The following information is intended for medical or healthcare professionals only:

(For further information, consult the Summary of Product Characteristics.)

Refolinon®

3 mg/ml Solution for Injection

calcium folinate

Description

Refolinon is a solution for injection. Each ampoule of 2 ml or 10 ml solution contains 3 mg/ml of folinic acid provided as calcium folinate. Each ampoule also contains water for injections, sodium chloride, sodium hydroxide and hydrochloric acid (to adjust the pH), sodium content of 0.192mmol/ampoule and 0.96mmol/ampoule respectively.

Uses:

• To diminish the toxicity and counteract the action of folic acid

antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as “Calcium Folinate Rescue”.

Warning: Calcium folinate 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.

Posology & Method of Administration:

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg 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 special precautions for disposal and other handling.

Calcium folinate rescue in methotrexate therapy:

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 >0.5 pmol/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 pmol/l:
>0.5 pmol/l	15 mg/m2
>1.0 pmol/l	100 mg/m2
>2.0 pmol/l	200 mg/m2

Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine:

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 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/mP. 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. Trimethoprim toxicity:

After stopping trimethoprim, 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.

Contraindications:

•    Hypersensitivity to calcium folinate, or to any of the excipients of this medicine.

•    Pernicious anaemia or other anaemias due to vitamin B₁₂ deficiency.

Regarding the use of calcium folinate with methotrexate during pregnancy and lactation, see Pregnancy and Lactation and the summaries of product characteristics for methotrexate containing medicinal products.

Precautions

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.

General

Calcium folinate should be used with methotrexate only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B₁₂ deficiency.

Many cytotoxic medicinal products - direct or indirect DNA synthesis inhibitors - lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interactions).

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.

Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SPC for methotrexate).

The presence of pre-existing- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.

Excessive calcium folinate doses must be avoided since this might impair the antitumor activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses.

Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.

An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

The possibility that the patient is taking other medications that interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

Refolinon solution for injection contains sodium 2.2 mg/ml. To be taken into consideration by patients on a controlled sodium diet.

Interaction with other medicaments and other forms of interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised. Therefore it should not be given in conjunction with a folic acid antagonist.

Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also Precautions and Undesirable).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil.

Concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the haematopoietic response to folic acid.

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.

Please refer to the SPC for methotrexate, other folate antagonists 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.

Effects on ability to drive and use machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

Undesirable Effects:

Immune system disorders

Very rare (<1/10,000): allergic reactions, including anaphylactoid reactions/ anaphylactic and urticaria.

Psychiatric disorders

Rare (>1/10,000 to <1/1000): insomnia, agitation and depression after high doses. Gastrointestinal disorders

Rare (>1/10,000 to <1/1000): gastrointestinal disorders after high doses. Neurological disorders

Rare (>1/10,000 to <1/1000): increase in the frequency of attacks in epileptics (see also Interaction with other medicaments and other forms of interaction).

General disorders and administration site conditions

Uncommon (>1/1000 to <1/100): fever has been observed after administration of calcium folinate as solution for injection.

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.

Overdose

There have been no reported sequel 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.

Special precautions for storage:

Store at 2°C - 8°C (in a refrigerator).

Store in original container to protect from light.

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 portion of the solution should be disposed of in accordance with local requirements.

Package Quantities: Refolinon Injection - 10 x 2 ml ampoules, 5 x 10 ml ampoules and 10 x 10 ml ampoules.

Not all pack sizes may be marketed POM

PL 00057/1039

Marketing Authorisation Holder:

Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.

Further information is available to the medical and allied professional on request from:

Medical Information Department, Pfizer Limited, Walton Oaks, Dorking Road, Tadworth, KT20 7NS - Tel: 01304 616161

Date of Preparation/revision: 01/2016 Ref: RE 9_0