Prescription information
FOLIBEL
Trade name: Folibel
International nonproprietary name: Calcium folinate
Pharmaceutical form: lyophilized powder for solution for intravenous and intramuscular injection
Appearance: Light yellow to yellow porous mass, non-uniform color. Hygroscopic.
Composition: Each vial contains: active ingredient:calcium folinate (calculated as folinic acid) – 50 mg; excipient: methylparahydroxybenzoate – 0.50 mg.
Pharmaceutical group: All other therapeutic products, detoxifying agents for antineoplastic treatment.
ATC code: V03AF03
Pharmacological characteristics
Pharmacodynamics
Calcium folinate is the folic acid reduced form and is used as an antidote of medicinal agents acting as folic acid antagonists. The compound is known as folinic acid as well. Folic acid antagonists, such as methotrexate, inhibit dihydrofolate reductase thus preventing folic acid produce tetrahydrofolate serving an important cofactor of single-carbon residuals transfer in the nucleic acids biosynthesis. As a result, the nucleic acids biosynthesis and cells division are blocked. Calcium folinate, in contrast to folic acid, does not need to be reduced by dihydrofolate reductase for being converted in tetrahydrofolate allowing recover the impaired biosynthesis of DNA, RNA, and proteins when it is administered. Calcium folinate protective effect is characteristic for healthy cells only. Drug product prevents from the methotrexate toxic action on the bone marrow and gastrointestinal tract cells, but not impacts evidently on the methotrexate nephrotoxic effect having already occurred.
It favors the folic acid supplementing in case of its deficit in the body.
Calcium folinate can increase the fluorouracil antitumor effect. When those two preparations are interacting a stable complex containing thymidylate synthetase is formed inhibiting or suppressing the DNA synthesis.
Onset of action: intramuscular injection of a substance – in 10-20 minutes, intravenous injection of a substance – in less than 5 minutes. Effective drug duration – about 3-6 hours regardless of the route of administration.
Pharmacokinetics
Maximum level of concentration of reduced folate form in blood plasma is reached in about 40 minutes when injection is intramuscular and in 10 minutes when injection is intravenous. Drug penetrates through blood-brain barrier in average quantities; mostly accumulates in liver. It mainly metabolizes in liver and mucous membrane of intestinal canal in active metabolite 5–methyltetrahydrofolate. Half-life – 6.2 hours regardless of the route of administration. Drug is excreted by the kidneys (80-90%), with fecal masses (5-8%).
Indications
- Intoxications caused by folic acid antagonists (methotrexate, trimethoprim, and pyrimetamine).
- Prevention of the methotrexate toxic effect when it is administered in elevated and high doses.
- Colorectal cancer (as a part of the combined therapy with 5-fluorouracil).
- Megaloblastic anemia on the background of folic acid deficit (including one on the background of malabsorption syndrome, undernutrition, pregnancy, sprue, in infancy in case of hereditary dihydrofolate reductase deficiency).
Dosage and mode administration
Inject the solution either intramuscularly or intravenously. Do not inject calcium folinate intrathecally.
To prepare solution for injection dissolve the 50 mg vial content in 5 ml of sterile water for injections to obtain concentration 10 mg/ml. The solution prepared is ready to be administered for 12 hours when it is stored at temperature below +25 °C.
Prior to intravenous administration of the product as infusions, dilute the solution prepared with 5% dextrose solution or 0.9% sodium chloride solution for injections. Infusion solution should be used immediately after preparation. In case the solution wasn’t immediately administrated, store it in aseptic conditions within 12 hours at temperature below +25 °C.
As drug product contains calcium high concentration the intravenous administration rate should not exceed 160 mg/min or 16 ml of the solution prepared with concentration being 10 mg/ml.
While choosing an adequate dose the doctor should follow special medical literature recommendations.
Calcium folinate should be prescribed in treatment with methotrexate in the dose exceeding 500 mg/m2, and should be planned with the dose of 100-500 mg/m2. In patients with malabsorption syndrome or other gastrointestinal disorders (vomiting, diarrhea, partial intestinal obstruction) accompanied by defective absorption, therapy with calcium folinate should be only parenterally performed. When drug product is prescribed in combination with methotrexate high doses (12 – 15 g/m2) its administration may be started in 24 hours after the methotrexate administration has been completed in the dose 10 g/m2 every 6 hours for 72 hours.
