Chemical formula: C₂₀H₂₁CaN₇O₇ Molecular mass: 473.446 g/mol PubChem compound: 6006
Calcium folinate interacts in the following cases:
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).
Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance both the efficacy and toxicity of 5-fluorouracil. Calcium folinate should be used with 5-fluorouracil only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
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.
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.
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.
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.
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); not known (cannot be estimated from the available data).
Very rare (<0.01%): allergic reactions, including anaphylactoid/anaphylactic reactions, and urticaria.
Rare (0.01-0.1%): insomnia, agitation and depression after high doses.
Rare (0.01-0.1%): gastrointestinal disorders after high doses.
Rare (0.01-0.1%): increase in the frequency of attacks in epileptics (see also section 4.5 Interactions).
Uncommon (0.1-1%): fever has been observed after administration of calcium folinate as solution for injection.
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.
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