Refolinon Injection

Clear pale yellow liquid for injection containing leucovorin 3 mg/ml in ampoules of 2 ml and 10 ml, as the calcium salt

Solution for injection

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 due to folate deficiency.

Warning: 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.

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.

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 B₁₂ is deficient.

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.

Calcium folinate should only be used with methotrexate and 5-fluorouracil by clinicians experienced in the use of cancer chemotherapeutic agents.

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.

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.

None stated.

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.

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.

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment; ATC Code: V03AF03

Calcium folinate is the calcium salt of 5-formyltetrahydrofolic acid. .) It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxics therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduce folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzymes forms of folic acid.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

Absorption

Calcium folinate is rapidly absorbed in the gastrointestinal tract after oral administration. The oral absorption of calcium folinate is saturable at doses above 25mg. The bioavailability of calcium folinate is 97% for 25mg, 75% for 50mg, and 37% for 100mg. Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer. The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known. Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration. AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyltetrahydrofolate. Folate is concentrated in the cerebrospinal fluid, although distribution occurs to all body tissues.

Elimination

The elimination half-life is 32 - 35 minutes for the active L-form and 352 - 485 minutes for the inactive D-form, respectively. The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.

None stated.

Sodium Chloride

Sodium Hydroxide

Hydrochloric Acid

Water for injections

None stated.

24 Months

Store at 2^oC – 8^oC and protect from light.

Type 1 colourless glass ampoules containing 2 or 10 ml. Packs of 5 or 10 ampoules.

Prior to administration, calcium folinate should be inspected visually. The solution for injection or infusion should be clear and yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded. Calcium folinate solution for injection or infusion is intended only for single use. Any unused potion of the solution should be disposed of in accordance with local requirements.

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

PL 00032/0346

17^th July 2002

October 2009

Ref: REA5.0