Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Sandoz Limited, Park View, Riverside Way, Watchmoor Park, Camberley, Surrey, GU15 3YL, United Kingdom
For the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6 and the Summaries of Product Characteristics for methotrexate- and 5-fluorouracil-containing medicinal products.
Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally.
Death has been reported when folinic acid has been administered intrathecally, following intrathecal overdose of methotrexate.
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 such as hydroxycarbamide, cytarabine, mecaptopurine, thioguanine) lead to macrocytosis. Such macrocytosis should not be treated with folinic acid.
In epileptic patients treated with phenobarbital, phenytoine, primidone, and succinimides there is a risk of increased frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possible monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during and after calcium folinate administration is recommended (see also section 4.5).
Calcium folinate may enhance the toxicity 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. In cases of toxicity when calcium folinate and 5-fluorouracil are used in combination, the 5-fluorouracil dosage should be reduced more than in cases of toxicity 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 stomatitits occur, it is advisable to reduce the dose of 5-FU until symptoms have fully disappeared. The elderly and patients with a low physical performance due to their illness are especially 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 generally not be mixed with 5-fluorouracil in the same intravenous injection or infusion. For more information, please refer to section 6.2.
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.
For specific details on reduction of methotrexate toxicity refer to the Summary of Product Characteristics for methotrexate.
Calcium folinate has no effect on the 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 other 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 also implies resistance to folinic acid rescue as both medicinal products share the same transport system.
An accidental overdose with a folinate antagonist, such as methotrexate, should be treated as a medicinal emergency. As the time interval between methotrexate administration and Calcium Folinate Rescue increases, the effectiveness of calcium folinate to counteract the toxicity decreases.
The possibility that the patient is taking other medications that interact with methotrexate (eg. medication which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.
This medicinal product contains 3.3 mg (0.14mmol) sodium per ml.
Doses below 7ml (70mg): This medicinal product contains less than 1mmol sodium (23mg), that is to say essentially sodium-free.
For maximum single doses of 500 mg/m², i.e. 850 mg (for an average body surface of 1.7 m²): This medicinal product contains 280.5 mg sodium per 85 ml dose, equivalent to 14% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
When calcium folinate is given in conjunction with a folic acid antagonist (e.g. co-trimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.
Calcium folinate may diminish the effect of the anti-epileptic substances: phenobarbital, primidone and phenytoine, 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 sections 4.4 and 4.8).
Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance both the efficacy and toxicity of 5-fluorouracil (see section 4.5, 4.4 and 4.8).
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 is no indication that folinic 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 folinate 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 breast-feeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.
Please refer also to the Summaries of Product Characteristics for methotrexate-, other folate antagonists and 5-fluorouracil containing medicinal products.
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.
There is no evidence that calcium folinate has an effect on the ability to drive or use machines.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).
Very rare: allergic reactions, including anaphylactoid/anaphylactic reactions and urticaria.
Rare: insomnia, agitation and depression after following high doses.
Rare: increase in the frequency of attacks in epileptics (see also section 4.5)
Rare: gastrointestinal disorders after high doses.
Uncommon: fever has been observed after administration of calcium folinate as solution for injection.
Generally, the safety profile depends on the applied regimen of 5-fluorouracil, due to enhancement of the 5-fluorouracil induced toxicities.
Not known: Hyperammonaemia
Very common: bone marrow failure, including fatal cases
Very common: mucositis, including stomatitis and chelitis. Fatalities have occurred as a result of mucositis
Common: Palmar-Plantar Erythrodysaesthesia
Very common: vomiting and nausea
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Very common: diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.
Generally, calcium folinate must not be mixed in the same infusion as fluorouracil because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5 % in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32°C in polyvinyl chloride containers.
However, a 1:1 mixed solution of calcium folinate solution (10 mg/ml) and fluorouracil solution (50 mg/ml) has been shown to be compatible and stable over a period of 48 hours stored at maximum 32°C protected from light.
The formation of a cloudy yellow solution has been reported when foscarnet 24 mg/ml is mixed with calcium folinate 20 mg/ml.
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