an intrathecal overdose of methotrexate, can result in death.
Talk to your doctor before taking Lederfolin if you think any of the following apply to you:
- you are undergoing cancer treatment with one of the following medicines: hydroxycarbamide, cytarabine, mercaptopurine, thioguanine.These medicines can cause red blood cells to form in the blood that are larger than normal in diameter (a condition known as 'macrocytosis'). This condition should not be treated with Lederfolin;
- have epilepsy and are undergoing treatment with one of the following medicines: phenobarbital, phenytoin, primidone, succinimide. Combination with Lederfolin may cause an increase in the frequency of seizures. Your doctor will check you frequently and may adjust the dosage of your epilepsy medicine while you are taking and after stopping Lederfolin (see section Other medicines and Lederfolin);
- you are being treated for cancer with one of the medicines in a category called fluoropyrimidines, especially if the cancer has spread to the central nervous system. Treatment with Lederfolin together with these medicines can cause, although rarely, seizures and syncope (see section Other medicines and Lederfolin);
- you have been treated with excessive doses of anticancer medicines that prevent the detoxifying action of folic acid. Lederfolin must be used within 1 hour after administration of the anticancer drugs, because after a period of 4 hours this medicine is ineffective;
- have diabetes or are following a calorie restricted diet. Lederfolin 2.5 mg granules for oral solution should be used with caution as it contains sucrose, a type of sugar.
Laboratory tests
If your condition requires treatment with Lederfolin in combination with methotrexate, your doctor may need to have frequent blood and urine tests.
Interactions Which drugs or foods can modify the effect of Lederfolin
Tell your doctor if you are taking, have recently taken or might take any other medicines.
Lederfolin may reduce the effectiveness of the following medicines:
- medicines such as methotrexate, co-trimoxazole and pyrimethamine. Calcium folinate, the active substance in Lederfolin, may reduce the effectiveness of these medicines until they are completely neutralized (see section If you take more Lederfolin than you should);
- medicines for the treatment of epilepsy such as phenobarbital, primidone, phenytoin, succinimide. Calcium folinate may decrease the effectiveness of these medicines, resulting in an increase in the frequency of seizures.
Lederfolin may increase some side effects caused by the treatment of the following medicines:
- medicines belonging to a category called fluoropyrimidines (see section Warnings and precautions).
Tell your doctor if you are taking the following medicine due to the risk of particle formation when given together with Lederfolin 25 mg powder for solution for injection for intravenous use:
- ceftriaxone (an antibiotic) due to the risk of particle formation
Warnings It is important to know that:
Pregnancy and breastfeeding
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 taking this medicine.
Pregnancy
During pregnancy you may experience an increased need for folate (folate deficiency anemia), substances that are generally assimilated with food. The administration of low doses of calcium levo-folinate, the active ingredient of Lederfolin, can replenish the missing quantities of folate, with improvement or disappearance of this type of anemia. There is no information that the administration of high doses of calcium folinate is harmful in pregnancy.
Your doctor will recommend the dose that is best for you and your condition.
Feeding time
Calcium folinate passes into breast milk. As its effect on the baby is not known, ask your doctor for advice before taking this medicine while breastfeeding.
Driving and using machines
It is not known whether Lederfolin alters the ability to drive or use machines. If you are unsure, ask your doctor.
Lederfolin 7.5 mg tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine (see also section Warnings and precautions).
Lederfolin 2.5 mg granules for oral solution contains sucrose. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicine (see also section Warnings and precautions).
Dosage and method of use How to use Lederfolin: Dosage
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor.
Lederfolin 7.5 mg tablets and Lederfolin 2.5 mg granules for oral solution are administered orally. Lederfolin 25 mg powder for solution for injection can be administered quickly (intravenously) or slowly (infusion) into a vein. Lederfolin 25 mg powder for solution for injection will be prepared by a doctor, pharmacist or nurse and will not be mixed with or given to you at the same time as injections containing ceftriaxone. When Lederfolin is administered intravenously, it is important that no more than 80 mg of the active substance is administered per minute due to the presence of calcium. This medicinal product must not be administered intrathecally (see also section 2 Warnings and precautions).
- Use in combination with other anticancer medicines Lederfolin can be used in combination with anticancer medicines such as methotrexate to reduce their side effects. Your doctor will decide the amount of medicine that is best for you based on your condition and the other medicines you are taking. The recommended starting dose is 5-6 mg every 6 hours intravenously 4 times. Thereafter, a dose of 7.5 mg every 6 hours orally 4 times is recommended. Lederfolin can also be used as an antidote if you have received an overdose of methotrexate. In this case Lederfolin will be administered intravenously. The recommended dose is equal to or greater than the dose of methotrexate that you have been given, but should not exceed 50 mg in 12 hours. It is important that Lederfolin is given within 1 hour of taking too much methotrexate for maximum effect.
