Calcium Folinate Sandoz

Calcium Folinate Sandoz

calcium folinate

Manufacturer:

Sandoz

Distributor:

Zuellig
/
Agencia Lei Va Hong
Full Prescribing Info
Contents
Calcium folinate.
Description
Each vial of 35 ml solution for injection or infusion contains 350 mg of folinic acid as calcium folinate.
Excipients/Inactive Ingredients: Water for injection, Sodium chloride, Sodium hydroxide, Hydrochloric acid, Nitrogen as an inert gas.
Action
Pharmacotherapeutic group: Substance which counteracts the toxicity of a cytostatic treatment. ATC code: V03AF03.
Pharmacology: Pharmacodynamics: Calcium folinate is the calcium salt of 5-formyl-tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme of nucleic acid synthesis in cytotoxic therapy.
Calcium folinate is frequently used to reduce the toxicity of folate antagonists such as methotrexate and counteract their effects. Calcium folinate and folate antagonists share the same membrane transport carriers and compete for transport in the cells, which stimulates the efflux of the folate antagonist. It also protects the cells from the effects of the folate antagonists by filling the pools of reduced folates. Calcium folinate is used as a pre-reduced source of H4 folate; it can therefore bypass the blockade by the folate antagonist and represent a source for the various coenzyme forms of folic acid.
Calcium folinate is also frequently used for the biochemical modulation of fluoropyridine (5-FU) in order to increase its cytotoxic activity. 5-FU inhibits thymidilate synthase (TS), a key enzyme involved in pyrimidine biosynthesis, and calcium folinate increases the inhibition of TS by increasing the intracellular folate pool, which stabilises the 5-FU/TS complex and increases its activity.
Finally, intravenous calcium folinate can be used for the prevention and treatment of folate deficiency if this cannot be prevented by the oral use of folic acid or corrected. This may be the case during complete parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency when oral use is not possible.
Indications/Uses
Calcium folinate is indicated: to reduce or counteract the toxicity and effects of folic acid antagonists such as methotrexate in cytotoxic therapy or overdose in adults and children. In cytotoxic therapy, this approach is commonly known as "Calcium Folinate Rescue".
in combination with fluorouracil in cytotoxic therapy.
Dosage/Direction for Use
Calcium folinate should only be used intravenously or intramuscularly. In the case of intravenous application, not more than 160 mg per minute should be injected due to the calcium content of the solution.
For intravenous infusion, calcium folinate can be diluted before use with 0.9% sodium chloride solution or 5% glucose solution.
Calcium folinate rescue in methotrexate therapy: As the dosage regimen of the calcium folinate rescue strongly depends on the type and method of application of the medium or high-dose methotrexate application, the methotrexate protocol dictates the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the medium or high dose methotrexate protocol as regards the type and method of calcium folinate application.
The following guidelines can be used to illustrate the protocols used in adults, the elderly and children: The calcium folinate rescue must be given parenterally to patients with malabsorption syndromes or other gastrointestinal disorders when enteral absorption is not guaranteed. Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.
The calcium folinate rescue becomes necessary if methotrexate is given in doses greater than 500 mg/m2 of body surface, and should be considered at doses of 100 mg-500 mg/m2 of body surface.
The dosage and duration of calcium folinate rescue depend primarily on the type and dosage of methotrexate therapy, the appearance of toxicity symptoms and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate 15 mg (6-12 mg/m2) should be given 12-24 hours (no more than 24 hours) after the start of methotrexate infusion. The same dose is administered every 6 hours during the next 72 hours. After several parenteral doses, one may switch to the oral form.
There are measures in addition to the use of calcium folinate that ensure the prompt excretion of methotrexate (maintaining a high flow of urine and alkalisation of the urine), which are integral to the calcium folinate rescue. Renal function should be monitored by daily measurements of serum creatinine levels.
Residual methotrexate levels should be measured 48 hours after the start of the methotrexate infusion. If the residual methotrexate level is >0.5 μmol/l, the calcium folinate dosages should be adjusted according to the following table: (See table.)

