4.1. Therapeutic indications

Leucovorin (folinic acid) is the formyl derivative of tetrahydrofolic acid which is a metabolite and active form of folic acid.

Calcium Folinate is indicated in:

a) Neutralising the immediate toxic effects of folic acid antagonists, e.g. Methotrexate.

b) Calcium Folinate Rescue - a treatment technique using Calcium Folinate in conjunction with folic acid antagonists, e.g. methotrexate, to minimise systemic toxicity.

c) The treatment of megaloblastic anaemias due to sprue, nutritional deficiency, pregnancy, infancy, liver disease and malabsorption syndrome.

4.2. Posology and method of administration

Posology

Adults and children

Calcium folinate rescue:

Depending upon the dose of methotrexate administered, dosage regimens of calcium folinate vary. Up to 120 mg calcium folinate 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 serum creatinine increases after methotrexate therapy or if methotrexate plasma concentrations are above certain threshold (see table 1), the dose of calcium folinate should be increased according to the plasma methotrexate concentrations, as soon as the risk is recognized. In the presence of gastrointestinal toxicity, nausea, or vomiting, calcium folinate should be administered parenterally. Further, oral administration of doses greater than 25-50 mg is not recommended since the digestive absorption of calcium folinate is saturable; these doses should be administered parenterally.

Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of calcium folinate and/or prolonged administration may be indicated.

Table 1: Dosage and Administration Guidelines for Calcium Folinate Rescue

Clinical situation

Laboratory findings

Calcium folinate dosage and duration

Normal methotrexate elimination

Serum methotrexate level ≤10 μM at 24 hours after administration, ≤1 μM at 48 hours, and <0.2 μM at 72 hours.

15 mg PO, IM, or IV (switching to the oral form after one or more parenteral doses) every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

Delayed late methotrexate elimination

Serum methotrexate level remaining <0.2 μM at 72 hours, and >0. 05 μM at 96 hours after administration.

Continue 15 mg PO, IM or IV every 6 hours, until methotrexate level is less than 0.05 μM.

Delayed early methotrexate elimination and/or evidence of acute renal failure

Serum methotrexate level of >50 μM at 24 hours, or >5 μM at 48 hours after administration OR a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration.

150 mg IV every 3 hours, until methotrexate level is less than 1 μM; then 15 mg IV every 3 hours until methotrexate level is less than 0.05 μM.

PO – oral administration

IM – intramuscular administration

IV – intravenous administration

Neutralising the immediate toxic effects of folic acid antagonists:

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 or orally 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 intravenously 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:

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 count.

Methotrexate overdose:

Calcium folinate should be administered as soon as the inadvertent overdose of methotrexate is recognized or when renal impairment is diagnosed after standard dose methotrexate administration. Serum creatinine and plasma methotrexate concentrations should be immediately determined and followed-up periodically until the serum creatinine is within the normal limits and methotrexate is less than 0.1 μM. In non-oliguric patients, urine output should be increased by oral and/or intravenous fluids to a rate above 100 mL per hour in adults. Urine alkalinization should also be instituted.

Calcium folinate 15 mg (approximately 10 mg/m²) should be administered intravenously, intramuscularly, or by mouth every 6 hours until the serum methotrexate level is less than 0.05 μM. In the presence of gastrointestinal toxicity, nausea or vomiting, calcium folinate should be administered parenterally. If the 24 hour methotrexate level is 50 μM or greater or the 48 hour level is 5 μM or greater, the dose of calcium folinate should be increased to 150 mg/m² intravenously every 3 hours until the methotrexate level is less than 1 μM, then 15 mg every 3 hours until the methotrexate level is less than 0.05 μM.

Megaloblastic anaemia (folate deficiency):

One tablet of calcium folinate per day.

Method of administration

To be given orally.

Although calcium folinate may also be available as a solution for injection, Calcium Folinate should not be administered intrathecally.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Calcium Folinate tablet is contraindicated in the treatment of pernicious anaemia or other megaloblastic anaemias where vitamin B12 is deficient. Its use can lead to an apparent response of the haematopoietic system, but neurological damage may occur or progress if already present.

