Active ingredients: Folic acid (calcium levofolinate pentahydrate)
Levofolene 4 mg tablets
Levofolene package inserts are available for pack sizes:- Levofolene 4 mg tablets
- Levofolene 7.5 mg tablets
Why is Levofolene used? What is it for?
Pharmacotherapeutic group
Detoxifying substances for cytostatic treatments.
Therapeutic indications
All folate deficiency anemic forms due to increased demand, reduced use or insufficient dietary intake of folate.
Contraindications When Levofolene should not be used
Hypersensitivity to the active substance or to any of the excipients.
Levofolene should not be administered for the treatment of pernicious anemia or other megaloblastic anemia when vitamin B12 is deficient, except in association with it.
Precautions for use What you need to know before taking Levofolene
None.
Interactions Which drugs or foods can modify the effect of Levofolene
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Calcium levofolinate antagonizes the effects of antifolics.
The concomitant use of Levofolene with antiepileptic drugs such as phenobarbital, phenytoin, primidone and succinimide may result in an increase in the frequency of access.
Warnings It is important to know that:
Levofolene constitutes 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. The administration of the drug must be performed with attention in order to avoid the danger of allergic reactions or side effects The administration of Levofolene in epileptic patients treated with phenobarbital, phenytoin, primidone and succinimide causes an increase in the frequency of accesses due to a decrease in the concentration of the antiepileptic drug in the plasma. Clinical monitoring, eventual monitoring of plasma concentration and, if necessary, modification of the antiepileptic drug dosage during and after levofolene is recommended.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine. Anemias in pregnancy resulting from the increased need for folate can be improved or normalized with the administration of levofolinic acid.
Effects on ability to drive and use machines
Levofolene does not affect the ability to drive and use machines.
Dosage and method of use How to use Levofolene: Dosage
Levofolene must be administered orally.
In the treatment of folate deficiency anemia:
the treatment will begin with the oral administration of Levofolene (1 tablet of 4 mg), continuing 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.
Overdose What to do if you have taken too much Levofolene
No cases of overdose have been reported.
In case of accidental ingestion / intake of an excessive dose of Levofolene, notify your doctor immediately or go to the nearest hospital.
IF YOU ARE IN ANY DOUBT ABOUT THE USE OF LEVOFOLENE, CONTACT YOUR DOCTOR OR PHARMACIST.
Side Effects What are the side effects of Levofolene
Like all medicines, Levofolene can cause side effects, although not everybody gets them.
The administration of the product may be followed, albeit rarely, by general hypersensitivity reactions (fever, urticaria, arterial hypotension, tachycardia, bronchospasm, anaphylactic shock).
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date printed on the package. The expiry date refers to the product in intact packaging, correctly stored. Warning: do not use the medicine after the expiry date shown on the package. Store at a temperature not exceeding 25 ° C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN.
Composition and pharmaceutical form
Composition
Each tablet contains:
Active ingredient: 4 mg levofolinic acid (as calcium levofolinate pentahydrate)
Excipients: corn starch, dibasic calcium phosphate, magnesium stearate, gum arabic.
Pharmaceutical form and content
Tablets. Box containing 30 tablets
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
LEVOFOLENE 175 MG POWDER FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial of powder for solution for infusion contains:
Active principle:
175 mg levofolinic acid (as calcium levofolinate pentahydrate)
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for infusion.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Levofolene 175 mg is useful as an antidote to excessive doses of folic acid antagonists and to counteract the side effects induced by aminopterin (4-aminopteroyl-glutamic acid) and by methotrexate (4-amino-N10-methyl-pteroyl-glutamic acid) .
Levofolene 175 mg is also indicated as rescue therapy after treatment with methotrexate and as a potentiator of the effects of 5-fluorouracil during antiblastic chemotherapy protocols.
04.2 Posology and method of administration
Levofolene 175 mg should be administered intravenously.
In the field of antiblastic chemotherapy with high doses of methotrexate, the therapeutic protocols provide for the use of levo-folinic acid at dosages, which vary according to the scheme adopted, from 10 to 200 mg / m2 / day; in a second phase, can be switched to a dosage of 10-12 mg / m2 / day every 3-6 hours. At the moment, however, general dosage schedules are not defined with certainty. Since calcium levo-folinate is a methotrexate antagonist, their concomitant administration can be implemented only 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.
When used in antiblastic chemotherapy to exploit the potentiating activity of the effects of 5-fluorouracil, folinate dosages are variable from 15 to 25 mg / m2 / day intravenously (low dose folinate) up to dosages from 200 to 550 mg / m2 / day in continuous infusion (high-dose folinate), corresponding to an average dose of calcium-folinate between 100-250 mg / m2 / day. According to some therapeutic protocols, the folinate infusion should be started 24 hours before and ended 12 hours after the end of 5-fluorouracil treatment. However, even in this case, the concomitant administration of calcium levo-folinate and 5-fluorouracil can only be carried out 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.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Levofolene 175 mg should not be administered for the treatment of pernicious anemia or other megaloblastic anemia when vitamin B12 is deficient, except in association with it.
04.4 Special warnings and appropriate precautions for use
Levofolene 175 mg constitutes an improper therapy of pernicious anemia or other megaloblastic anemia resulting from vitamin B12 deficiency: in fact, haematological remission may occur while neurological manifestations remain progressive; the therapy must therefore be conducted under haematological control.
