SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Refolinon 15mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Leucovorin calcium equivalent to

leucovorin (folinic acid)    15.0 mg

3 PHARMACEUTICAL FORM

Uncoated tablet for oral use

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

To be given orally.

Although leucovorin calcium may also be available as a solution for injection, leucovorin calcium should not be administrated 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 ing 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.

4.3 Contraindications

Leucovorin calcium should not be used in patients who have a known hypersensitivity to any of the constituents of the product.

Calcium folinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemia where vitamin B_i2 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.

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.

Lactation

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.

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

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.

6.1 List of excipients

Avicel PH101 Magnesium stearate Lactose

6.2 Incompatibilities

None known.

6.3 Shelf life

60 months.

6.4 Special precautions for storage

Store below 25°C. Do not refrigerate or freeze. Keep out of the reach and sight of children.

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.

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

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/12/2005

DATE OF REVISION OF THE TEXT

08/04/2014

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