Patients having acidic urine reaction, exudates, renal function disorders, intestinal obstruction can need calcium folinate higher and/or more long management as methotrexate elimination can be slower in those patients. Calcium folinate administration should be based on the plasma methotrexate concentration mandatory determination in such cases. For preventing chronic renal insufficiency development hydration (3 l/24 hours) and sodium hydrocarbonate administration are indicated for supporting the urine pH at the level 7 or higher. Kidney function should also be monitored by measuring serum creatinine level.
Residual level of blood methotrexate should be measured within 48 hours after the start of methotrexate infusion. If the residual level of methotrexate >0.5 µmole/l, the doses of calcium folinate should be adapted in accordance with the following table:
| Residual blood concentration of methotrexate within 48 hours after the start of methotrexate administration
| Additional dose of calcium folinate which is administered every 6 hours within 48 hours, or till the methotrexate level is less than 0.05 µmole/l
|
| >0.5 µmole/l
| 15 mg/m2
|
| >1.0 µmole/l
| 100 mg/m2
|
| >2.0 µmole/l
| 200 mg/m2
|
In case of the methotrexate accidental overdosing administer calcium folinate in the dose equal or exceeding the methotrexate administered dose within 1 hour after the methotrexate injection followed by 10 mg/m2 every 3 hours until the toxicity symptoms resolve.
In combination:
When calcium folinate is combined with 5-fluorouracil, inject it before the 5-fluorouracil administration.
No data on the use of calcium folinate in combination with 5-fluorouracil in children are available.
The following regimens were used in adults in treatment of advanced or metastatic colorectal cancer.
Once per two months regimen: calcium folinate 200 mg/m2 via intravenous infusion for two hours followed by intravenous bolus 400 mg/m2 of 5-fluorouracil and 22-hour intravenous infusion of 5-fluorouracil (600 mg/m2) for two subsequent days, every two weeks on 1st and 2nd days.
Every week regimen: 20 mg/m2 as a bolus or 200 mg/m2 as an intravenous infusion for 2 hours plus 500 mg/m2 of 5-fluorouracil as a bolus in the middle or in the end of the calcium folinate infusion.
Every month regimen: calcium folinate 20 mg/m2 as a bolus or 200 to 500 mg/m2 as an intravenous infusion for 2 hours, immediately followed by 425 or 370 mg/m2 of 5-fluorouracil as an intravenous bolus injection during 5 subsequent days.
Number of repetition cycles of 5-fluorouracil and administration interval depend on the patient status, clinical response and toxicity risk specified in the instruction for 5-fluorouracil. Reduction of calcium folinate dose is not required.
For managing megaloblastic anemia associated with folic acid deficit calcium folinate is prescribed in the dose 1 mg intramuscularly or intravenously once a day.
No data on the use of calcium folinate in combination with 5-fluorouracil in children are available.
The following regimens were used in adults in treatment of advanced or metastatic colorectal cancer.
Every other month regimen: calcium folinate 200 mg/m2 via intravenous infusion for two hours followed by intravenous bolus 400 mg/m2 of 5-fluorouracil and 22-hour intravenous infusion of 5-fluorouracil (600 mg/m2) for two subsequent days, every two weeks on 1 and 2 days.
Every week regimen: 20 mg/m2 as a bolus or 200 mg/m2 as an intravenous infusion for 2 hours plus 500 mg/m2 of 5-fluorouracil as a bolus in the middle or in the end of the calcium folinate infusion.
Every month regimen: calcium folinate 20 mg/m2 as a bolus or 200 to 500 mg/m2 as an intravenous infusion for 2 hours, immediately followed by 425 or 370 mg/m2 of 5-fluorouracil as an intravenous bolus injection during 5 subsequent days.
Number of repetition cycles of 5-fluorouracil and administration interval depend on the patient status, clinical response and toxicity risk specified in the instruction for 5-fluorouracil. Reduction of calcium folinate dose is not required.
As an antidote in use of folic acid antagonists: trimetrexate, trimethoprim, pyrimethamine
Trimetrexate toxicity:
· prevention: calcium folinate should be daily administrated during treatment with trimetrexate during 72 hours after the last dose of trimetrexate. Calcium folinate may be either intravenously in the dose of 20 mg/m2 for 5-10 minutes every 6 hours (total daily dose is 80 mg/m2), either orally administrated: four doses of 20 mg/m2 at regular intervals. Daily doses of calcium folinate should be regulated depending on the trimetrexate hematological toxicity.
