Summary of Product Characteristics (SmPC) - Refolinon 15 mg tablets
1 NAME OF THE MEDICINAL PRODUCT
Refolinon 15mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15mg of leucovorin (folinic acid)
Excipients with known effect:
Lactose
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
Light yellow, round, flat, scored, uncoated tablet marked with ‘CF’ on the scored side.
4 CLINICAL PARTICULARS
4.1. Therapeutic indications
Leucovorin (folinic acid) is the formyl derivative of tetrahydrofolic acid and is an intermediate product of the metabolism of folic acid.
Leucovorin is used in cytotoxic therapy as an antidote to folic acid antagonists such as methotrexate.
Leucovorin is effective in the treatment of megaloblastic anaemia.
4.2 Posology and method of administration
Posology
Although leucovorin calcium may also be available as a solution for injection, leucovorin calcium should not be administered intrathecally.
Adults and children:
Leucovorin rescue: Depending upon the dose of methotrexate administered, dosage regimens of leucovorin calcium vary. Up to 120 mg leucovorin calcium are generally given, usually in divided doses over 12-24 hours by intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline. This is followed by 12-15 mg intramuscularly or 15 mg orally every 6 hours for 48 hours. Rescue therapy is usually started 24 hours after the commencement of methotrexate administration.
If overdosage of methotrexate is suspected, the dose of leucovorin calcium should be equal to or greater than the dose of methotrexate and should be administered within one hour of the methotrexate administration.
Megaloblastic anaemia (folate deficiency): 15 mg (one tablet) leucovorin per day.
Method of administration
To be given orally.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pernicious anaemia or other megaloblastic anaemia where vitamin B12 is deficient.
4.4 Special warnings and precautions for use
Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.
Refolinon contains lactose.
Patients with rare hereditary problems of galacatose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Leucovorin should not be given simultaneously with a folic acid antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, as well as primidone and increase the frequency of seizures.
Concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the haematopoietic response to folic acid.
Calcium folinate may enhance the toxicity of fluorouracil.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate and well-controlled clinical studies conducted in pregnant or breast feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.
5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.
Please refer to the SPC for methotrexate, other folate antagonists (and 5-fluorouracil) containing medicinal products.
Breast-feeding
It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.
4.7 Effects on ability to drive and use machines
None known.
4.8 Undesirable effects
Adverse reactions to leucovorin calcium are rare, but following intravenous and intramuscular administration occasional pyrexial reactions have been reported.
The most common dose-limiting adverse reaction occurring in patients receiving combination of calcium folinate and 5-fluorouracil are stomatitis and diarrhoea. In addition, haematological adverse reactions, such as leucocytopenia and thrombocytopenia, may occur. These adverse reactions are dose-dependent and their occurrence can usually be decreased by reducing the dosage of cytotoxic drugs. These adverse reactions can be controlled by close monitoring of haematological values, e.g. blood leucocyte and thrombocyte levels, and serum electrolyte (e.g. Na, K, Ca) and creatinine levels.
Anaphylactoid and urticaria allergic reactions have also been reported with the use of leucovorin.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
There have been no reported sequelae in patients who have received significantly more calcium folinate then the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.
Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.
5 PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC Code: V03AF03
Methotrexate rescue: Leucovorin (5-formyltetrahydrofolinate) acts partly by providing a fresh supply of tetrahydrofolate and also by competitively displacing methotrexate from dihydrofolate reductase so that its excretion is accelerated (methotrexate binds to the enzyme dihydrofolate reductase which is responsible for reducing dietary folic acid to dihydrofolate and tetrahydrofolate thus inhibiting its action.
Megaloblastic anaemia: Leucovorin is an active folic acid derivative and it can therefore relieve pathological conditions associated with folic acid deficiency e.g. megaloblastic anaemia.
5.2 Pharmacokinetic properties
The bioavailability of leucovorin following administration of both tablet and parenteral formulations is comparable. After 30 minutes approximately 90% of the total reduced folates were assayed as 5-methyltetrahydrofolate following oral administration compared with only 72% following i.m. administration. The half-life of leucovorin after reaching peak plasma levels was 35-45 minutes by both routes. Peak serum tetrahydrofolate levels were reached 2 hours after oral administration and approximately 40 minutes after i.m administration.
5.3 Preclinical safety data
None stated.
6 PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Microcrystalline cellulose NF
Magnesium stearate Ph. Eur
Lactose Ph. Eur
6.2 Incompatibilities
None known.
6.3 Shelf-life
5 years.
6.4 Special precautions for storage
Store below 25 °C. Do not refrigerate or freeze.
6.5 Nature and contents of container
The tablets are contained in white high density polyethylene containers with polyethylene screw closures. The bottles contain 30 or 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The tablets are contained in white high density polyethylene containers with polyethylene screw closures. The bottles contain 30 or 100 tablets.
7 MARKETING AUTHORISATION HOLDER
Pfizer Ltd
Ramsgate Road
Sandwich
Kent
CT13 9NJ
8 MARKETING AUTHORISATION NUMBER(S)
PL 00057/1040
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
02/12/2005
10 DATE OF REVISION OF THE TEXT
16/11/2016