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PRESCRIBER INFORMATION LEAFLET

NAME OF THE MEDICINAL PRODUCT Calcium Folinate 10mg/ml Solution for Injection QUALITATIVE AND QUANTITATIVE COMPOSITION

Calcium Folinate 10mg/ml Solution for Injection contains Calcium Folinate, the formyl derivate of tetrahydrofolic acid in the form of the calcium salt.

Each ml of Calcium Folinate 10mg/ml Solution for Injection contains 10.8mg of calcium folinate, equivalent to 10.0mg of folinic acid

5ml solution for injection contains 54mg calcium folinate, equivalent to 50mg folinic acid.

10ml solution for injection    contains    108mg calcium    folinate, equivalent to    100mg folinic acid.

20ml solution for injection    contains    216mg calcium    folinate, equivalent to    200mg folinic acid.

30ml solution for injection    contains    324mg calcium    folinate, equivalent to    300mg folinic acid.

50ml solution for injection    contains    540mg calcium    folinate, equivalent to    500mg folinic acid.

Excipients with known effect: Each ml of solution for injection contains 0.14 mmol (3.22 mg) sodium.

For the full list of excipients see 6.1

PHARMACEUTICAL FORM

Solution for injection

Calcium Folinate 10mg/ml Solution for Injection is a clear, yellow, particle-free solution.

CLINICAL PARTICULARS Therapeutic indications Calcium folinate is indicated:

-    to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy and overdose in adults and children. In cytotoxic therapy, this procedure is commonly known as "Calcium Folinate Rescue";

-    In combination with 5-fluorouracil in cytotoxic therapy.

Posology and method of administration

Method of administration

For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160mg calcium folinate should be injected per minute due to the calcium content of the solution. For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. Refer also to sections 6.3 and 6.6.

Posology

Calcium folinate rescue in methotrexate therapy:

Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured. Dosages above 25 -50mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500mg/m² body surface and should be considered with doses of 100mg - 500mg/m² body surface.

Dosage and duration of calcium folinate rescue primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of calcium folinate is 15mg (6 - 12mg/m²) to be given 12 - 24 hours (24 hours at the latest) after the beginning of methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the prompt excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the calcium folinate rescue treatment. Renal function should be monitored through daily measurements of serum creatinine.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5pmol/l, calcium folinate dosages should be adapted according to the following table:

496

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.

The following regimens have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of these combinations in children: Bimonthly regimen: Calcium folinate 200mg/m² by intravenous infusion over 2 hours, followed by bolus 400mg/m² of 5-FU and 22-hour infusion of 5-FU (600mg/m²) for two consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen: Calcium folinate 20mg/m² by bolus i.v. injection or 200 to 500mg/m² as i.v. infusion over a period of 2 hours plus 500mg/m² 5-fluorouracil as i.v. bolus injection in the middle or at the end of the calcium folinate infusion.

Monthly regimen: Calcium folinate 20mg/m² by bolus i.v. injection or 200 to 500mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370mg/m² 5-fluorouracil as i.v. bolus injection during five consecutive days.

For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

The number of repeat cycles used is at the discretion of the clinician.

Antidote to the folic acid antagonists, trimetrexate, trimethoprim, and pyrimethamine:

Trimetrexate toxicity:

- Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either by the intravenous route at a dose of 20mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80mg/m², or by oral route with four doses of 20mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

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-    Overdosage (possibly occurring with trimetrexate doses above 90mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40mg/m² IV every 6 hours for 3 days.

Trimethoprim toxicity:

-    After stopping trimethoprim, 3-10mg/day calcium folinate until recovery of a normal blood count. Pyrimethamine toxicity:

-    In cases of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

4.3    Contraindications

-    Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.

-    Pernicious anaemia or other anaemias due to vitamin B12 deficiency.

Regarding the use of calcium folinate with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6 Pregnancy and Lactation, and the summaries of product characteristics for methotrexate- and 5-fluorouracil-containing medicinal products.

4.4    Special warnings and precautions for use

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally. When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.

General

Calcium folinate should be used with methotrexate or 5-fluorouracil only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.

Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.

Many cytotoxic medicinal products - direct or indirect DNA synthesis inhibitors - lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interaction with other medicinal products and other forms of interaction).

Calcium folinate/5-fluorouracil

Calcium folinate may enhance the toxicity risk of 5-fluorouracil, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and/or diarrhoea, which may be dose limiting. When calcium folinate and 5-fluorouracil are used in combination, the 5-fluorouracil dosage has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone.

