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Calcium levofolinate parenteral


Solution for injection containing calcium levofolinate

Drugs List

  • calcium levofolinate 175mg/17.5ml injection
  • calcium levofolinate 25mg/2.5ml injection
  • ISOVORIN 175mg/17.5ml injection (solution)
  • ISOVORIN 25mg/2.5ml injection (solution)
  • Therapeutic Indications


    Adjunct to 5-fluorouracil in advanced colorectal cancer
    Neutralisation of immediate toxic effects of folic acid antagonists

    In combination with 5-fluorouracil to enhance the cytotoxic effect of 5-fluorouracil in therapy of advanced or metastatic colorectal carcinomas.

    To diminish toxicity and counteract the action of folic acid antagonists ('folinate rescue') such as methotrexate.

    Treatment of suspected methotrexate overdosage.


    The following doses are recommended by the manufacturer. However, local cancer network protocols should also be consulted.


    Treatment of advanced or metastatic colorectal carcinomas

    Different dosage schedules are used as the optimum schedule has not been determined. Patients should be monitored and the dosage adjusted according to response.

    The recommended dosage is 100 mg/square metre of calcium levofolinate over a period of at least 3 minutes, followed by 370 mg/square metre of 5-fluorouracil by intravenous injection. The recommended dosage should be administered daily for 5 consecutive days. If further treatment is required the dosage can be repeated after a treatment free period of 21 to 28 days. The number of repeat administrations should be determined by the patient's response. Modification of the 5-fluorouracil dosage may be necessary depending on the patient condition, clinical response and dose limiting toxicity. A reduction of the calcium levofolinate dosage is not required.

    'Folinate rescue'

    Treatment should commence 24 hours after the beginning of the methotrexate infusion.

    In general, 7.5 mg (approximately 5 mg/square metre) of calcium levofolinate should be administered every 6 hours for a total of 10 injections. The injection can be by intramuscular, intravenous bolus or intravenous infusion. In addition, steps should be taken to ensure prompt excretion of the methotrexate (see Dosage; Additional).

    The following can be used as a guide to adjusting the dose based upon serum methotrexate levels:

    Normal methotrexate elimination
    (serum methotrexate level approximately 10 micromolar after 24 hours, 1 micromolar after 48 hours and less than 0.2 micromolar at 72 hours)

    7.5 mg of calcium levofolinate by intramuscular or intravenous injection every 6 hours for 60 hours (10 doses starting 24 hours after methotrexate infusion).

    Delayed late methotrexate elimination
    (serum methotrexate level remaining above 0.2 micromolar at 72 hours and more than 0.05 micromolar at 96 hours after methotrexate administration)

    Continue 7.5 mg of calcium levofolinate by intravenous injection or intramuscular injection every 6 hours until methotrexate level is less than 0.05 micromolar.

    Delayed early methotrexate elimination and/or acute renal injury
    (serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours or a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration)

    75 mg intravenously every 3 hours until methotrexate level is less than 1 micromolar, then 7.5 mg intravenously every 3 hours until methotrexate level is less than 0.05 micromolar.

    An over-rescue may impair the efficacy of methotrexate. With inadequate rescue, considerable side effects are likely with high-dose methotrexate therapy.

    Suspected methotrexate overdosage

    If overdose of methotrexate is suspected, calcium levofolinate should be administered within one hour of methotrexate at an initial dose of at least 50% of the dose of methotrexate.


    (see Dosage; Adult)


    Treatment of advanced or metastatic colorectal carcinomas

    At the time of writing there was insufficient data available regarding the use of calcium levofolinate for this patient population.

    'Folinate rescue'

    (see Dosage; Adults)

    Suspected methotrexate overdosage

    If overdose of methotrexate is suspected, calcium levofolinate should be administered within one hour of methotrexate at an initial dose of 50% of the dose of methotrexate.

    Additional Dosage Information

    Measures to insure the prompt excretion of methotrexate in folinate rescue therapy include:
    Alkalinisation of urine to pH 7.0 or greater before methotrexate infusion (to increase solubility in urine)
    Maintenance of high urine output of 1800 to 2000 ml/square metre/24 hr by increased oral or intravenous fluids on days 2, 3 and 4.

    Plasma methotrexate concentration, blood urea nitrogen and creatinine should be measured on days 2, 3 and 4. These measures must be continued until the plasma methotrexate level is less than 0.1 micromolar.


    For intravenous injection or infusion. Intramuscular route only licensed for the prevention of methotrexate-induced adverse effects ('folinate rescue').

    Calcium levofolinate should be administered at a rate not exceeding 160 mg/min.

