Drugs List

Therapeutic Indications

Uses

Cytotoxic therapy in combination with 5-fluorouracil
Neutralisation of immediate toxic effects of folic acid antagonists

In combination with fluorouracil in cytotoxic therapy.

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

Dosage

Due to the complexity and specialist nature of dosage regimens for this agent, specific dosing information is not included.
Doses may vary significantly if this agent is used as monotherapy or different combinations.
When using this agent, specialist literature, national guidelines, cancer network protocols and Trust chemotherapy protocols should be consulted.

Administration

For intravenous injection or infusion only.

Contraindications

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

Precautions and Warnings

Ascites
Debilitation
Elderly
Recent radiotherapy
Breastfeeding
Dehydration
Epileptic disorder
Pregnancy
Renal impairment
Significant pleural effusion

May mask pernicious anaemia or vitamin B12 deficiency
Not for monotherapy in pernicious anaemia or vitamin B12 deficiency
Not suitable for treatment of cytotoxic induced macrocytosis
Methotrexate overdose: administer as soon as possible
Consult local policy on the safe use of anti-cancer drugs
Folinic acid rescue: ensure adequate hydration and alkalinisation of urine
Folinic acid rescue: Initiate 12 to 24 hours after methotrexate
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Concurrent methotrexate: monitor serum methotrexate levels
Folinic acid rescue: Monitor BUN and creatinine on days 2,3 and 4
Monitor adverse reactions, especially gastrointestinal toxicity
Monitor patients with epilepsy while taking this treatment
Monitor toxicity - discontinue or modify dose if necessary
Advise patient to report diarrhoea and/or stomatitis immediately
Suspend treatment if gastrointestinal toxicity occurs
Combination myelosuppressive drug therapy may necessitate dose adjustment

An increase in the frequency of epileptic seizures has been reported in patients treated with phenobarbital, phenytoin, primidone and succinimides when levofolinic acid is administered. This is likely due to a decrease in the plasma concentrations of anti-epileptic medicines. Therefore, patients with epileptic disorders should be treated with caution.

In the treatment of folic acid antagonist overdose, levofolinic acid should be administered as soon as possible. Increasing time between overdose and administration of levofolinic acid decreases its effectiveness in counteracting the toxicity of the antagonist. Serum monitoring of the antagonist is essential in determining dosage and duration of levofolinic acid treatment.

Antagonist excretion may be delayed by third space fluid accumulation, renal insufficiency, non-steroidal anti-inflammatory drugs or salicylate drugs. In these cases, higher doses and prolonged treatment with levofolinic acid may be required.

Measures to ensure the prompt excretion of methotrexate, such as maintenance of high urine output and alkalinisation of urine, should be carried out in conjunction with levofolinic acid administration.

Pregnancy and Lactation

Pregnancy

Use levofolinic acid with caution during pregnancy.

The manufacturer states that the use of levofolinic acid itself may be permissible during pregnancy, and that there are no limitations on the use of levofolinic acid to counteract the effects of folate antagonists.

As levofolinic acid is normally given in combination with or to counteract other drugs, the effect of these drugs during pregnancy must also be evaluated.

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use levofolinic acid with caution in breastfeeding.

The manufacturer states that the use of levofolinic acid alone may be used in breastfeeding. It is not clear whether levofolinic acid is excreted in breast milk.

As levofolinic acid is normally given in combination with or to counteract other drugs, the effect of these drugs on breastfeeding must also be evaluated.

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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Agitation
Anaphylactoid reaction
Dehydration
Depression
Diarrhoea
Exacerbation of epilepsy
Gastro-intestinal toxicity
Hypersensitivity reactions
Mucosal toxicity
Nausea
Pyrexia
Sleep disturbances
Urticaria
Vomiting

Presentation

Parenteral formulations of levofolinic acid.