- Treatment of folate deficiency anemias The recommended starting dose is 7.5 mg per day orally for 10-15 days. In case of improvement, the doctor may decide to halve the dose until the anemia and its symptoms disappear.
Overdose What to do if you have taken too much Lederfolin
If you take more Lederfolin than you should
If you take more Lederfolin than recommended, contact your doctor immediately. There are no known side effects in people who took much higher doses of calcium folinate than recommended. Excessive doses of calcium folinate may reduce the effectiveness of some anticancer medicines until they are completely neutralized (see section Other medicines and Lederfolin).
If you have any further questions on the use of this medicine, ask your doctor.
Side Effects What are the side effects of Lederfolin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately if you experience the following side effects as they can be serious and your doctor may decide to stop taking Lederfolin:
- Stevens-Johnson syndrome, a severe acute hypersensitivity reaction of the skin and mucous membranes in various areas of the body, with the formation of areas of necrosis and flaking. This reaction can sometimes be fatal;
- Toxic Epidermal Necrolysis, a severe acute hypersensitivity reaction, with almost total necrosis of the skin and mucous membranes. This reaction can be fatal;
- Very rare (may affect up to 1 in 10,000 people): severe allergic reaction (anaphylactic shock).
Rare side effects (may affect up to 1 in 1000 people):
- convulsions
- sudden and transient loss of consciousness (syncope)
Undesirable effects with frequency not known (frequency cannot be estimated from the available data):
- allergic reactions
- urticaria
- fever
- inflammation of the skin of the lips which is manifested by cuts, swellings and small ulcerations starting from the corners or edges and extending to the lips (cheilitis)
- kidney problems caused by calcium-ceftriaxone deposits. You may experience pain when you urinate, or the amount of urine produced may decrease.
Side effects after using Lederfolin 25 mg powder for solution for injection together with the anticancer medicine 5-fluorouracil. The following side effects depend on the strength of the medicine being used 5-fluorouracil. Contact your doctor immediately if you experience the following side effects as they may be serious (sometimes fatal) and your doctor may decide to stop Lederfolin treatment:
- severe problems with the stomach and intestines, which can also occur with inflammation of the mucous membranes and with diarrhea;
- reduction in the production of red blood cells (anemia), white blood cells (increased sensitivity to infections) and platelets (bleeding) by the bone marrow (myelosuppression).
Very common side effects (may affect more than 1 in 10 people):
- nausea
- He retched
- diarrhea
Undesirable effects with frequency not known (frequency cannot be estimated from the available data):
- redness, swelling, swelling and peeling of the palms of the hands and soles of the feet (palmar-plantar erythrodysaesthesia syndrome)
- excessive ammonia content in the blood (hyperammonaemia)
- inflammation of the mucous membranes, including inflammation of the mouth (stomatitis)
- inflammation of the skin of the lips which is manifested by cuts, swellings and small ulcerations starting from the corners or edges and extending to the lips (cheilitis)
Other side effects:
- excessive lowering of blood pressure (hypotension)
- excessive speeding of the heartbeat (tachycardia)
- narrowing of the bronchi with difficulty in breathing (bronchospasm)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at: http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine. .
Expiry and Retention
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 carton, blister and vial after "EXP". The expiry date refers to the last day of that month.
Lederfolin 7.5 mg tablets
Do not store above 30 ° C.
Lederfolin 2.5 mg granules for oral solution
Do not store above 25 ° C.
Lederfolin 25 mg powder for solution for injection
Do not store above 25 ° C.
The reconstituted solution should be used within 12 hours and stored in a refrigerator (2 ° C - 8 ° C).
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.
Composition and pharmaceutical form
What Lederfolin contains
The active ingredient is calcium folinate pentahydrate.
Each Lederfolin 7.5 mg tablet contains 9.53 mg of calcium levo-folinate pentahydrate, equivalent to 7.5 mg of levo-folinic acid.
The other ingredients are: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate.
Each sachet of Lederfolin 2.5 mg granules for oral solution contains 3.18 mg of calcium levofolinate pentahydrate, equivalent to 2.5 mg of levo-folinic acid.
The other ingredients are: sucrose, strawberry flavor.
Each vial of Lederfolin 25 mg powder for solution for injection contains 31.77 mg of calcium levo-folinate pentahydrate, equivalent to 25 mg of levo-folinic acid.
The other ingredients are: mannitol, sodium hydroxide and / or hydrochloric acid (for pH adjustment).
