4.1. Therapeutic indications

Calcium folinate is indicated

a) 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”

b) in combination with 5-fluorouracil in cytotoxic therapy.

4.2. Posology and method of administration

Posology

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 however in the presence of gastrointestinal toxicity, nausea, or vomiting, calcium folinate should be administered parenterally.

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 µmol/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:

> 0.5 µmol/l

15 mg/m²

> 1.0 µmol/l

100 mg/m²

> 2.0 µmol/l

200 mg/m²

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 (see section 4.4). Under such circumstances, higher doses of calcium folinate and/or prolonged administration may be indicated.

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.

The following regimens have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of these combinations in children. Particular care should be taken when treating elderly or debilitated patients as these patients are at increased risk of severe toxicity with this therapy.

Bimonthly regimen: Calcium folinate 200 mg/m2 by intravenous infusion over two hours, followed by bolus 400 mg/m2 of 5-FU and 22-hour infusion of 5-FU (600 mg/m2) for 2 consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours plus 500 mg/m² 5-fluorouracil as i.v. bolus injection in the middle or at the end of the calcium folinate infusion.

Monthly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as i.v. bolus injection during five consecutive days.

For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

The number of repeat cycles used is at the discretion of the clinician.

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 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.

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.

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 sections 6.3 and 6.6.

Calcium folinate must not be injected intrathecally (see section 4.4).

4.3. Contraindications

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

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

Regarding the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, and any additional contraindications relating to these products, refer to section 4.6, and the Summaries of Product Characteristics for methotrexate- and 5-fluorouracil- containing medicinal products.

4.4. Special warnings and precautions for use

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 or 5-fluorouracil 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 section 4.5).

Calcium folinate/5-fluorouracil

Calcium folinate may enhance the toxicity risk of 5-fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea, which may be dose limiting. When calcium folinate and 5-fluorouracil are used in combination, the 5- fluorouracil dosage has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone.

Combined 5-fluorouracil/calcium folinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.

Because diarrhoea may be a sign of gastrointestinal toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and/or stomatitis occur, it is advisable to reduce the dose of 5-fluorouracil until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to their illness are prone to these toxicities. Therefore, particular care should be taken when treating these patients.

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-fluorouracil.

Calcium folinate must not be mixed with 5-fluorouracil in the same IV injection or infusion.

Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate treatment and calcium supplementation should be provided if calcium levels are low.

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the Summary of Product Characteristics 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 Summary of Product Characteristics 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 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.

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.

Laboratory tests

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.

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

Calcium folinate/5-fluorouracil

Full blood count (FBC) with differential and platelets: prior to each treatment, weekly during the first two courses, and at the time of anticipated white blood cell (WBC) nadir in all courses thereafter.

Electrolytes and liver function tests: prior to each treatment for the first three courses and prior to every other course thereafter.

Calcium folinate/methotrexate

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

Calcium folinate 50 mg/5 ml solution for injection contains 16.74 mg of sodium per 5 ml vial, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Calcium folinate 100 mg/10 ml solution for injection contains 33.5 mg of sodium in each 10 ml vial, equivalent to 1.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Calcium folinate 300 mg/30 ml solution for injection contains 100.5 mg sodium in each 30 ml vial, equivalent to 5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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, antibiotic with antifolic effect, methotrexate) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.

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 sections 4.4 and 4.8).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil (see sections 4.2, 4.4 and 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). However, there are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, 5-flurouracil and 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 also to the Summaries of Product Characteristics for methotrexate-, 5-fluorouracil and other folate antagonist-containing medicinal products.

Breast-feeding

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.

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).

Monotherapy:

System Organ Class

Uncommon

Rare

Very rare

Frequency not known

Immune system disorders

Hypersensitivity, Anaphylactoid reaction, Anaphylactic reaction

Anaphylactic shock

Psychiatric disorders

Insomnia, Agitation and 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

Combination therapy with 5-fluorouracil only:

Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities. Additional undesirable effects when used in combination with 5-fluorouracil are presented in below table:

System Organ Class

Very common

Common

Frequency not known

Blood and lymphatic system disorders

Bone marrow failurem, Leukopenia, Neutropenia, Thrombocytopenia, Anaemia

Gastrointestinal disorders

Vomiting and Nausean.

Diarrhoea and Dehydrationo

Stomatitis

Metabolism and nutrition disorders

Hyperammonaemia

Skin and subcutaneous tissue disorders

Palmar-plantar erythrodysaesthesia syndromep

General disorders and administration site conditions

Mucosal inflammationm, Cheilitis.

m: Including fatal cases

n: Monthly regimen: No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity)

o: Weekly regimen: With higher grades of toxicity and dehydration, resulting in hospital admission for treatment and even death

p: Hand-foot syndrome

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.

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-fluorouracil should be followed.