· overdose (possible in case of use of trimetrexate in the doses higher than 90 mg/m2 without concomitant prescription of calcium folinate): the product in the dose of 40 mg/ m2 is intravenously administrated every 6 hours during 3 days after treatment with trimetrexate is discontinued.
Trimethoprim toxicity:
Upon discontinuation of treatment with trimethoprim, calcium folinate is intravenously administrated in the dose of 3-10 mg per day until health hematological status is reconstructed.
Pyrimethamine toxicity:
In use of high dose pyrithamine or long-term treatment with low doses, calcium folinate is administrated in the dose from 5 to 50 mg per day as a single dose, according to the results of peripheral blood status.
Side effect
Immune system disorders: very rarely (<0.01%): allergic reaction, including as anaphylactoid reaction and urticaria.
Nervous system disorders: rarely (0.01% - 0.1%): insomnia, excitation and depression (in case of high doses administration), increased amount of epileptic seizure.
Gastrointestinal disorders: rarely (0.01% - 0.1%): gastrointestinal disorders upon high doses administration.
General disorders: uncommon (0.1% - 1%): fever.
Combined therapy with 5-fluorouracil:
Generally, toxicity level also depends on the therapy regimen used:
Every month regimen:
Gastrointestinal disorders: very often (>10%): nausea, vomiting.
General disorders and complaints after administration: very often (>10%): mucous membrane lesions.
No other signs of toxicity induced by 5-fluorouracil (for example, neurotoxicity) was observed.
Every week regimen:
Gastrointestinal disorders: very often (>10%): diarrhea, water depletion requiring hospitalization and even leading to lethal outcome. Elderly patients require particular attention.
Contra Indications
- Hypersensitivity to calcium folinate or another substance drug product contains.
- Megaloblastic anemia associated with the cyancobalamin (vitamin B12) deficit.
With caution: alcoholism, epilepsy, chronic renal insufficiency, infancy (up to 2 years of age – drug product safety and efficiency for children has not been confirmed), pregnancy and lactation (see “Precautions” section).
Overdose
Calcium folinate is nontoxic. Symptoms of overdosing were not observed even after drug product had been administered in very high doses. However, extremely high amounts of calcium folinate are able to neutralize chemotherapeutic effect of folic acid antagonists (methotrexate).
In case of overdose with calcium folinate in combination with 5-fluorouracil, it is necessary to refer to the instructions on 5-fluorouracil overdose.
Precautions
Calcium folinate is indended for intramuscular and intravenous administration.
Do not administrate intrathecally.
Patient deaths have been reported in case of intrathecal administration of folinic acid as a result of overdose induced by intrathecal administration of methotrexate.
Treatment with calcium folinate in combination with methotrexate or 5-fluorouracil should be conducted under supervision of skilled oncologist.
Calcium folinate may mask the symptoms of pernicious anemia and other types of anemia conditioned by B12 vitamin deficit.
Many cytotoxic products, which are direct or indirect DNA synthesis inhibitors, cause macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, tioguanine in particular). This macrocytosis should not be treated with folinic acid.
In epileptic patients, receiving phenobarbital, phenytoin, primidone, succinamides, in case of calcium folinate therapy, epileptic seizures may be increased due to reduced blood plasma concentration of antiepileptic products. That is why thorough clinical supervision, as well as monitoring of blood plasma concentration of antiepileptic products and their doses correction, as necessarily, during the period of treatment with calcium folinate and upon its withdrawal are necessary.
Use of calcium folinate in combination with 5-fluorouracil
Calcium folinate may enhance toxic action of 5-fluorouracil, especially in elderly and fragile patients. Leukopenia, mucous membrane inflammation, stomatitis, diarrhea are common signs of toxic action. These side effects may be dose limiting. If the doses need to be reduced due to the toxic effects upon combined administration of 5-fluoroutacil and calcium folinate, the doses of 5-fluorouracil should be more reduced than in case of 5-fluorouracil monotherapy.
