Refolinon Injection 2 ml / 10 ml

1. Name Of The Medicinal Product

Refolinon Injection

2. Qualitative And Quantitative Composition

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

3. Pharmaceutical Form

Solution for injection

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 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.

4.2 Posology And Method Of Administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

1) Treatment of adverse drug reactions and intoxication induced by folic acid antagonists (injection only)

Trimetrexate toxicity: Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m2 administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

Overdosage (possibly occurring with trimetrexate doses above 90 mg/m2 without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m2 IV every 6 hours for 3 days.

Trimethoprime toxicity:

After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity:

In case of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

2) Therapy after high-dose methotrexate

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children: Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate. Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m2 body surface and should be considered with doses of 100 mg – 500 mg/m2 body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5µmol/l, calcium folinate dosages should be adapted according to the following table:

Residual methotrexate blood level 48 hours after the start of the methotrexate administration:	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:
	15 mg/m2
	100 mg/m2
	200 mg/m2

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 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.

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.

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 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 stated.

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

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.

5.2 Pharmacokinetic Properties

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.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Sodium Hydroxide

Hydrochloric Acid

Water for injections

6.2 Incompatibilities

None stated.

6.3 Shelf Life

24 Months

6.4 Special Precautions For Storage

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

6.5 Nature And Contents Of Container

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

6.6 Special Precautions For Disposal And Other Handling

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.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00032/0346

9. Date Of First Authorisation/Renewal Of The Authorisation

17^th July 2002

10. Date Of Revision Of The Text

November 2009

Ref: REA6.0