Disodium folinate parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Solution for injection containing folinic acid as disodium folinate.
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 to enhance the effect of fluorouracil in cytotoxic therapy.
To diminish toxicity and counteract the action of folic acid antagonists both in therapy and overdose ('folinate rescue') such as methotrexate.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
54.65 mg of disodium folinate is equivalent to 50 mg/ml of folinic acid.
Adults
Combination with 5-fluorouracil in cytotoxic therapy
Different dosage schedules are used as the optimum schedule has not been determined. Patients should be monitored and the fluorouracil should be adjusted according to the toxicity observed. (See Additional Dosage)
Weekly regime
Moderately high dose fluorouracil
500 mg/square metre of folinic acid (equivalent to 546.5 mg/square metre of disodium folinate) as an intravenous infusion over a period of 2 hours. An intravenous bolus of 600 mg/square metre of fluorouracil should be administered 1 hour after the start of disodium folinate administration.
One cycle of treatment consists of one dose per week for six weeks. This is followed by a rest interval of two weeks before the next cycle. The number of cycles needed will depend on the response of the tumour.
High dose fluorouracil
500 mg/square metre of folinic acid (546.5 mg/square metre of disodium folinate) as an intravenous infusion over a period of 1 to 2 hours. Subsequently 2.6 g/square metre of fluorouracil should be administered by continuous infusion over 24 hours.
One cycle of treatment consists of one dose per week for six weeks. This is followed by a rest interval of two weeks before the next cycle. The number of cycles needed will depend on the response of the tumour.
Monthly regime
Moderately high dosed disodium folinate
200 mg/square metre of folinic acid (218.6 mg/square metre of disodium folinate) once per day, followed by 370 mg/square metre of fluorouracil daily. Both disodium folinate and fluorouracil should be administered by intravenous bolus injection.
One cycle of treatment equals one dose per day for five days. The cycle should be repeated after 4 and 8 weeks and then every 5 weeks. The number of cycles needed will depend on the response of the tumour.
Low dose disodium folinate
20 mg/square metre of folinic acid (equivalent to 21.86 mg/square metre of disodium folinate) once per day, followed by 425 mg/square metre of fluorouracil once per day. Both disodium folinate and fluorouracil should be administered by intravenous bolus injection.
One cycle of treatment equals one dose per day for five days. The cycle should be repeated at 4 and 8 weeks and then every 5 weeks. The number of cycles needed will depend on the response of the tumour.
The fluorouracil dose should be increased by 10% in the absence of toxicity (especially the absence of significant bone marrow and non-haematological side-effects).
'Folinate rescue'
Treatment should commence 18 to 30 hours after the beginning of methotrexate infusion.
A dose of greater than or equal to 100 mg/square metre of methotrexate must always be followed by disodium folinate administration. Treatment may commence before the determination of methotrexate serum levels. The dosage should be adapted once methotrexate serum levels are known.
The doses below are recommendations on the methotrexate serum levels 24 to 30 hours after administration of methotrexate.
Methotrexate serum levels between 1.0 x 10 to the power of minus 8 mol/l and 1.5 x 10 to the power of minus 6 mol/l
10 to 15 mg/square metre of folinic acid (10.93 to 16.4 mg/square metre of disodium folinate) every 6 hours for 48 hours.
Methotrexate serum levels between 1.5 x 10 to the power of minus 6 mol/l and 5.0 x 10 to the power of minus 6 mol/l
30 mg/square metre of folinic acid (32.79 mg/square metre of disodium folinate) every 6 hours until methotrexate serum levels are less than 5 x 10 to the power of minus 8 mol/l.
Methotrexate serum level greater than 5.0 x 10 to the power of minus 6 mol/l
60 to 100 mg/square metre of folinic acid (65.58 to 109.3 mg/square metre of disodium folinate) every 6 hours until methotrexate serum levels are less than 5 x 10 to the power of minus 8 mol/l.