Combined 5-fluorouracil/calcium folinate treatment should neither be initiated nor maintained in patients with symptoms of gastrointestinal toxicity, regardless of the severity, until all of these symptoms have completely disappeared.

Because diarrhoea may be a sign of gastrointestinal toxicity, patients presenting with diarrhoea must be carefully monitored until the symptoms have disappeared completely, since a rapid clinical deterioration leading to death can occur. If diarrhoea and/or stomatitis occur, it is advisable to reduce the dose of 5-FU until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to illness are prone to these toxicities. Therefore, particular care should be taken when treating these patients.

In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dosage of 5-fluorouracil.

Calcium folinate must not be mixed with 5-fluorouracil in the same i.v injection or infusion.

Calcium levels should be monitored in patients receiving combined 5-fluorouracil/calcium folinate treatment and calcium supplementation should be provided if calcium levels are low.

Calcium folinate/methotrexate

For specific details on reduction of methotrexate toxicity refer to the SmPC of methotrexate.

Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SmPC for methotrexate). The presence of pre-existing or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.

Excessive calcium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses. Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.

An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.

The possibility that the patient is taking other medications that interact with methotrexate (e.g. medications that may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.

Each ml of solution contains 0.14 mmol (3.22 mg) sodium. This should be taken into account in patients on a controlled sodium diet.

4.5    Interaction with other medicinal products and other forms of interaction

When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised. Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see also sections 4.4 and 4.8).

Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil (see sections 4.2, 4.4 and 4.8).

4.6    Fertility, pregnancy and lactation Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with calcium folinate have been conducted. There are no indications that folic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the drug to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other

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5.2

folate antagonists take place despite pregnancy or lactation, there are no limitations as to the use of calcium folinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and contraindicated during breastfeeding; this applies also to the combined use of calcium folinate with 5-fluorouracil.

Please refer also to the summaries of product characteristics for methotrexate, other folate antagonists and 5-fluorouracil-containing medicinal products.

Breast-feeding

It is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast-feeding when considered necessary according to the therapeutic indications.

Effects on ability to drive and use machines

There is no evidence that calcium folinate has an effect on the ability to drive or use machines.

Undesirable effects

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)    5.3

Very rare (<1/10,000) including isolated reports

not known (cannot be estimated from the available data)

Both therapeutic indications:    6

Immune system disorders    6.1

Very rare, including incidental reports (<0.01%):

Allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare

Insomnia, agitation and depression after high doses.    _6.2

Gastrointestinal disorders

Rare

Gastrointestinal disorders after high doses.

Neurological disorders

Rare

Increase in the frequency of attacks in epileptics (see also section 4.5 Interaction with other medicinal products and other forms of interaction).

General disorders and administration site conditions

Uncommon

Fever has been reported after administration of calcium folinate as solution for injection.

Combination therapy with 5-fluorouracil:

Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities:

Monthly regimen:

Gastrointestinal disorders

Very common Vomiting and nausea

General disorders and administration site conditions

Very common (Severe) mucosal toxicity

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

Weekly regimen:

Gastrointestinal disorders

Very common

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.

Overdose

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

Should overdosage of the combination of 5-fluorouracil and calcium folinate occur, the overdosage instructions for 5-FU should be followed.

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties

Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment ATC code: V03AF03.

Calcium folinate is the sodium salt of 5-formyl tetrahydrofolic acid. It is an active metabolite of folinic acid and an essential coenzyme for nucleic acid synthesis in cytotoxic therapy.

Calcium folinate is frequently used to diminish the toxicity and counteract the action of folate antagonists, such as methotrexate. Calcium folinate and folate antagonists share the same membrane transport carrier and compete for transport into cells, stimulating folate antagonist efflux. It also protects cells from the effects of folate antagonist by repletion of the reduced folate pool. Calcium folinate serves as a pre-reduced source of H4 folate; it can therefore bypass folate antagonist blockage and provide a source for the various coenzyme forms of folic acid.

Calcium folinate is also frequently used in the biochemical modulation of fluorouracil (5-FU) to enhance its cytotoxic activity. 5-FU inhibits thymidylate synthase (TS), a key enzyme involved in pyrimidine biosynthesis, and calcium folinate enhances TS inhibition by increasing the intracellular folate pool, thus stabilising the 5FU-TS complex and increasing activity.

