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Drug Details

LEUCOVORIN

• Drug Class Description
  Folic acid derivatives.
• Generic Name
  Folinic acid [calcium folinate/ calcium leucovorin] - anaemia
• Presentation
  Solution for Injection or Infusion Clear, yellow solution
• Description
  Each vial of 35 ml solution contains 10 mg/ml of folinic acid provided as calcium folinate
• 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.
• Adult Dosage
  

  For intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg of calcium folinate should be injected per minute due to the calcium content of the solution.

  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 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

  Calcium folinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and should be considered with doses of 100 mg – 500 mg/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 15 mg (6-12 mg/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>0.5 µmol/l, calcium folinate dosages should be adapted according to the following table:

  Residual methotrexate blood level 48 hours after the start of the methotrexate administration:	Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:
  > 0.5 µmol/l	15 mg/m²
  > 1.0 µmol/l	100 mg/m²
  > 2.0 µmol/l	200 mg/m²

  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 200 mg/m² by intravenous infusion over two hours, followed by bolus 400 mg/m² of 5-FU and 22-hour infusion of 5-FU (600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.

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

  Monthly regimen: Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/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, trimethoprime, 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 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.

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

  Trimethoprime toxicity:

  · After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

  Pyrimethamine toxicity:

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

• Child Dosage
  Up to 12 years, 0.25mg/kg per day.
• Contra Indications
  

  Known hypersensitivity to calcium folinate, or to any of the excipients.

  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, and the summaries of product characteristics for methotrexate- and 5-fluorouracil- containing medicinal products.

• Special Precautions
  12 Pregnancy and lactation.
• Interactions
  

  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, phenytoine 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).

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

• Adverse Drug Reactions
  

  Both therapeutic indications:

  Immune system disorders

  Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and urticaria.

  Psychiatric disorders

  Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

  Nervous system disorders

  Rare (0.01-0.1%): increase in the frequency of attacks in epileptics.

  Gastrointestinal disorders

  Rare (0.01-0.1%): gastrointestinal disorders after high doses.

  General disorders and administration site conditions

  Uncommon (0.1-1%): fever has been observed 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:

  General disorders and administration site conditions

  Unknown frequency: Mucositis, including stomatitis and cheilitis

  Monthly regimen:

  Gastrointestinal disorders

  Very common (>10%): vomiting and nausea

  General disorders and administration site conditions

  Very common (>10%): (severe) mucosal toxicity.

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

  Weekly regimen:

  Gastrointestinal disorders

  Very common (>10%): diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.