1. Name Of The Medicinal Product
Calcium Folinate 15mg Tablets.
2. Qualitative And Quantitative Composition
Each tablet contains Calcium Folinate (Calcium Leucovorin) equivalent to folinic acid (leucovorin) 15mg.
For excipients, see 6.1
3. Pharmaceutical Form
Tablet
Light yellow, round, convex, uncoated tablets. The tablets are scored and marked “CF” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Leucovorin (folinic acid) is the formyl derivative of tetrahydrofolic acid which is a metabolite and active form of folic acid.
Calcium Folinate is indicated in:
a) Neutralising the immediate toxic effects of folic acid antagonists, e.g. Methotrexate.
b) Calcium Folinate Rescue - a treatment technique using Calcium Folinate in conjunction with folic acid antagonists, e.g. methotrexate, to minimise systemic toxicity.
c) The treatment of megaloblastic anaemias due to sprue, nutritional deficiency, pregnancy, infancy, liver disease and malabsorption syndrome.
4.2 Posology And Method Of Administration
Adults and Children
Calcium Folinate Rescue
Calcium Folinate may be used in conjunction with folic acid antagonists, e.g. methotrexate, to reduce their systemic toxicity. It is given 12 to 24 hours after the antineoplastic drug. Doses of up to 120mg may be given over 12 to 24 hours by intramuscular injection or intravenous injection or infusion, followed by 12 to 15mg intramuscularly, or 15mg orally, every 6 hours for the next 48 hours. With lower doses of methotrexate, folinate 15mg orally every 6 hours for 48 to 72 hours may be sufficient.
Treatment should be accompanied by alkalinisation of urine with maintenance of urinary output at 2000 ml/m²/24 hours and should be continued until plasma methotrexate is less than 10-7 molar. (see section 4.4)
Treatment of Megaloblastic Anaemia
The dose should not exceed 1mg daily given intramuscularly. When given orally, the recommended dosage is one Calcium Folinate Tablet (15mg) daily. Children up to 12 years; 0.25 mg/kg/day. Normal adult oral dosage; 10 – 20 mg daily.
Treatment of Overdosage of Folic Acid Antagonists
In cases of overdosage of folic acid antagonists, Calcium Folinate may be administered by intravenous infusion in doses of up to 75mg within 12 hours, followed by 12mg intramuscularly every 6 hours for 4 doses.
In general, where overdosage is suspected, the dose of Calcium Folinate should be equal to or greater than the offending dose of the folic acid antagonist administered, and should be given as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.
Although Calcium Folinate may also be available as a solution for injection, Calcium Folinate should not be administered intrathecally.
4.3 Contraindications
Calcium Folinate is contraindicated in patients who have previously shown hypersensitivity to folinate or any of the excipients.
Calcium Folinate Injection is contraindicated in the treatment of pernicious anaemia or other megaloblastic anaemias where vitamin B12 is deficient. Its use can lead to an apparent response of the haematopoietic system, but neurological damage may occur or progress if already present.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take calcium folinate tablets.
4.4 Special Warnings And Precautions For Use
Calcium Folinate should only be used with methotrexate or 5-FU under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
In the treatment of inadvertent overdosage of a folic acid antagonist, folinate should be administered as soon as possible; if a period exceeding 4 hours intervenes, the treatment may not be effective.
In general, Calcium Folinate should not be given simultaneously with folic acid antagonists, e.g. methotrexate, to abort clinical toxicity as the therapeutic effect of the antagonist may be nullified. However, Calcium Folinate given concurrently with folate antagonists, such as pyrimethamine and trimethoprim does not inhibit their antibacterial activity.
Parenteral administration of folinate is preferable to oral dosing following chemotherapy with folic acid antagonists if there is a possibility that the patient may vomit and not absorb the folinate.
Measures to ensure the prompt excretion of methotrexate are important as part of Calcium Folinate Rescue Therapy. These measures include:
1) Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites)
2) Maintenance of urine output of 1800-2000 cc/m2/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.
3) Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4.
These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1μM).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Folinates given in large amounts may counteract the antiepileptic effect of phenobarbitone, phenytoin and primidone and increase the frequency of seizures in susceptible patients.