Finally intravenous calcium folinate can be administered for the prevention and treatment of folate deficiency when it cannot be prevented or corrected by the administration of folic acid by the oral route. This may be the case during total parenteral nutrition and severe malabsorption disorders. It is also indicated for the treatment of megaloblastic anaemia due to folic acid deficiency, when oral administration is not feasible.

Pharmacokinetic properties Absorption

Following intramuscular administration of the aqueous solution, systemic availability is comparable to an intravenous administration. However, lower peak serum levels (Cmax) are achieved.

Metabolism

Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer.

6.3

6.4

6.5

6.6

7

8

9

10

The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.

Distribution

The distribution volume of folinic acid is not known.

Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after i.v. administration.

AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5mg.min/l and 129±112mg.min/l after a dose of 25mg. The inactive D-isomer is present in higher concentration than L-5-formyl-tetrahydrofolate.

Elimination

The elimination half-life is 32-35 minutes for the active L-form and 352-485 minutes for the inactive D-form, respectively.

The total terminal half-life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).

Excretion

80-90% with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8% with the faeces. Preclinical safety data

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SmPC.

PHARMACEUTICAL PARTICULARS List of excipients

Sodium chloride Sodium hydroxide Hydrochloric acid Water for injections

Incompatibilities

Calcium Folinate 10mg/ml Solution for Injection should not be mixed with any other drug, unless compatibility has been satisfactorily demonstrated.

Incompatibilities have been reported between injectable forms of calcium folinate and injectable forms of droperidol, fluorouracil, foscarnet and methotrexate.

Droperidol

1.    Droperidol 1.25mg/0.5ml with calcium folinate 5mg/0.5ml, immediate precipitation in direct admixture in syringe for 5 minutes at 25°C followed by 8 minutes of centrifugation.

2.    Droperidol 2.5mg/0.5ml with calcium folinate 10mg/0.5ml, immediate precipitation when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections.

Fluorouracil

Calcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. Fluorouracil 50mg/ml with calcium folinate 20mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32°C in polyvinyl chloride containers.

Foscarnet

Foscarnet 24mg/ml with calcium folinate 20mg/ml: formation of a cloudy yellow solution reported.

Shelf life

Shelf-life as packed for sale

2 years

Shelf-life after first opening the container: For single dose use only. Any unused solution should be discarded immediately after initial use.

Shelf-life after dilution according to directions

When diluted according to directions with the recommended infusion fluids, 0.9% w/v Sodium Chloride Intravenous Infusion or 5% w/v Glucose Intravenous Infusion, chemical and physical in-use stability of diluted solution has been demonstrated for 72 hours at room temperature (below 25°C).

From a microbiological point of view, the product 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, unless dilution has taken place in controlled and validated aseptic conditions.

Special precautions for storage

Store in a refrigerator (2 °C - 8°C). Keep the vial in the outer carton.

For storage conditions after dilution of the medicinal product, see section 6.3.

Nature and contents of container

Clear, Type I glass vials with chlorobutyl rubber stoppers, Type I, with aluminium crimping caps. Vials containing 5ml, 10ml, 20ml, 30ml and 50ml solution for injection.

Package size: 1 vial per carton Not all pack sizes may be marketed.

Special precautions for disposal and other handling

Calcium Folinate 10mg/ml Solution for Injection is intended for single dose use only. Any unused solution should be discarded immediately after initial use.

For intravenous infusion, calcium folinate may be diluted according to directions with the recommended infusion fluids, 0.9% w/v Sodium Chloride Intravenous Infusion or 5% w/v Glucose Intravenous Infusion before administration.

The administration of Calcium Folinate 10mg/ml Solution for Injection depends on the individual dosage regime. See also section 4.2. In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

Prior to administration, the sterile solution for injection should be visually inspected for clarity, particulate matter, discolouration and the integrity of the container. The solution should only be used if it is clear and the container is undamaged.

Any unused portion of the solution any unused medicinal product or waste material should be disposed of in

accordance with the local requirements

MARKETING AUTHORISATION HOLDER

Teva UK Limited

Brampton Road, Hampden Park

Eastbourne, East Sussex BN22 9AG

MARKETING AUTHORISATION NUMBER(S)

PL 00289/0851

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/04/2006 /    11/02/2008

DATE OF REVISION OF THE TEXT

84025-N

6-29116170/D

To be completed upon approval

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No 420 mm 300 mm N/A N/A

Colours Used:

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93.131.319-A

In combination with 5-fluorouracil in cytotoxic therapy:

Different regimens and different dosages are used, without any dosage having been proven to be the optimal one.