Calcium Folinate Tablets 15mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Calcium Folinate 15 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 19.07 mg of calcium folinate, which is equivalent to 15 mg folinic acid.
Excipient with known effect:
Each tablet contains 155 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablets
Off white to pale yellow scored biconvex tablets marked with "CF/15" on one side and "G" on the other.
4.1 Therapeutic indications
Calcium Folinate is indicated in:
1. Neutralising the immediate toxic effects of folic acid antagonists, e.g. Methotrexate.
2. Calcium Folinate Rescue - a treatment technique using Calcium Folinate in conjunction with folic acid antagonists, e.g. methotrexate, to minimise systemic toxicity.
3. The treatment of megaloblastic anaemias due to sprue, nutritional deficiency, pregnancy, infancy, liver disease and malabsoption syndrome.
4.2 Posology and method of administration
Posology
Adults and children Calcium Folinate Rescue
Depending upon the dose of methotrexate administered, dosage regimens of calcium folinate vary.
Up to 120 mg calcium folinate is generally given, usually in divided doses over 12 to 24 hours by intramuscular injection, bolus intravenous injection or intravenous infusion in normal saline. This is followed by 12 to 15mg intramuscularly or 15 mg orally every 6 hours for 48 hours.
Rescue therapy is usually started 24 hours after the commencement of methotrexate administration.
Neutralising the immediate toxic effects of folic acid antagonists:
If overdosage of methotrexate is suspected, the dose of Calcium Folinate should be equal to or greater than the dose of the methotrexate, and should be administered within one hour of the methotrexate administration.
Megaloblastic anaemia (folinate deficiency)
Adults: One tablet of calcium folinate per day Children: Other more suitable formulations are available.
Method of administration For oral use.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Calcium Folinate is contraindicated in the treatment of pernicious anaemia or other megaloblastic anaemias due to Vitamin Bi2 deficiency. Its use can lead to an apparent response of the haematopoietic system, but neurological damage may occur or progress if already present.
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 an antineoplastic folic acid antagonist, e.g. methotrexate for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified. Concomitant Calcium Folinate will not however inhibit the antibacterial activity of other folic acid antagonists such a trimethoprim and pyrimethamine.
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 is 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 1800-2000ml/m /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 (0.1 pM).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Calcium Folinate tablets.
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 Fertility, pregnancy and lactation
Pregnancy
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.
Breast-feeding
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
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.
|
System Organ Class |
Uncommon (>1/1,000 to <1/100) |
Rare (>1/10,000 to <1/1,000) |
Very rare (<1/10,000) |
|
Immune system disorders |
allergic reactions, |
|
including anaphylactoid / anaphylactic reactions, and urticaria | |||
|
Psychiatric disorders |
insomnia, agitation and depression after high doses | ||
|
Gastrointestinal disorders |
gastrointestinal disorders after high doses | ||
|
Neurological disorders |
increase in the frequency of attacks in epileptics (see also section 4.5) | ||
|
General disorders and administration site conditions |
fever has been observed after administration of calcium folinate as a solution for injection |
Combination therapy with 5-fluorouracil only:
Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities.
|
Very common (> 1/10) |
Common (>1/100 to <1/10) |
Not known (frequency cannot be estimated from the available data) | |
|
Metabolism and Nutritional Disorder |
hyperammonaemia | ||
|
Blood and lymphatic system disorders |
bone marrow failure, including fatal cases | ||
|
General disorders and administration site conditions |
mucositis, including stomatitis and chelitis. Fatalities have occurred as a result of mucositis | ||
|
Skin and subcutaneous tissue disorders |
Palmar-Plantar Erythrodysaesthesia |
Monthly regimen:
Gastrointestinal disorders
Very common (> 1/10): vomiting and nausea
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Weekly regimen:
Gastrointestinal disorders
Very common (> 1/10): diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.
Reporting of suspected adverse reactions
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
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
ATC code: V03 AF03
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment
Folinic acid is the 5-formyl derivative of tetrahydrofolic acid, the active 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, folinic acid is used principally as an antidote for both hematopoietic and reticuloendothelia toxic effects of folic acid antagonists, such as Methotrexate, Pyrimethamine or Trimethoprim which block the conversion of folic acid to tetrahydrofolate by binding the enzyme dihydrofolate reductase. 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".
Pharmacokinetic properties
5.2
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 pg/mL. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016-0.021 pg/mL. Normal erythrocyte folate concentrations range from 0.175-0.316 pg/mL.
In general, serum folate concentrations less than 0.005 pg/mL indicate folate deficiency and concentrations less than 0.002 pg/mL usually result in megaloblastic anemia. Following I.M. administration of a 15mg (7.5 mg/m2) dose in healthy men, mean peak serum folate concentrations of 0.241 pg/mL occur within about 40 minutes. Following oral administration of a 15mg (7.5 mg/m2) dose in healthy men, mean peak serum folate concentrations of 0.268 pg/mL occur within about 1.72 hours. Areas under the serum folate concentration-time curves (AUCs) are reported to be about 8% less following
1. 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 2 mg 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 1 mg
5.3 Preclinical safety data
There are no additional 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
Lactose monohydrate Maize starch
Magnesium stearate
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Store below 25°C.
Store in the original packaging in order to protect from light.
6.5 Nature and contents of container
Polypropylene containers with polyethylene caps (with optional polyethylene ullage filler) containing 7, 10, 14, 20, 21, 28 or 30 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited T/A Mylan Station Close Potters Bar Hertfordshire EN6 1TL
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0212
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28/10/1987
10/08/2016