For additional contraindications of methotrexate e.g. pregnancy and lactation, refer to the product information for this medicinal product.

4.4. Special warnings and precautions for use

General

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

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

In the treatment of inadvertent overdosage of a folic acid antagonist, folinate should be administered as soon as possible; if a period exceeding 4 hours intervenes, the treatment may not be effective.

In general, Calcium Folinate should not be given simultaneously with folic acid antagonists, such as methotrexate, to abort clinical toxicity as the therapeutic effect of the antagonist may be nullified. However, Calcium Folinate given concurrently with folate antagonists, such as pyrimethamine and trimethoprim does not inhibit their antibacterial activity.

Parenteral administration of folinate is preferable to oral dosing following chemotherapy with folic acid antagonists if there is a possibility that the patient may vomit and not absorb the folinate.

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

In epileptic patients treated with phenobarbitone, 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 (see section 4.5). 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.

Calcium folinate/methotrexate

Measures to ensure the prompt excretion of methotrexate are important as part of Calcium Folinate Rescue Therapy. These measures include:

1) Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites).

2) Maintenance of urine output of 1800-2000 cc/m2/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.

3) Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4.

These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1μM).

For specific details on reduction of methotrexate toxicity refer to the health-care professional labelling for methotrexate. An accidental overdose with a folate antagonist, such as methotrexate, should be treated quickly as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

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. 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 antitumour 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.

Laboratory tests

The following provides general advice for monitoring patients; however, specific monitoring recommendations may vary with local medical practice.

Methotrexate/calcium folinate therapy

Serum creatinine levels and serum methotrexate levels: at least once daily.

Urine pH: in cases of methotrexate overdose or delayed excretion, monitor as appropriate, to ensure maintenance of pH ≥7.0.

Excipient information

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g., cotrimoxazole, pyrimethamine, methotrexate, antibiotic with antifolic effect) the efficacy of the folic acid antagonist may either be reduced or completely neutralized.

Folinates given in large amounts may counteract the antiepileptic effect of phenobarbitone, phenytoin and primidone and increase the frequency of seizures in susceptible patients.

Caution is required during concurrent administration of Calcium Folinate with fluoropyrimidine as this has been associated with seizures and syncope (see section 4.8).

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Calcium Folinate should only be used in pregnant women if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

Since it is not known if Folinate is distributed into milk, the drug should be used with caution in nursing women.

Fertility

Calcium folinate is an intermediate product in the metabolism of folic acid and occurs naturally in the body. No fertility studies have been conducted with calcium folinate in animals.

4.7. 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.

4.8. Undesirable effects

Frequencies are defined using the following convention:

Very common (≥1/10);

Common (≥1/100 to <1/10);

Uncommon (≥1/1,000 to <1/100);

Rare (≥1/10,000 to <1/1,000);

Very rare (<1/10,000);

Frequency not known (cannot be estimated from the available data).

System Organ Class

Uncommon

Rare

Very rare

Frequency not known

Immune system disorders

Hypersensitivity, Anaphylactoid reaction, Anaphylactic reaction

Anaphylactic shock

Psychiatric disorders

Insomniaa, Agitationa, Depressiona

Gastrointestinal disorders

Gastrointestinal disordersa

Nervous system disorders

Seizureb

Syncope

Skin and subcutaneous tissue disorders

Urticaria

General disorders and administration site conditions

Pyrexiac

a: After high doses

b: Increase in the frequency of attacks in epileptics (see section 4.5)

c: Has been observed after administration of calcium folinate as solution for injection

Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving calcium folinate in combination with other agents known to be associated with these disorders. A contributory role of calcium folinate in these occurrences of SJS/TEN cannot be excluded.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of Calcium Folinate may nullify the chemotherapeutic effect of folic acid antagonists.

There is no specific antidote to calcium folinate overdose. In cases of overdosage patients should be given appropriate supportive care.