Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: medac, Gesellschaft für klinische, Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
The combination of disodium folinate with 5-fluorouracil is not indicated in:
Therapy with disodium folinate combined with 5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity until those symptoms have completely resolved. Patients with diarrhoea must be monitored with particular care until the diarrhoea has resolved, as rapid clinical deterioration leading to death can occur (see also sections 4.2, 4.4 and 4.5).
Regarding the use of folinic acid with methotrexate or 5-fluorouracil during pregnancy and lactation, see section 4.6 and the summaries of product characteristics for methotrexate- and 5-fluorouracil-containing medicinal products.
Disodium folinate is not suitable for the treatment of pernicious anaemia or other anaemias due to vitamin B12 deficiency. Although haematological remissions may occur, the neurological manifestations remain progressive.
Disodium folinate 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.
Disodium 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.
Disodium 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, mercaptopurine, thioguanine). Such macrocytosis should not be treated with disodium folinate.
In epileptic patients treated with phenobarbital, phenytoine, 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 folinate administration and after discontinuation is recommended (see section 4.5).
Disodium folinate 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).
Concomitant disodium folinate will not, however, inhibit the antibacterial activity of other folic acid antagonists such as trimethoprim and pyrimethamine.
For specific details on reduction of methotrexate toxicity refer to the summary of product characteristics of methotrexate.
Disodium 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 summary of product characteristics for methotrexate). 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 folinate or prolonged administration may be indicated.
Excessive disodium folinate doses must be avoided since this might impair the antitumour activity of methotrexate, especially in CNS tumours where disodium 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.
In the treatment of accidental overdose of folic acid antagonists, disodium folinate should be administered as promptly as possible. With increasing time interval between antifolate administration (e.g. methotrexate) and disodium folinate rescue the effectiveness of disodium folinate in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with disodium folinate.
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.
In the combination regimen with 5-fluorouracil, the toxicity profile of 5-fluorouracil may be enhanced or shifted by disodium folinate, particularly in elderly or debilitated patients. The most common manifestations are leukopenia, mucositis, stomatitis and/or diarrhoea which may be dose limiting. When disodium folinate 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. Toxicities observed in patients treated with the combination are qualitatively similar to those observed in patients treated with 5-fluorouracil 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 folinate, and supportive intravenous therapy. 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).
Combined 5-fluorouracil/disodium 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-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.
In elderly patients and patients who have undergone preliminary radiotherapy, it is recommended to begin with a reduced dose of 5-fluorouracil.
For vials with 2 ml, 4 ml:
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.
For vials with 6 ml:
This medicinal product contains 29.38 mg sodium per vial, equivalent to 1.47% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
For vials with 8 ml:
This medicinal product contains 39.18 mg sodium per vial, equivalent to 1.96% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
For vials with 10 ml:
This medicinal product contains 48.97 mg sodium per vial, equivalent to 2.45% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
For vials with 18 ml:
This medicinal product contains 88.15 mg sodium per vial, equivalent to 4.41% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
When disodium folinate is given in conjunction with a folic acid antagonist– (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may be either reduced or completely neutralised.
Concomitant administration of disodium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil.
The following side effects for disodium folinate used in conjunction with 5-fluorouracil were reported frequently: diarrhoea, dehydration, stomatitis and leukopenia. Less commonly infections, thrombocytopenia, nausea, vomiting, constipation, malaise, alopecia, dermatitis and anorexia have been observed.
Life-threatening diarrhoeas have been observed if 600 mg/m² of 5-fluorouracil (IV bolus once weekly) is given together with disodium folinate. When disodium folinate 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 folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoine, and succinimides, and may increase the frequency of seizures (decreased 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).
There are no adequate and well-controlled clinical studies conducted in pregnant or breast-feeding women. No formal animal reproductive toxicity studies with disodium folinate 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 or lactation, there are no limitations as to the use of disodium folinate 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 folinate with 5-fluorouracil (see section 4.3). Please refer also to the summaries of product characteristics for methotrexate-, other folate antagonists and 5-fluorouracil-containing medicinal products.
It is not known whether disodium folinate is excreted into human breast milk. Disodium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.
No information is available on the effects of folinic acid alone on fertility and general reproductive performance.
Disodium folinate 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.
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).
Very rare: Allergic reactions – sensitisation, including anaphylactoid reactions and urticaria
Rare: Insomnia, agitation and depression after high doses
Rare: Increase in the frequency of attacks in epileptics (see also section 4.5)
Rare: Gastrointestinal disorders after high doses
Uncommon: Fever has been observed after administration of disodium folinate as solution for injection.
Disodium folinate enhances the toxicity of 5-fluorouracil (see section 4.5). Generally, the safety profile depends on the applied regimen of 5-fluorouracil.
Very common: Bone marrow failure, including fatal cases
Not known: Hyperammonaemia
Common: Palmar-plantar erythrodysaesthesia
Very common: Mucositis, including stomatitis and cheilitis. Fatalities have occurred as a result of mucositis.
Very common: Vomiting and nausea
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Very common: Bone marrow failure, including fatal cases
Very common: Diarrhoea with higher grades of toxicity, and dehydration resulting in hospital admission for treatment and even death
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
