LEVOFOLINIC ACID Solution for injection/infusion Ref.[9512] Active ingredients: Levoleucovorin

Disodium levofolinate should only be given intravenously, either undiluted by injection or by infusion after dilution and must not be administered intrathecally.

When folinic acid has been administered intrathecally following intrathecal overdose of methotrexate, death has been reported.

General

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

Disodium levofolinate 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, mercaptopurine, thioguanine). Such macrocytosis should not be treated with disodium levofolinate.

Epileptic patients

In epileptic patients treated with phenobarbital, phenytoin, primidone and succinimides there is a risk to increase the frequency of seizures due to decrease of plasma concentrations of anti-epileptic medicinal products. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic medicinal product during disodium levofolinate administration and after discontinuation is recommended (see section 4.5).

Disodium levofolinate/5-fluorouracil

In the combination regimen with 5-fluorouracil, the toxicity profile of 5-fluorouracil may be enhanced or shifted by disodium levofolinate, particularly in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis and/or diarrhoea which may be dose limiting. When disodium levofolinate and 5-fluorouracil are used in combination, the 5-fluorouracil dose has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone.

Gastrointestinal toxicities are observed more commonly and may be more severe or even life threatening (particularly stomatitis and diarrhoea). In severe cases, treatment is withdrawal of 5-fluorouracil and disodium levofolinate, and supportive intravenous therapy.

Combined 5-fluorouracil/disodium levofolinate 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-fluorouracil until symptoms have fully disappeared. Especially the elderly and patients with a low physical performance due to their illness are prone to these toxicities. Therefore, particular care should be taken when treating these patients.

Patients should be instructed to consult their treating physician immediately if stomatitis (mild to moderate ulcers) and/or diarrhoea (watery stools or bowel movements) two times per day occur (see also section 4.2).

Particular care should be taken in the treatment of elderly or debilitated patients or patients who have undergone preliminary radiotherapy, as these patients may be at increased risk of severe toxicity; in these patients it is recommended to begin with a reduced dose of 5-fluorouracil.

Disodium levofolinate/methotrexate

Disodium levofolinate should not be given simultaneously with an antineoplastic folic acid antagonist (e.g. methotrexate) to modify or abort clinical toxicity, as the therapeutic effect of the antagonist may be nullified except in the case of folic acid antagonist overdose (see below).

For specific details on reduction of methotrexate toxicity refer to the summary of product characteristics of 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 disodium levofolinate rescue increases, disodium levofolinate effectiveness in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with disodium levofolinate. Delayed methotrexate excretion may be caused by third space fluid accumulation (i.e. ascites, pleural effusion), renal insufficiency, inadequate hydration or administration of non-steroidal anti-inflammatory drugs or salicylates. Under such circumstances, higher doses of disodium levofolinate or prolonged administration may be indicated.

Disodium 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 (please refer to the summary of product characteristics 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 disodium levofolinate.

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

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

Excipient(s) with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium-free”.

Disodium levofolinate is an antidote of folic acid antagonists – e.g. methotrexate. Following the use of methotrexate, disodium levofolinate overdose may lead to a loss of the effect of methotrexate therapy (“over-rescue”).

When disodium 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.

Concomitant administration of disodium levofolinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil.

Life-threatening diarrhoeas have been observed if 600 mg/m² of 5-fluorouracil (i.v. bolus once weekly) is given together with disodium levofolinate. When disodium levofolinate and 5-fluorouracil are used in combination, the 5-fluorouracil dose must be reduced more than when 5-fluorouracil is used alone (see sections 4.2, 4.4 and 4.8).

Disodium levofolinate 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 medicinal products may be observed because the hepatic metabolism is increased as folates are one of the cofactors) (see sections 4.4 and 4.8).

Pregnancy

There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with disodium levofolinate have been conducted. There are no indications that folinic acid induces harmful effects if administered during pregnancy. During pregnancy, methotrexate should only be administered on strict indications, where the benefits of the medicinal product to the mother should be weighed against possible hazards to the foetus. Should treatment with methotrexate or other folate antagonists take place despite pregnancy, there are no limitations as to the use of disodium levofolinate to diminish toxicity or counteract the effects.

5-fluorouracil use is generally contraindicated during pregnancy and breast-feeding; this applies also to the combined use of disodium levofolinate 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 disodium levofolinate is excreted into human milk. Disodium levofolinate alone can be used during breast feeding when considered necessary according to the therapeutic indications.

However, methotrexate or 5-fluorouracil are excreted in human milk, and both active substances are contraindicated during breast-feeding. Breast-feeding must be discontinued before such treatment is initiated.

Fertility

No information is available on the effects of folinic acid alone on fertility and general reproductive performance.

Disodium levofolinate has no or negligible influence on the ability to drive and use machines. The general condition of the patient is likely to be more significant than any effects induced by this medicinal product.

Frequencies: 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), Very rare (<1/10,000), not known (cannot be estimated from the available data).

All therapeutic indications

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:

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

Weekly regimen:

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

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.