Click on icon to see table/diagram/image

In combination with 5-fluorouracil in cytotoxic therapy: Different treatment protocols and dosages are used without one dosage having been demonstrated as optimal.
The following regimens have been used in adults and the elderly for the treatment of advanced or metastatic colorectal cancer and are mentioned as examples. No data are available on the application of these combinations in children.
Two-month treatment protocol: Calcium folinate at 200 mg/m2 as intravenous infusion for 2 hours, followed by 5-FU as a bolus with 400 mg/m2 and 22 hours of infusion of 5-FU (600 mg/m2) on 2 consecutive days, every 2 weeks on days 1 and 2.
Weekly treatment protocol: Calcium folinate 20 mg/m2 as i.v. bolus injection or 200-500 mg/m2 as i.v. infusion over 2 hours with 500 mg/m2 fluorouracil as i.v. bolus injection in the middle or at the end of the calcium folinate infusion.
Monthly treatment protocol: Calcium folinate at a dose of 20 mg/m2 as i.v. bolus injection or 200-500 mg/m2 i.v. infusion, immediately followed by fluorouracil at a dose of 425 or 370 mg/m2 as an i.v. bolus injection on 5 consecutive days.
In combination therapy with fluorouracil, a modification of the fluorouracil doses and the treatment intervals may be necessary based on the condition of the patient, clinical response and dose limiting toxicity, as specified in the product information for fluorouracil. A reduction of the calcium folinate dose is not necessary.
The number of repeat cycles will be decided on by the physician.
Antidote to the folic acid antagonists trimetrexate, trimethoprim, and pyrimethamine: Trimetrexate toxicity: Prevention: Calcium folinate should be given daily during treatment with trimetrexate and for 72 hours after the last trimetrexate dose. Calcium folinate can be given either intravenously at a dose of 20 mg/m2 for 5-10 minutes every 6 hours until a total daily dose of 80 mg/m2 has been achieved, or it can be given orally divided into 4 doses per day of 20 mg/m2 each at equal intervals. The daily calcium folinate doses should be adjusted depending on the haematological toxicity of trimetrexate.
Overdose (possibly occurring with trimetrexate doses over 90 mg/m2 without concomitant calcium folinate administration): After discontinuing trimetrexate: Administration of calcium folinate 40 mg/m2 i.v. every 6 hours for 3 days.
Trimethoprim toxicity: After discontinuing trimethoprim: Administration of calcium folinate 3-10 mg/day until blood count has returned to normal.
Pyrimethamine toxicity: In cases of high-dose therapy with pyrimethamine or in cases of longer treatment with low doses, calcium folinate should be used at a dose of 5 to 50 mg/day based on the results of the peripheral blood count.
Overdosage
There have been no reports, so far, of consequences in patients who received significantly more than the recommended dose of calcium folinate. However, excessive quantities of calcium folinate may eliminate the chemotherapeutic effect of folic acid antagonists.
In cases of an overdose of the combination of fluorouracil and calcium folinate, the instructions on measures to take in case of an overdose of fluorouracil should be followed.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Pernicious anaemia or other megaloblastic anaemias due to a vitamin B12 deficiency.
With regard to the treatment of pregnant or breast-feeding women with calcium folinate and methotrexate or fluorouracil, see Use in Pregnancy & Lactation and the summary of product characteristics for medicines containing methotrexate and fluorouracil.
Special Precautions
Calcium folinate may only be given as an intramuscular or intravenous injection, and may not be applied intrathecally. Deaths have been reported after the intrathecal administration of folinic acid following previous intrathecal overdose of methotrexate.
General: Calcium folinate should be only be used with methotrexate or fluorouracil under the direct supervision of a doctor who has experience with the application of chemotherapy drugs for cancer.
Treatment with calcium folinate can mask a pernicious anaemia or other anaemia caused by vitamin B12 deficiency.
Many cytotoxic drugs direct or indirect inhibitors of DNA synthesis lead to macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine).
Macrocytosis should not be treated with folinic acid.
