Hospira UK Ltd

Folinic Acid (as Calcium Folinate) 15 mg Tablets

Each tablet contains calcium folinate equivalent to folinic acid 15 mg.

Excipients: contains lactose monohydrate 145mg

For a full list of excipients, see section 6.1.

Tablet

A yellowish-white, round, flat, scored, uncoated tablet engraved with 'CF'.

The scoreline is present to facilitate breaking for ease of swallowing and not to divide into equal doses.

1. As an intermediate in folic acid metabolism to reduce or counteract the toxicity of folic acid antagonists such as methotrexate, either in cytotoxic therapy (folinic acid rescue) or in cases of inadvertent overdosage.

2. In the treatment of megaloblastic anaemia due to sprue, nutritional deficiency, pregnancy, infancy, liver disease and malabsorption syndrome.

Adults and Children:

a) Folinic Acid Rescue

Folinic acid 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 120 mg 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, folinic acid 15mg orally every 6 hours for 48 to 72 hours may be sufficient.

Treatment should be accompanied by alkalinization 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.

b) Treatment of Megaloblastic Anaemia

The dose should not exceed 1mg daily given intramuscularly.

When given orally, the recommended dosage is one Folinic Acid Tablet (15mg) daily, for children up to 12 years, 0.25 mg/kg/day; normal adult oral dosage, 10-20mg daily.

c) Treatment of Overdosage of Folic Acid Antagonists

In cases of overdosage of folic acid antagonists, folinic acid 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 folinic acid 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.

Folinic acid is contraindicated in patients who have previously shown hypersensitivity to folinic acid or any of the excipients.

Folinic acid 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 Folinic Acid Tablets.

Folinic acid 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, folinic acid should be administered as soon as possible; if a period exceeding 4 hours intervenes, the treatment may not be effective.

In general, folinic acid 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, folinic acid given concurrently with folate antagonists, such as pyrimethamine and trimethoprim does not inhibit their antibacterial activity.

Parenteral administration of folinic acid 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 folinic acid.

Patients with rare hereditary problems of galactose intolerance, the lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Folinate 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 folinic acid with fluoroyrimidine as this has been associated with seizures and syncope (see Section 4.8).

Not applicable.

Immune system disorders

Very rare (<0.01%): allergic reactions, including anaphylactoid / anaphylactic reactions, and urticaria.

Psychiatric disorders

Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

Gastrointestinal disorders

Rare (0.01-0.1%): gastrointestinal disorders after high doses.

Neurological disorders

Rare (0.01-0.1%): increase in the frequency of attacks in epileptics (see also section 4.5 Interactions).

General disorders and administration site conditions

Uncommon (0.1-1%): fever has been observed after administration of calcium folinate as 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.

Metabolism and Nutritional Disorder:

Not known: Hyperammonaemia

Blood and lymphatic system disorders:

Very common: bone marrow failure, including fatal cases

General disorders and administration site conditions

Very common: mucositis, including stomatitis and chelitis. Fatalities have occurred as a result of mucositis

Skin and subcutaneous tissue disorders:

Common: Palmar-Plantar Erythrodysaesthesia

Monthly regimen:

Gastrointestinal disorders

Very common (>10%): vomiting and nausea

No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).

Weekly regimen:

Gastrointestinal disorders

Very common (>10%): diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.

Seizures and/or syncope; have been reported rarely in cancer patients receiving folinic acid, 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.

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:

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail:

medsafety@hpra.ie

There have been no reported sequelae in patients who have received significantly more calcium folinate then the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

There is no specific antidote to folinic acid overdose. In cases of overdosage, patients should be given appropriate supportive care.

Should overdosage of the combination of 5-FU with folinic acid occur, the overdosage instructions for 5-FU should be followed.

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 anaemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, folinic acid is a potent antidote for both hematopoietic and reticuloendothelia toxic effects of folic acid antagonists, (e.g. methotrexate, pyrimethamine, trimethprim).

It is postulated that in some cancers, folinic acid 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 "folinic acid rescue".

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 microgram/mL. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016-0.021 microgram/mL. Normal erythrocyte folate concentrations range from 0.175-0.316 microgram/mL.

In general, serum folate concentrations less than 0.005 microgram/mL indicate folate deficiency and concentrations less than 0.002 microgram/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 0.241µg/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 microgram/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.

There are no preclinical data of relevance to the prescriber which are additional to the data already included in other sections of the SPC.

Microcrystalline cellulose

Magnesium stearate

Lactose monohydrate

Not applicable.

Product as packaged for sale: 3 years.

Do not store above 25°C.

Keep container in the outer carton in order to protect from light.

White polyethylene bottle with a high density polyethylene screw closure containing 10 tablets.

No special requirements.

Hospira UK Limited

Horizon

Honey Lane

Hurley

Maidenhead

SL6 6RJ

United Kingdom

PA 437/10/1

Date of first authorisation: 28 July 1986

Date of last renewal: 25 January 2010

January 2016