Rescue should end no sooner than 72 hours after methotrexate administration. Methotrexate serum levels should be less than 1 x 10 to the power of minus 7 mol/l, preferably below 1 x 10 to the power of minus 8 mol/l.
An over rescue may impair the efficacy of methotrexate. With inadequate rescue, considerable side effects are likely with high dosed methotrexate therapy.
Elderly
(See Dosage; Adult)
Children
Consult local treatment protocols for details.
Additional Dosage Information
Dose adjustments of fluorouracil in toxicities
Weekly regime
Moderately high dose fluorouracil
Gastrointestinal toxicity WHO greater than or equal to 1: Reduce dose to 500 mg/square metre. Resume treatment only when toxicity has completely resolved.
Bone marrow toxicity WHO greater than or equal to 1: Reduce dose to 500 mg/square metre. Resume treatment only when leukocytes are greater than 3 000 per microlitre and thrombocytes greater than 100 000 per microlitre.
High dose fluorouracil
Life-threatening cardiotoxicity: Terminate treatment.
Gastrointestinal toxicity WHO greater than or equal to 3: Reduce dose by 20%.
Bone marrow toxicity WHO greater than or equal to 1: Reduce dose by 20%. Resume treatment only when leukocytes greater than 3 000 per microlitre and thrombocytes greater than 100 000 per microlitre.
Monthly regime
WHO toxicity 0: Increase daily dose by 30 mg/square metre.
WHO toxicity 1: Daily dose unchanged.
WHO toxicity greater than or equal to 2: Reduce daily dose by 30 mg/square metre.
Administration
For intravenous injection (given undiluted) or diluted for infusion.
Contraindications
Gastrointestinal toxicity - if combined with 5-fluorouracil therapy
Pernicious anaemia
Severe diarrhoea - if combined with 5-fluorouracil therapy
Vitamin B12 deficiency
Precautions and Warnings
Ascites
Debilitation
Elderly
Breastfeeding
Dehydration
Epileptic disorder
Pregnancy
Renal impairment
Significant pleural effusion
Treatment to be prescribed under the supervision of a specialist
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 18 to 30 hours after methotrexate
Concurrent methotrexate: monitor serum methotrexate levels
Monitor adverse reactions, especially gastrointestinal toxicity
Monitor patients with epilepsy while taking this treatment
Advise patient to report diarrhoea and/or stomatitis immediately
Combined with fluorouracil: Discontinue if life threatening cardiotoxicity
Suspend treatment if gastrointestinal toxicity occurs
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, disodium folinate should be administered as soon as possible. Increasing time between overdose and administration of disodium folinate decreases the effectiveness of disodium folinate in counteracting the toxicity of the antagonist. Serum monitoring of the antagonist is essential in determining dosage and duration of disodium folinate 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 disodium folinate may be required.
Pregnancy and Lactation
Pregnancy
Folinic acid use with caution in pregnancy.
However, disodium folinate is contraindicated when used in combination with 5-fluorouracil during pregnancy.
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 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 disodium folinate for 'folinate rescue'.
Disodium folinate is a derivative of the active metabolite of folic acid. It is unknown if disodium folinate crosses the placenta but folic acid does cross the placental barrier. Whilst noting the inadequacy of the data available, Briggs 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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Folinic acid use with caution in breastfeeding.
However, disodium folinate is contraindicated when used in combination therapy with 5-fluorouracil during breastfeeding.
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 disodium folinate for 'folinate rescue'. Meanwhile, Briggs states that folinic acid is compatible with 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 https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Side Effects
Anaphylactoid reaction
Diarrhoea
Exacerbation of epilepsy
Gastro-intestinal toxicity
Hypersensitivity reactions
Leucopenia
Mucosal toxicity
Mucositis
Pyrexia
Stomatitis
Urticaria
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: December 2014
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 15 December, 2014.
Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications. Accessed on 15 December, 2014.
Summary of Product Characteristics: Sodiofolin 50 mg/ml solution for injection. Medac GmBH. Revised June 2014.
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