Treatment with 5-fluorouracil in combination with calcium folinate should not be started or continued until complete improvement of symptoms of gastrointestinal toxicity, irrespective of their severity. Since diarrhea may be the sign of gastrointestinal toxicity (which may lead to rapid clinical deterioration of the patient status, up to lethal outcome), the patients with diarrhea should be under thorough supervision until complete improvement of respective symptoms. If diarrhea and/or stomatitis are observed, it is recommended to reduce the doses of 5-fluorouracil until complete improvement of the symptoms. In treatment of fragile patients and elderly persons, special caution is required.
It is recommended to prescribe low starting doses of 5-fluorouracil in elderly patients and patients who received radiation therapy earlier.
Calcium folinate and 5-fluorouracil should be separately administrated.
In case of combination therapy with 5-fluorouracil and calcium folinate, calcium level should be monitored, and calcium preparation should be prescribed as necessarily.
Use of calcium folinate in combination with methotrexate
Recommendations on prevention of toxic effects in methotrexate therapy are specified in the instruction on medicinal administration of methotrexate.
Calcium folinate does not protect from non-haemotological toxic effects in methotrexate therapy (for example, from nephrotoxic action due to methotrexate residue and/or metabolites thereof in renal tubuli). Patients with delay in methotrexate elimination at early stage are characterized by greater probability of development of reversible renal failure and other toxic effects caused by methotrexate administration. Renal failure (developed during the methotrexate therapy or existing before the treatment) is potentially associated with delay in methotrexate elimination, that is why it may be necessary to use calcium folinate in elevated doses or during long-term period.
Administration of calcium folinate in extremely high doses should be avoided, as it may lead to reduction in antineoplastic activity of methotrexate, especially in case of central nervous system tumors where calcium folinated is accumulated after several treatment courses.
In case of resistance to methotrexate due to deteriorated membrane transport, resistance to calcium folinate develops as well, since both substances are transferred by one and the same system.
In case of folic acid antagonists (for example, methotrexate) overdose, administration of calcium folinate should be immediately started. The greater is the interval between administration of methotrexate and calcium folinate, the less is effectiveness of the last as an antidote.
If deviations of the laboratory parameters or clinical symptoms of toxic action are detected, it is always necessary to verify, whether the patient takes other drug products, which interact with methotrexate (for example, influence methotrexate elimination or its binding to blood plasma proteins).
Solutions for infusions prepared by dilution of the product with 0.9% sodium chloride solution or 5% glucose solution, are chemically and physically stable during at least 12 hours in case they are stored at temperature not above +25 °C.
From microbiological point of view, the solution for infusion should be administrated immediately upon preparation. If the solution is not used immediately, storage duration and conditions should be supervised by healthcare personnel. Generally, storage time should not exceed 12 hours at temperature 2-8°C, unless the solution is prepared in controlled and aseptic conditions.
Incompatibility
Calcium folinate is incompatible with droperidol, fluorouracil, methotrexate and foskarnet injection forms.
Use during pregnancy and lactation period. No study of calcium folinate effect on reproductive function in animals and in human subjects was performed. It is unknown, whether calcium folinate has a negative effect on fetus, if it is prescribed to pregnant women, and whether it can effect on the reproductive function. It is unknown, whether calcium folinate penetrates mother’s milk.
Use of the drug product during pregnancy and lactation is possible, only if potential benefit to the mother outweighs any potential risk to the fetus.
Effect of ability to drive vehicle and other potentially hazardous mechanisms. Does not effect.
Interaction with other drug product
When concomitantly administrated, calcium folinate reduces effectiveness of folic acid antagonists.
It reduces anticonvulsant activity of phenobarbital, phenytoin and primidone. Incompatibility of calcium folinate injection forms with droperidol, methotrexate and foskarnet has been reported.
It may cause enhancement both of therapeutic and toxic effect of fluorouracil, wherefore in case of concomitant administration, the fluorouracil doses should be reduced.
Storage conditions
Store in protected from light place at temperature below 25 °C.
Keep out of reach of children.
Shelf life
2 years.
Do not use after expiration of a shelf life.
Package
100 mg in a vial. A vial together with leaflet is placed in a cardboard pack.
Package for hospitals: 40 vials with corresponding quantity of patient information leaflets in group boxes.
Pharmacy purchasing terms
On prescription.
Manufacturer
Belmedpreparaty RUE
Republic of Belarus,
Minsk, 220007,
30, Fabritsius str.