In epileptics treated with phenobarbital, phenytoin, primidone and succinimides, there is a risk that the frequency of seizures may increase, which is caused by a decrease in the plasma concentrations of the anti-epileptic medicines. While using calcium folinate and after stopping it, clinical monitoring, possibly monitoring of plasma levels and, if necessary, a dose adjustment of the anti-epileptic medicine are recommended (see also Interactions).
Calcium folinate/fluorouracil: Calcium folinate can increase the risk of toxicity of fluorouracil, especially in elderly or debilitated patients. The most common signs that may be dose limiting are leukopenia, mucositis, stomatitis, and/or diarrhoea. If calcium folinate and fluorouracil are used in combination and toxicity occurs, the fluorouracil dosage must be reduced more than when fluorouracil is given alone.
Combination treatment with fluorouracil and calcium folinate should be neither initiated nor continued in patients with symptoms of gastrointestinal toxicity, regardless of severity, until the patient shows no more symptoms.
Because diarrhoea can be a sign of gastrointestinal toxicity, patients who have diarrhoea must be carefully monitored until the patient shows no more symptoms, as rapid clinical deterioration leading to death may occur. If diarrhoea and/or stomatitis occurs, it is advisable to reduce the dose of 5-FU until the symptoms have subsided completely. Especially elderly patients and patients who are in a bad condition due to their illness are subject to an increased risk of the occurrence of these toxicities. Therefore, caution is advised in the treatment of these patients.
In elderly patients and patients who have undergone previous radiation therapy, we recommend starting with a reduced dosage of fluorouracil.
In patients receiving a combined fluorouracil/calcium folinate treatment, the calcium level should be monitored and additional calcium given if the calcium level is low.
Calcium folinate/methotrexate: For specific details on reducing methotrexate toxicity, please see the summary of product characteristics for methotrexate.
Calcium folinate has no effect on the non-haematological toxicities of methotrexate, such as nephrotoxicity as a result of methotrexate and/or the precipitation of metabolites in the kidneys. In patients who have delayed early methotrexate elimination there is a high probability that they will develop reversible renal impairment and all toxicities associated with methotrexate (please see the summary of product characteristics for methotrexate). The presence of pre-existing or methotrexate-induced renal impairment may be associated with delayed excretion of methotrexate and may require higher doses or longer use of calcium folinate.
Too high doses of calcium folinate must be avoided as they may reduce the anti-tumour activity of methotrexate. This is particularly true for CNS tumours in which calcium folinate accumulates after repeated treatment cycles.
Methotrexate resistance as a result of reduced membrane transport also suggests a resistance to folinic acid rescue as both medicines have the same transport mechanism.
Accidental overdose of folic acid antagonists such as methotrexate should be treated as a medical emergency. The longer the time interval between the methotrexate application and the calcium folinate rescue, the lower the effectiveness of calcium folinate as a countermeasure for reducing the toxicity.
The possibility that the patient is taking other medications that interact with methotrexate (e.g. medications that interact with methotrexate elimination or the binding to serum albumin) should always be considered if laboratory deviations or clinical toxicities are observed.
Excipients: 1 ml solution for injection contains 0.14 mmol (3.29 mg) of sodium. This must be taken into consideration in individuals on a sodium-controlled (low sodium/low salt) diet.
Effects on ability to drive and use machines: There is no evidence that calcium folinate influences the ability to drive or use machines.
Use In Pregnancy & Lactation
Pregnancy: No adequate and well-controlled studies have been conducted with pregnant or breast-feeding women. No animal studies on the reproductive toxicology of calcium folinate have been conducted. There are no indications that folinic acid causes harmful effects if it is given during pregnancy. During pregnancy, methotrexate should only be used after strict determination of the indication in which the benefit of the medicine for the mother is weighed against the possible risk for the foetus. If treatment with methotrexate or other folic acid antagonists takes place in spite of pregnancy or breast-feeding, there are no limitations as regards the use of calcium folinate to reduce toxicity or counteract the effects.
