SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

ISOVORIN* Solution for Injection 10 mg/ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Calcium levofolinate (INN: calcium levofolinate) equivalent to 1.00% w/v (10mg/ml) of levoleucovorin (levofolinic acid).

The product is presented as vials containing 25mg, 50mg or 175mg of levofolinic acid (as calcium levofolinate) in 2.5ml, 5ml or 17.5ml of solution respectively.

3 PHARMACEUTICAL FORM

Solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Calcium Levofolinate Rescue

Calcium levofolinate is used to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy. This procedure is known as Calcium Levofolinate Rescue.

Advanced Colorectal Cancer - Enhancement of 5-Fluorouracil (5-FU) Cytotoxicity

Calcium levofolinate increases the thymine depleting effects of 5-FU resulting in enhanced cytotoxic activity. Combination regimens of 5-fluorouracil and levofolinate give greater efficacy compared to 5-FU given alone.

4.2 Posology and method of administration

For single use only

Calcium Levofolinate Rescue

Adults, Children and the Elderly:

Calcium Levofolinate Rescue therapy should commence 24 hours after the beginning of methotrexate infusion. Dosage regimes vary depending upon the dose of methotrexate administered. In general, the calcium levofolinate should

be administered at a dose of 7.5mg (approximately 5mg/m²) every 6 hours for 10 doses by intramuscular injection, bolus intravenous injection or intravenous infusion, (refer to 4.2.2 for information concerning use of calcium levofolinate with infusion fluids). Do not administer calcium levofolinate intrathecally.

Where overdosage of methotrexate is suspected, the dose of calcium levofolinate should be at least 50% of the offending dose of methotrexate and should be administered in the first hour. In the case of intravenous administration, no more than 160mg of calcium levofolinate should be injected per minute due to the calcium content of the solution.

In addition to calcium levofolinate administration, measures to ensure the prompt excretion of methotrexate are important as part of Calcium Levofolinate Rescue therapy. These measures include:

a.    Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites).

b.    Maintenance of urine output of 1800-2000 cc/m /24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.

c.    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.l^M).

Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of calcium levofolinate or prolonged administration may be indicated. Dosage and administration guidelines for these patients are given in Table 1. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.

TABLE 1:

Dosage and Administration Guidelines for Calcium Levofolinate Rescue

Normal Methotrexate Elimination	Serum methotrexate level approximately 10^M at 24 hours after administration, 1^M at 48 hours and less than 0.2^M at 72 hours.	7.5mg IM or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion)
Delayed Late Methotrexate Elimination	Serum methotrexate level remaining above 0.2^M at 72 hours, and more than 0.05at 96 hours after administration.	Continue 7.5mg IM or IV every 6 hours until methotrexate level is less than 0.05^M.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury.	Serum methotrexate level of 50 ^M or more at 24 hours or 5^M or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration.	75mg IV every 3 hours, until methotrexate level is less than 1^M; then 7.5mg IV every 3 hours until methotrexate level is less than 0.05^M

Colorectal Cancer: Enhancement of 5-FU Cytotoxicity Adults and the Elderly:

Administration: The 175mg in 17.5ml vial of Calcium Levofolinate Solution for injection should be used to administer the high doses of calcium levofolinate required in combination regimens.

When used in combination regimens with 5-FU, calcium levofolinate should only be given by the intravenous route. The agents should not be mixed together. Each vial of calcium levofolinate 175mg contains 0.7mEq (0.35mmol) of calcium per vial and it is recommended that the solution is administered over not less than 3 minutes.

For intravenous infusion, the 175mg in 17.5ml Solution for injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% injection; Compound Sodium Lactate Injection.

Calcium levofolinate should not be mixed together with 5-FU in the same infusion and, because of the risk of degradation, the giving set should be protected from light.

Dosage: Based on the available clinical evidence, the following regimen is effective in advanced colorectal carcinoma:

Calcium levofolinate given at a dose of 100mg/m by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370mg/m by intravenous injection. The injection of levofolinate should not be given more rapidly than over 3 minutes because of the calcium content of the solution. This treatment is repeated daily for 5 consecutive days. Subsequent courses may be given after a treatment-free interval of 21-28 days.

For the above regimen, modification of the 5-FU dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity. A reduction of calcium levofolinate dosage is not required. The number of repeat cycles used is at the discretion of the clinician.

On the basis of the available data, no specific dosage modifications are recommended in the use of the combination regimen with 5-FU in the elderly. However, particular care should be taken when treating elderly or debilitated patients as these patients are at increased risk of severe toxicity with this therapy (See 'Special warnings and precautions for use').

Children:

There are no data available on the use of this combination in children.

4.3 Contraindications

Known hypersensitivity to calcium levofolinate, or to any components of the excipients.

Calcium levofolinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemias due to vitamin B12 deficiency.

Regarding the use of calcium levofolinate with methotrexate or 5-FU during pregnancy and lactation, see section 4.6, and the Summaries of Product Characteristics for methotrexate and 5-FU-containing medicinal products.

4.4 Special warnings and precautions for use

Calcium levofolinate must not be administered intrathecally. When levofolinic acid has been administered intrathecally, following intrathecal overdose of methotrexate, a death has been reported.

General

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

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

Many cytotoxic medicinal products - direct or indirect DNA synthesis inhibitors - lead to macrocytosis    (hydroxy carbamide,    cytarabine,

mercaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.

Calcium levofolinate / 5-FU

Calcium levofolinate may enhance the toxicity profile of 5-FU, particularly in elderly or debilitated patients. The most common manifestations are leucopenia, mucositis, stomatitis and / or diarrhoea, which may be dose limiting.