Caution is required during concurrent administration of Calcium Folinate with fluoropyrimidine as this has been associated with seizures and syncope (see Section 4.8).
4.6 Pregnancy And Lactation
Reproduction studies have been performed in rats and rabbits at doses of at least 50 times the human dose. These studies have revealed no evidence of harm to the foetus due to Calcium Folinate. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, Calcium Folinate should only be used in pregnant women if the potential benefit justifies the potential risk to the foetus.
Since it is not known if Folinate is distributed into milk, the drug should be used with caution in nursing women.
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Adverse reactions are rare but occasional allergic reactions including anaphylactoid reactions and urticaria have been reported; pyrexia has occurred after parenteral administration.
Seizures and/or syncope have been reported rarely in cancer patients receiving folinate, usually in association with fluoropyrimidine administration and most commonly in those with CNS metastases or other predisposing factors; however, a causal relationship has not been established.
4.9 Overdose
There is no specific antidote to calcium folinate overdose. In cases of overdosage patients should be given appropriate supportive care.
Should overdosage of the combination of 5-FU with Calcium Folinate occur, the overdosage instruction for 5-FU should be followed.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Folinate is a derivative of tetrahydrofolic acid, the reduced form of folic acid, which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purine and pyrimidines of nucleic acids.
Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, Folinate is a potent antidote for both hematopoietic and reticuloendothelia toxic effects of folic acid antagonists, (e.g. Methotrexate, Pyrimethamine, Trimethoprim). It is postulated that in some cancers, Folinate enters and "rescues" normal cells from the toxic effects of folic acid antagonists, in preference to tumour cells, because of a difference in membrane transport mechanisms; this principle is the basis of high-dose Methotrexate therapy with "Folinate rescue".
5.2 Pharmacokinetic Properties
ABSORPTION AND DISTRIBUTION
In vivo, Calcium Folinate is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body.
Normal total serum folate concentrations have been reported to range from 0.005-0.015 μg/mL. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016-0.021 μg/mL. Normal erythrocyte folate concentrations range from 0.175-0.316 μg/mL.
In general, serum folate concentrations less than 0.005 μg/mL indicate folate deficiency and concentrations less than 0.002 μg/mL usually result in megaloblastic anemia. Following I.M. administration of a 15mg (7.5mg/m²) dose in healthy men, mean peak serum folate concentrations of 0.241 μg/mL occur within about 40 minutes. Following oral administration of a 15mg (7.5mg/m²) dose in healthy men, mean peak serum folate concentrations of 0.268 μg/mL occur within about 1.72 hours. Areas under the serum folate concentration-time curves (AUCs) are reported to be about 8% less following I.M. injection in the gluteal region than in the deltoid region and about 12% less following I.M. injection in the gluteal region than following I.V. or oral administration.
Tetrahydrofolic acid and its derivatives are distributed to all body tissues; the liver contains about one-half of total body folate stores. In a small number of patients, biliary concentration of folates was about 4.5 times the plasma folate concentration after oral administration of a 2mg dose of Folinate; this is believed to represent the hepatic folate pool rather than excretion of the administered dose.
ELIMINATION
Folinate is excreted in urine, mainly as 10-formyl tetrahydrofolate and 5, 10-methenyl tetrahydrofolate. There is some evidence that 5-methyl tetrahydrofolate may be conserved by the kidneys in preference to 5-formyl tetrahydrofolate (Folinate). Loss of folate in the urine becomes approximately logarithmic as the amount of Folinate administered exceeds 1mg.
5.3 Preclinical Safety Data
There is no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Microcrystalline cellulose
Magnesium Stearate
Lactose
There is no overage included in the formulation.
6.2 Incompatibilities
Immediate precipitation results when Calcium Folinate injection is combined with Droperidol in syringe.
6.3 Shelf Life
Product as packaged for sale: 3 years
6.4 Special Precautions For Storage
Do not store above 25°C
Keep container in outer carton
6.5 Nature And Contents Of Container
White polyethylene bottle with high density polyethylene screw closure containing 10 tablets.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire, CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL No. 4515/0017.
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of First Authorization: 27/8/85.
First Renewal of Authorization: 14/9/90.
10. Date Of Revision Of The Text
05 March 2009
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