What Lederfolin looks like and contents of the pack
Lederfolin 7.5 mg tablets are off-white, oval-shaped tablets marked "LL" on one side and "7.5" on the other side. The tablets are available in blister packs of 10 tablets.
Lederfolin 2.5 mg granules for oral solution is packed in sachets containing light yellow granules. This medicine is available in packs of 20 and 30 sachets.
Lederfolin 25 mg powder for solution for injection is available in a pack containing 1 glass vial.
Not all pack sizes may be marketed.
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
LEDERFOLIN tablets
LEDERFOLIN granules for oral solution
LEDERFOLIN powder for intravenous solution
LEDERFOLIN solution for injection
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Oral Lederfolin
One tablet contains:
Active principle:
Calcium folinate pentahydrate 9.53 mg
equiv. with levo-folinic acid 7.5 mg
One sachet of ganulate for oral solution contains:
Active principle:
Calcium folinate pentahydrate 3.18 mg
equiv. with levo-folinic acid 2.5 mg
Parenteral Lederfolin
One vial of powder for solution for injection contains:
Active principle:
Calcium folinate pentahydrate 31.77 mg
equiv. with levofolinic acid 25 mg
Each 1 ml vial of solution for injection contains:
Active principle:
Calcium folinate pentahydrate 1.91 mg
equiv. with levo-folinic acid 1.5 mg
For excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Oral Lederfolin.
Round, flat, ocher yellow tablets.
Sachets containing light yellow granules.
Parenteral Lederfolin.
Lyophilized powder in white glass bottle.
Solution for parenteral use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Lederfolin is useful as an antidote to excessive doses of folic acid antagonists and to combat the side effects induced by aminopterin (4-aminopteroylglutamic acid) and by methotrexate (4-amino-N10-methyl-pteroyl-glutamic acid).
Lederfolin is also indicated in all anemic forms of folate deficiency due to increased demand, reduced use, insufficient dietary intake of folate.
04.2 Posology and method of administration
Lederfolin can be administered orally, by infusion, intravenously or intramuscularly.
Use of calcium folinate (Lederfolin) in the context of particular protocols of antiblastic chemotherapy with high dosages of methotrexate.
According to the most recent acquisitions, to improve the therapeutic index of methotrexate, Lederfolin is used in a sequential antidotic treatment (Lederfolin "rescue"). In fact, it is possible to better control the forms of cancer, without recording, at the same time, significant increases in toxicity. The therapeutic protocol provides for the use of Lederfolin parenterally in the first phase corresponding to antidotism by competition, orally (tablets) in the second phase in which mainly the biochemical-metabolic component comes into play. At the moment, however, general dosage schedules are not defined with certainty.
Since calcium levofolinate is an antagonist of methotrexate, their concomitant administration can only be implemented when, in individual cases, a specific therapeutic protocol has been defined. For this purpose it is advisable to consult the most recent literature on the subject.
Antidote in case of methotrexate overdose.
Lederfolin (calcium levo-folinate), a specific antidote of methotrexate, allows to neutralize the toxic effects exerted by the antimetabolite on the hematopoietic system and on the mucous membranes of the digestive system. In its role as an antidote, Lederfolin is used at different dosages depending on the effect to be obtained. In cases of accidental overdosing, to obtain a competition effect, Lederfolin is recommended for intravenous infusion (up to 50 mg within 12 hours); to obtain a biochemical-metabolic effect, Lederfolin is recommended intramuscularly or intravenously (5-6 mg every 6 hours for 4 doses) or orally (7.5 mg every 6 hours for 4 doses). conventional doses of methotrexate are recommended parenteral Lederfolin (IM or IV 5-6 mg every 6 hours for 4 doses) or orally (7.5 mg every 6 hours for 4 doses). Lederfolin should be administered in doses equal to or greater than methotrexate within the first hour; subsequent administration of Lederfolin is less effective.
In the treatment of folate deficiency anemias.
Treatment will begin with the oral administration of Lederfolin (7.5 mg / day) and then continue daily with this dose for 10-15 days.
In the event of a favorable response, the dose can be halved, continuing until the haematological picture is normalized and the clinical signs disappear.
For particular pathologies the intramuscular route is recommended. The treatment will begin with an administration of 5 mg of Lederfolin and then continue daily with this dose for 10-15 days. In the event of a favorable response, the dose may therefore decrease to 2.5 mg of Lederfolin per day, continuing until the haematological picture is normalized and the clinical signs disappear.
04.3 Contraindications
Lederfolin should not be administered for the treatment of pernicious anemia or other magaloblastic anemia when vitamin B12 is deficient, except in association with it.
Individual ascertained hypersensitivity to calcium folinate.