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

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. The elderly and patients with a low physical performance due to their illness are especially 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-FU.

Calcium levofolinate must not be mixed with 5-FU in the same IV injection or infusion.

Calcium levofolinate / methotrexate

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

Calcium levofolinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotexate 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. 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 levofolinate.

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

Excessive calcium levofolinate doses must be avoided since this might impair the anti-tumour activity of methotrexate, expecially in CNS tumours where calcium levofolinate 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.

4.5 Interaction with other medicinal products and other forms of interaction

When calcium levofolinate 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 levofolinate may diminish the antiepileptic effect of phenobarbital, phenytoin, primidone and succinimides, and may increase the frequency of seizures in susceptible patients. Clinical monitoring is therefore recommended.

4.6 Pregnancy and lactation

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women.

Calcium levofolinate may be excreted in human milk and should only be administered where the benefits of the drug to the mother outweigh possible hazards to the infant. Calcium levofolinate can be used during breast-feeding when considered necessary according to the therapeutic indications.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Within the organ system classes, adverse reactions are listed under the headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); not known (could not be accurately estimated through clinical studies).

Immune system disorders:

Very rare:	Anaphylactoid / anaphylactic reactions (including shock)
Not known:	Allergic reactions, urticaria

Nervous system disorders:

Rare:	Seizures and syncope
General disorders ant	administration site conditions:
Not known:	Fever

Cases of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), some fatal, have been reported in patients receiving calcium levofolinate in combination with other agents known to be associated with these disorders. A contributory role of calcium levofolinate in these cases cannot be excluded.

Calcium levofolinate may enhance 5-FU induced toxicities depending on the applied regimen. Additional undesirable effects when used in combination with 5-FU:

Gastrointestinal disorders:

Very common:	Nausea, vomiting, diarrhoea
Hepatobiliary disorders:
Not known:	Hyp erammonemia
Skin and subcutaneous tissue disorders:
Not known:	Palmer-Plantar Erythrodysaesthesia
General disorders and administration site conditions:
Not known:	Mucositis, including stomatitis and chelitis

Fatalities have occurred as a result of gastrointestinal toxicity (predominantly mucositis and diarrhoea) and myelosuppression.

4.9 Overdose

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

Should overdose of the combination of 5-FU with calcium levofolinate occur, the overdose instructions for 5-FU should be followed.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Levofolinate is the pharmacologically active isomer of 5-formyltetrahydrofolic acid. Levofolinate does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilising folates as a source of "one carbon" moieties. Levofolinate is actively and passively transported across cell membranes.

Administration of levofolinate can "rescue" normal cells and thereby prevent toxicity of folic acid antagonists such as methotrexate which act by inhibiting dihydrofolate reductase.

Levofolinate can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolised to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FDUMP), which binds to and inhibits thymidylate synthase. Levofolinate is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilise the binding of FDUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.

Levofolinate is also effective in the treatment of megaloblastic anaemias due to folate deficiencies.

5.2 Pharmacokinetic properties

When levofolinate is injected intravenously it is 100% bioavailable.

The pharmacokinetics of levofolinate after intravenous administration of a 15mg dose were studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722ng/ml. Serum levo-5-methyl-THF concentrations reached a mean peak of 275ng/ml and the mean time to peak concentration was 0.9 hours. The mean half-life for total-THF and levo-5-methyl-THF was

5.1 and 6.8 hours respectively.

The distribution and plasma levels of levofolinate following intramuscular administration have not been established.

The distribution in tissue and body fluids and protein binding have not been determined.

In vivo, levofolinate is converted to levo-5-methyltetrahydrofolic acid (levo-5-methyl-THF), the primary circulating form of active reduced folate. Levofolinate and levo-5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.

Levofolinate and levo-5-methyl-THF are excreted renally.

Due to the inherent lack of levofolinate toxicity, the influence of impaired renal or hepatic function on levofolinate disposition was not evaluated.

5.3 Preclinical safety data

The pre-clinical data raises no concerns for the clinical uses indicated.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride, Water for injection, Hydrochloric acid, Sodium hydroxide

6.2 Incompatibilities

Calcium levofolinate should not be mixed together with 5-FU in the same intravenous injection or infusion.

In addition to 5-FU, incompatibilities have also been reported between injectable forms of calcium levofolinate and injectable forms of droperidol, foscarnet and methotrexate.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store ISOVORIN Solution for Injection under refrigerated conditions (2 - 8 °C) in original containers. Protect from light.

6.5 Nature and contents of container

Type I amber glass vials each containing the equivalent of 25 mg, 50 mg or 175 mg of calcium levofolinate in 2.5 ml, 5 ml or 17.5 ml of solution respectively. ISOVORIN Solution for Injection is packed in boxes of 1 vial.

6.6 Special precautions for disposal

For intravenous infusion, calcium levofolinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use.

When ISOVORIN Solution for Injection is diluted with the recommended infusion fluids, the resulting solutions are intended for immediate use but may be stored for up to 24 hours under refrigerated conditions (2 - 8°C). Because of the risk of degradation, reconstituted solutions should be protected from light prior to use if necessary.

Prior to administration, calcium levofolinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance, or if particles are observed, the solution should be discarded. Calcium levofolinate solution for injection or infusion is intended only for single use.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited Ramsgate Road Sandwich Kent

CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00057/1282

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

12^th June 1998.

DATE OF REVISION OF THE TEXT

17/08/2011