    Administration by other routes may be fatal


    Gastrointestinal toxicity - if combined with 5-fluorouracil therapy
    Severe diarrhoea - if combined with 5-fluorouracil therapy

    Precautions and Warnings

    Recent radiotherapy
    Epileptic disorder
    Renal impairment

    May mask pernicious anaemia or vitamin B12 deficiency
    Not suitable for treatment of cytotoxic induced macrocytosis
    Folinic acid rescue: administer 24 hrs after start of methotrexate infusion
    Methotrexate overdose: administer as soon as possible
    Folinic acid rescue: ensure adequate hydration and alkalinisation of urine
    Treatment to be administered by or under supervision of specialist
    Concurrent methotrexate: monitor serum methotrexate levels
    Monitor adverse reactions, especially gastrointestinal toxicity
    Monitor toxicity - discontinue or modify dose if necessary
    Advise patient to report diarrhoea and/or stomatitis immediately
    Interrupt or reduce dose if significant gastrointestinal disturbances occur
    Combination myelosuppressive drug therapy may necessitate dose adjustment

    In rare cases, an increase in the frequency of epileptic seizures (due to the reduced effect of phenytoin, primidone and phenobarbital) has been reported. Therefore, patients with epileptic disorders should be treated with caution.

    In the treatment of folic acid antagonist overdose, calcium levofolinate should be administered as soon as possible. Increasing time between overdose and administration of calcium levofolinate, decreases the effectiveness of calcium levofolinate in counteracting the toxicity of the antagonist. Serum monitoring of the antagonist is essential in determining dosage and duration of calcium levofolinate treatment. Antagonist excretion may be delayed by third space fluid accumulation, renal insufficiency, inadequate hydration, non steroidal anti-inflammatory drugs or salicylate drugs. In these cases, higher doses and prolonged treatment with calcium levofolinate may be required.

    When abnormal laboratory test results or clinical toxicities are observed consider the possibility that drugs which the patient is taking concurrently are interacting with this medication.

    Avoid excessive calcium levofolinate doses as this medication may impair the anti-tumour activity of methotrexate. This should especially be observed in CNS tumours as calcium levofolinate accumulates here after repeated doses.

    Resistance to methotrexate as a result of decreased membrane transport also implies resistance to folinic acid rescue as both medicinal products share the same transport system.

    Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. 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.

    Pregnancy and Lactation


    Calcium levofolinate is contraindicated in pregnancy when used in combination therapy with 5-fluorouracil. Consult the 5-fluorouracil monograph for pregnancy specific information.

    Although no evidence of harm to the foetus has been demonstrated in rat and rabbit studies, there are currently no adequate and well-controlled studies in pregnant women. Methotrexate is normally contraindicated in pregnancy but if an informed decision has been made to prescribe it or another folic acid antagonist despite pregnancy, there are no limitations on the use of calcium levofolinate for 'folinate rescue'. Consult the monograph of the relevant folic acid antagonist for further pregnancy-specific information.

    Calcium levofolinate is a derivative of the active metabolite of folic acid. It is unknown if calcium levofolinate crosses the placenta but folic acid does cross the placental barrier. Whilst noting the inadequacy of the data available, Briggs (2011) considers that folinic acid is compatible for use in pregnancy if the potential risk justifies its use.

    The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( ) or if this is unavailable at the backup site ( ).


    Calcium levofolinate is contraindicated during breastfeeding when used in combination therapy with 5-fluorouracil. Consult the 5-fluorouracil monograph for lactation specific information.

    There are currently no adequate or well-controlled studies in breastfeeding women but if a folic acid antagonist is clearly indicated despite breastfeeding, there are no limitations on the use of calcium levofolinate for 'folinate rescue'. The monograph for the relevant folic acid antagonist should be consulted. Meanwhile, Briggs (2011) states that folinic acid is compatible with breastfeeding.

    It is unknown if calcium levofolinate is excreted into breast milk so use with caution during breastfeeding.

    Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
    Specialist advice is available from the UK Drugs in Lactation Advisory Service at

    Side Effects

    Anaphylactic shock
    Anaphylactoid reaction
    Exacerbation of epilepsy
    Gastro-intestinal toxicity
    Hypersensitivity reactions
    Mucosal toxicity
    Palmar-plantar erythrodysaesthesia
    Stevens-Johnson syndrome
    Toxic epidermal necrolysis


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: December 2013

    Reference Sources

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

    Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press Accessed on: December 4, 2013.

    Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications Accessed on: December 4, 2013.

    Summary of Product Characteristics: Isovorin. Pfizer Ltd. Revised August 2011.

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