In the treatment of folic acid antagonist overdose, the administration of levo-folinic acid should be carried out possibly 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.
Administration of Levofolene 175 mg in epileptic patients treated with phenobarbital, phenytoin, primidone and succinimide results in an increase in the frequency of accesses due to a decrease in plasma concentration of the antiepileptic drug. Clinical monitoring, eventual monitoring of plasma concentration and, if necessary, modification of the antiepileptic drug dosage during and after the intake of Levofolene 175 mg is recommended (see section 4.5).
Calcium levofolinate may potentiate the toxicity profile of 5-fluorouracil, especially in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis and / or diarrhea, which may depend on the dosage of 5-fluorouracil used. Combined treatment with 5-fluorouracil / calcium levofolinate should not be initiated or continued in patients with symptoms of gastrointestinal toxicity, regardless of severity, until all these symptoms have completely disappeared. Patients presenting with diarrhea should be monitored closely until symptoms disappear completely, as rapid clinical deterioration leading to death can occur.
If diarrhea and / or stomatitis occur, it is advisable to reduce the dose of 5-fluorouracil.
The elderly and patients with low physical performance caused by the disease are particularly prone to this type of toxicity. Therefore, special care should be taken when treating these patients.
In elderly patients and in patients undergoing preliminary radiotherapy, it is recommended to start with a reduced dose of 5-fluorouracil.
Calcium levofolinate must not be mixed with 5-fluorouracil in the same intravenous injection or infusion.
04.5 Interactions with other medicinal products and other forms of interaction
Levofolinic acid antagonizes the effects of antifolics.
Acts as a rescue in high dose methotrexate therapy and as an antidote to overdose.
Concomitant use of Levofolene 175 mg with antiepileptic drugs such as phenobarbital, phenytoin, primidone and succinimide may result in an increased frequency of access (see section 4.4).
04.6 Pregnancy and lactation
The indications of Levofolene 175 mg foresee the use of the drug in the context of therapeutic protocols with drugs that can be harmful to the fetus and the infant.
04.7 Effects on ability to drive and use machines
Levofolene does not affect the ability to drive and use machines.
04.8 Undesirable effects
The administration of the product may be followed, albeit rarely, by general hypersensitivity reactions (fever, urticaria, arterial hypotension, tachycardia, bronchospasm, anaphylactic shock).
Calcium levofolinate can potentiate the toxic effects induced by 5-fluorouracil, depending on the dosage regimen adopted. Following combined use with 5-fluorouracil the following undesirable effects have been reported:
Gastrointestinal disorders:
Very common: nausea, vomiting, diarrhea
Hepatobiliary disorders:
Frequency not known: hyperammonaemia
Skin and subcutaneous tissue disorders:
Frequency not known: palmar-plantar erythrodysaesthesia
General disorders and administration site conditions:
Frequency not known: mucositis, including stomatitis and cheilitis.
Fatal outcomes have occurred as a result of gastrointestinal toxicity (mainly mucositis and diarrhea) and myelosuppression.
04.9 Overdose
No cases of overdose have been reported.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying substances for cytostatic treatments
ATC code: V03AF04
Levofolinic acid plays an important role in purine and pyrimidine synthesis and is essential for DNA synthesis, especially at the level of hematopoietic tissue.
Furthermore, levo-folinic acid antagonizes the effects of antifolics, acting as a "rescue" in therapy with high doses of methotrexate or in case of overdose of this.
Levofolinic acid stabilizes the binding of fluorodeoxyuridine monophosphate with the thymidylate synthetase enzyme, enhancing the cytotoxic effects of 5-fluorouracil in the treatment of some cancers.
05.2 "Pharmacokinetic properties
Absorption of levo-folinate, administered intravenously, is rapid and complete. After parenteral administration, levofolinate and its main active metabolite are distributed to various peripheral tissues and to the liver. Levofolinate is distributed in the liver, and to a lesser extent. the mefolinate, are stored in the form of polyglutamate deposits.If necessary, the polyglutamic folates can be mobilized again following depolymerization.
Some studies conducted in healthy volunteers seem to show a prolongation of the elimination half-life of levofolinate with increasing dose: after i.v. administration. of a folinate dose equal to 28 mg / m2, the mean half-life of levofolinate was equal to 32 min, while following IV administration of high doses of racemic mixture, equal to 300 and 1000 mg, the mean half-life of levofolinate was equal to 56.5 and 58 min respectively.
05.3 Preclinical safety data
Per os the LD50 is higher than 7000 mg / kg in mice.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other products.
06.3 Period of validity
2 years
06.4 Special precautions for storage
This medicinal product does not require any special storage temperatures.
06.5 Nature of the immediate packaging and contents of the package
White type I glass vial with an elastomeric stopper and aluminum cap.
06.6 Instructions for use and handling
For reconstitution of the powder for solution for infusion contained in the 175 mg vial, 15-20 ml of water for injections should be used.
07.0 MARKETING AUTHORIZATION HOLDER
Alfa Wassermann S.p.A. via E. Fermi 1 65020 Alanno (PE)
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 027352071
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
19.03.1999/01.06.2010
10.0 DATE OF REVISION OF THE TEXT
AIFA Determination of January 2013
