ISOVORIN Solution for injection Ref.[8633] Active ingredients: Levoleucovorin

Calcium levofolinate must not be administered intrathecally. When levofolinic acid has been administered intrathecally, following intrathecal overdose of methotrexate, 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 (hydroxycarbamide, 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 leucopoenia, 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 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. 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, especially 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.

Excipient Information

Isovorin 25 mg/2.5 ml solution for injection contains 7.6 mg of sodium per 2.5 ml of solution, equivalent to 0.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Isovorin 50 mg/5 ml solution for injection contains 15.2 mg of sodium per 5 ml of solution, equivalent to 0.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Isovorin 175 mg/17. 5 ml solution for injection contains 53.03 mg of sodium per 17.5 ml of solution, equivalent to 2.65% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

Pregnancy and Breast-feeding

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.

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

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 (frequency cannot be estimated from the available data).

Immune system disorders

Very rare: Anaphylactoid/anaphylactic reactions (including shock)

Not known: Allergic reactions, urticaria

Nervous system disorders

Rare: Seizures and syncope

General disorders and 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

Metabolism and nutritional disorders

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: Palmer-Plantar Erythrodysaesthesia

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

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 or search MHRA Yellow Card in the Google Play or Apple App Store.

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.