The use of fluorouracil is generally contraindicated during pregnancy and breast-feeding. This also applies to the combined use of calcium folinate with fluorouracil.
See also the summary of product characteristics for other medicines containing methotrexate and other folic acid antagonists and fluorouracil.
Breast-feeding: It is not known whether calcium folinate passes into human breast milk. Calcium folinate can be given during breast-feeding if this is considered necessary in the context of the therapeutic indications.
Adverse Reactions
The evaluation of undesirable effects is based on the following frequency categories: 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).
All therapeutic indications: Immune system disorders: Very rare: anaphylactoid/anaphylactic reactions (including shock), allergic reactions and urticaria.
Psychiatric disorders: Rare: Insomnia, restlessness and depression following high doses.
Nervous system disorders: Rare: Increase in frequency of seizures in epileptic patients (see also Interactions).
Gastrointestinal disorders: Rare: gastrointestinal disorders following high doses.
General disorders and administration site conditions: Uncommon: Fever.
In patients who received calcium folinate in combination with other active substances which are known to be associated with these illnesses, cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were reported, some of which were fatal. It cannot be ruled out that calcium folinate contributed to the development of SJS/TEN.
Combination therapy with fluorouracil: In general, the safety profile depends on the treatment regimen used for fluorouracil due to the increase in toxicities induced by fluorouracil. Additional side effects in combination with fluorouracil: Monthly therapy protocol: Gastrointestinal disorders: Very common: Nausea and vomiting, diarrhoea.
Skin and subcutaneous tissue disorders: Very common: Palmar-plantar erythrodysaesthesia.
General disorders and administration site conditions: Very common: Mucositis including stomatitis, cheilitis, pharyngitis, oesophagitis, proctitis.
Due to the gastrointestinal toxicity (mainly mucositis and diarrhoea) and myelosuppression, deaths have occurred. In patients with diarrhoea, a rapid clinical worsening leading to death can occur.
No increase in the other toxicities induced by fluorouracil (e.g. neurotoxicity).
Weekly therapy protocol: Gastrointestinal disorders: Very common: More severe diarrhoea and dehydration that require admission to the hospital and may even lead to death.
Drug Interactions
If calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine), the effectiveness of the folic acid antagonist may be reduced or completely eliminated.
Calcium folinate may reduce the effects of anti-epileptic medicines such as phenobarbital, primidone, phenytoin and succinimide and thus lead to an increase in the frequency of seizures (a reduction in plasma levels of the enzymatic inducers of anticonvulsive medicines may be observed as the liver metabolism increases because folates are one of the co-factors) (see also Precautions and Adverse Reactions).
The simultaneous use of calcium folinate with fluorouracil has shown that this amplifies the efficacy and toxicity of fluorouracil (see Dosage & Administration, Precautions and Adverse Reactions).
Storage
Shelf life following dilution: In glucose 5% infusion media, the chemical and physical stability of diluted calcium folinate from concentration of 0.2 mg/mL to 4 mg/mL was demonstrated for 24 hours with light protection, at 2°C to 8°C.
In normal saline (NaCl 0.9%), the chemical and physical stability of diluted calcium folinate from concentration of 0.2 mg/mL to 4 mg/mL was demonstrated for 7 days with light protection, at 2°C to 8°C.
From a microbiological point of view, the ready-to-use preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C and protected from daylight, unless dilution has taken place in controlled and validated aseptic conditions.
ATC Classification
V03AF03 - calcium folinate ; Belongs to the class of detoxifying agents used in antineoplastic treatment.
Presentation/Packing
Soln for inj or infusion (vial) 350 mg/35 mL (clear, yellowish solution) x 1's.
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