04.4 Special warnings and appropriate precautions for use
Convulsions and / or syncope have been reported rarely in cancer patients treated with calcium folinate, usually in combination with fluoripyrimidines, and particularly in patients with central nervous system metastases or in predisposed patients; however, a direct correlation with these episodes has not been established.
Lederfolin is an improper therapy of pernicious anemia or other megaloblastic anemia resulting from vitamin B12 deficiency: in fact, haematological remission may occur while the neurological manifestations remain progressive. The therapy must therefore be conducted under haematological control. In the treatment of overdose by folic acid antagonists, the administration of Lederfolin should possibly be carried out within 1 hour, with administration generally ineffective after a period of 4 hours. The administration of the drug must be carried out carefully in order to avoid the danger of allergic reactions or side effects.
Keep out of reach of children.
04.5 Interactions with other medicinal products and other forms of interaction
Levofolinic acid antagonizes the effects of antifolics. It acts as a "rescue" in therapy with high doses of methotrexate and as an antidote in case of overdose.
04.6 Pregnancy and lactation
Anemias in pregnancy resulting from the increased need for folate can be improved or normalized with the administration of levofolinic acid.
04.7 Effects on ability to drive and use machines
Lederfolin does not affect the ability to drive and use machines.
04.8 Undesirable effects
Administration of the product may be followed by general hypersensitivity reactions (fever, urticaria, arterial hypotension, tachycardia, bronchospasm, anaphylactic shock).
04.9 Overdose
No overdose effects have been reported so far.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
ATC: V03AF04
Levofolinic acid plays an important role in purine and pyrimidine synthesis and is essential for the synthesis of DNA, especially at the level of hematopoietic tissue.
In fact, levo-folinic acid is active in all anemia due to folate deficiency.
05.2 Pharmacokinetic properties
Using C14 and H3 labeled calcium levo-folinate, results corresponding to those obtained with the microbiological assay were obtained.
In fact, oral administration of Lederfolin (7.5 mg) is followed by rapid absorption, resulting in a marked increase in folatemia after 60 minutes.
After i.m. administration of 7.5 mg the half-life as N5-formyl-tetrahydrofolic is 45 minutes.
05.3 Preclinical safety data
Per os the LD50 is higher than 7,000 mg / kg in mice.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lederfolin 7.5 mg tablets:
Lactose Monohydrate, Microcrystalline Cellulose, Sodium Starch Glycolate, Silicon Dioxide, Magnesium Stearate.
Lederfolin 2.5 mg granules for oral solution:
Sucrose, Strawberry flavor.
Lederfolin 25 mg powder for solution for injection:
Mannitol, Sodium hydroxide and / or hydrochloric acid
Lederfolin 1.5 mg / 1ml solution for injection:
Methyl p-hydroxybenzoate, Propyl p-hydroxybenzoate, Sodium hydroxide q.s. at pH 8.1, sterile water p.p.i. q.s.
06.2 Incompatibility
None.
06.3 Period of validity
Shelf life at room temperature:
7.5 tablets and 25 mg powder for solution for injection: 24 months;
2.5 mg granules for oral solution: 36 months;
1.5 mg / 1 ml solution for injection: 12 months.
The expiry date refers to the product in intact and correctly stored packaging.
Reconstitution and conservation Lederfolin 25 mg powder for solution for injection:
the lyophilized substance can be reconstituted with 5 ml of sterile p.p.i. water; for the infusion use physiological solution.
The solution obtained can be stored for a maximum of 12 hours at a temperature not exceeding 8 ° C.
06.4 Special precautions for storage
See "Validity".
06.5 Nature of the immediate packaging and contents of the package
Oral Lederfolin:
"7.5 mg Tablets" 10 tablets;
"2.5 mg granules for oral solution" 20 sachets;
"2.5 mg granules for oral solution" 30 sachets;
Parenteral Lederfolin:
"25 mg Powder for intravenous solution" 1 Vial;
"1.5 mg / 1 ml solution for injection" 6 Ampoules.
06.6 Instructions for use and handling
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07.0 MARKETING AUTHORIZATION HOLDER
Wyeth Lederle S.p.A., Via Nettunense n. 90 - 04011 APRILIA (LT)
08.0 MARKETING AUTHORIZATION NUMBER
Oral Lederfolin:
7.5 mg tablets 10 tablets AIC N. 024659118;
2.5 mg granules for oral solution 20 sachets AIC N. 024659157;
2.5 mg granules for oral solution 30 sachets AIC N. 024659169;
Parenteral Lederfolin:
25 mg Powder for solution for injection 1 Vial AIC N. 024659120;
1.5 mg / 1ml solution for injection 6 ampoules AIC N. 024659132;
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal May 2000
10.0 DATE OF REVISION OF THE TEXT
December 2003