Drugs List

Therapeutic Indications

Uses

Cytotoxic therapy in combination with 5-fluorouracil
Neutralisation of immediate toxic effects of folic acid antagonists

In combination with fluorouracil in cytotoxic therapy.

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

Dosage

Due to the complexity and specialist nature of dosage regimens for this agent, specific dosing information is not included.
Doses may vary significantly if this agent is used as monotherapy or different combinations.
When using this agent, specialist literature, national guidelines, cancer network protocols and Trust chemotherapy protocols should be consulted.

Administration

For intravenous injection or infusion only.

Contraindications

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

Precautions and Warnings

Ascites
Debilitation
Elderly
Recent radiotherapy
Breastfeeding
Dehydration
Epileptic disorder
Pregnancy
Renal impairment
Significant pleural effusion

May mask pernicious anaemia or vitamin B12 deficiency
Not for monotherapy in pernicious anaemia or vitamin B12 deficiency
Not suitable for treatment of cytotoxic induced macrocytosis
Methotrexate overdose: administer as soon as possible
Consult local policy on the safe use of anti-cancer drugs
Folinic acid rescue: ensure adequate hydration and alkalinisation of urine
Folinic acid rescue: Initiate 12 to 24 hours after methotrexate
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Concurrent methotrexate: monitor serum methotrexate levels
Folinic acid rescue: Monitor BUN and creatinine on days 2,3 and 4
Monitor adverse reactions, especially gastrointestinal toxicity
Monitor patients with epilepsy while taking this treatment
Monitor toxicity - discontinue or modify dose if necessary
Advise patient to report diarrhoea and/or stomatitis immediately
Suspend treatment if gastrointestinal toxicity occurs
Combination myelosuppressive drug therapy may necessitate dose adjustment

An increase in the frequency of epileptic seizures has been reported in patients treated with phenobarbital, phenytoin, primidone and succinimides when levofolinic acid is administered. This is likely due to a decrease in the plasma concentrations of anti-epileptic medicines. Therefore, patients with epileptic disorders should be treated with caution.

In the treatment of folic acid antagonist overdose, levofolinic acid should be administered as soon as possible. Increasing time between overdose and administration of levofolinic acid decreases its effectiveness in counteracting the toxicity of the antagonist. Serum monitoring of the antagonist is essential in determining dosage and duration of levofolinic acid treatment.

Antagonist excretion may be delayed by third space fluid accumulation, renal insufficiency, non-steroidal anti-inflammatory drugs or salicylate drugs. In these cases, higher doses and prolonged treatment with levofolinic acid may be required.

Measures to ensure the prompt excretion of methotrexate, such as maintenance of high urine output and alkalinisation of urine, should be carried out in conjunction with levofolinic acid administration.

Pregnancy and Lactation

Pregnancy

Use levofolinic acid with caution during pregnancy.

The manufacturer states that the use of levofolinic acid itself may be permissible during pregnancy, and that there are no limitations on the use of levofolinic acid to counteract the effects of folate antagonists.

As levofolinic acid is normally given in combination with or to counteract other drugs, the effect of these drugs during pregnancy must also be evaluated.

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Use levofolinic acid with caution in breastfeeding.

The manufacturer states that the use of levofolinic acid alone may be used in breastfeeding. It is not clear whether levofolinic acid is excreted in breast milk.

As levofolinic acid is normally given in combination with or to counteract other drugs, the effect of these drugs on breastfeeding must also be evaluated.

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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Agitation
Anaphylactoid reaction
Dehydration
Depression
Diarrhoea
Exacerbation of epilepsy
Gastro-intestinal toxicity
Hypersensitivity reactions
Mucosal toxicity
Nausea
Pyrexia
Sleep disturbances
Urticaria
Vomiting

Overdosage

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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: November 2018

Reference Sources

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 14 November 2018

Summary of Product Characteristics: Levofolinic acid 50mg/ml solution for injection. Medac GmBH. Revised March 2016.