Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: medac, Gesellschaft für klinische, Spezialpräparate mbH, Theaterstr. 6, 22880 Wedel, Germany
Disodium folinate is indicated:
Note:
Persistently high serum methotrexate levels may also be expected in low-dose methotrexate therapy particularly in pleural effusions, ascites, renal insufficiency and inadequate fluid intake during methotrexate therapy.
The combined use of disodium folinate and 5-fluorouracil is reserved for physicians experienced in the combination of folinates with 5-fluorouracil in cytotoxic therapy.
Different regimes and different doses are used, without any dose having been proven to be the optimal one.
The following regimes have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples.
500 mg/m² folinic acid (= 546.5 mg/m² disodium folinate) as IV infusion over a period of 2 hours plus 600 mg/m² 5-fluorouracil as IV bolus injection 1 hour after the start of the disodium folinate infusion.
Repeat once a week for a total of 6 weeks (= 1 cycle).
Repeat the cycle after a 2-week treatment interval. The number of cycles will depend on the response of the tumour.
Dose adjustment of 5-fluorouracil:
The 5-fluorouracil dose should be adjusted in accordance with the toxicity observed:
Gastrointestinal toxicity WHO ≥ 1:
Reduction to 500 mg/m².
Resumption of therapy only when findings have completely returned to normal.
Bone marrow toxicity WHO ≥ 1:
Reduction to 500 mg/m².
Resumption of therapy only when the findings are as follows:
Leukocytes >3,000/µl
Thrombocytes >100,000/µl
500 mg/m² folinic acid (= 546.5 mg/m² disodium folinate) as IV infusion over a period of 1-2 hours and subsequently 2,600 mg/m² 5-fluorouracil by continuous infusion over 24 hours.
Repeat once a week for a total of 6 weeks (= 1 cycle).
Repeat the cycle after a 2-week treatment interval. The number of cycles will depend on the response of the tumour.
Dose adjustment of 5-fluorouracil:
The 5-fluorouracil dose should be adjusted in accordance with the toxicity observed:
Life-threatening cardiotoxicity: Termination of therapy
Bone marrow toxicity WHO ≥ 3:
Reduction by 20%
Resumption of therapy only when the findings are as follows:
Leukocytes >3,000/µl
Thrombocytes >100,000/µl
Gastrointestinal toxicity WHO ≥ 3: Reduction by 20%
200 mg/m² folinic acid (= 218.6 mg/m² disodium folinate) daily, followed by 370 mg/m² 5-fluorouracil daily, both given as IV bolus injection. Repeat on 5 successive days (= 1 cycle).
Repeat the cycle after 4 weeks, 8 weeks and every 5 weeks after that. The number of cycles will depend on the response of the tumour.
Dose adjustment of 5-fluorouracil:
The dose of 5-fluorouracil should be adjusted in each subsequent cycle in accordance with the toxicity (WHO) observed, as follows:
WHO toxicity 0: Increase daily dose by 30 mg/m²
WHO toxicity 1: Daily dose unchanged
WHO toxicity ≥2: Reduce daily dose by 30 mg/m²
20 mg/m² folinic acid (= 21.86 mg/m² disodium folinate) daily, followed by 425 mg/m² 5-fluorouracil daily, both given as IV bolus injection. Repeat on 5 successive days (= 1 cycle).
Repeat the cycle after 4 weeks, 8 weeks and every 5 weeks after that. The number of cycles will depend on the response of the tumour.
Dose adjustment of 5-fluorouracil:
In the absence of toxicity (especially if no significant bone marrow toxicity and no non-haematological side-effects occur in the interval) it is recommended to increase the dose of 5-fluorouracil by 10 % in each case.
No data on the use of these combinations are available.
Only physicians experienced in the use of high-dose methotrexate therapy should use prophylactic disodium folinate.
The prophylactic use of disodium folinate with methotrexate may start as mentioned below, without waiting for results of methotrexate serum level monitoring, and then posology may be further adapted according to results of methotrexate serum levels when available.
The use of a dose of methotrexate at ≥ 100 mg/m² (body surface) must be followed by the administration of disodium folinate. There are no uniform recommendations for the dose and mode of use of disodium folinate as an antidote in high-dose methotrexate therapy. The following dose recommendations are therefore given as examples:
Disodium folinate rescue following the intravenous administration of methotrexate (MTX):
| MTX serum levels 24-30 hours after administration of MTX | Disodium folinate dose (mg/m² body surface) calculated as folinic acid and dose interval (hours) | Duration of treatment |
| 1.0 × 10-8 mol/l -1.5 × 10-6 mol/l | 10 to 15 mg/m² every 6 hours | 48 hours |
| 1.5 × 10-6 mol/l -5.0 × 10-6 mol/l | 30 mg/m² every 6 hours | up to MTX serum level <5 × 10-8 mol/l |
| >5.0 × 10-6 mol/l | 60 to 100 mg/m² every 6 hours | up to MTX serum level <5 × 10-8 mol/l |
Not later than 18 to 30 hours after the start of methotrexate intravenous administration.
72 hours after the start of methotrexate intravenous administration at the earliest. On completion of the rescue, the methotrexate level should be below 10-7 mol/l, preferably below 10-8 mol/l.
An “over-rescue” may impair the efficacy of methotrexate. With inadequate rescue, considerable toxic side-effects are likely with high-dosed methotrexate therapy.
Sodiofolin is for intravenous use only, either undiluted by injection or by infusion after dilution.
For instructions on dilution of the medicinal product before administration, see section 6.6.
There have been no reported sequelae in patients who have received significantly more disodium folinate than the recommended dose.
When using methotrexate, an overdose of disodium folinate may result in a decrease of efficacy of methotrexate (“over-rescue”).
Should overdose of the combination of 5-fluorouracil and disodium folinate occur, the overdose instructions for 5-fluorouracil should be followed.
3 years.
After dilution (see section 6.6): 72 hours.
After mixing with 5-fluorouracil or dilution with sodium chloride 9 mg/ml (0.9%) solution for injection (see section 6.6): Chemical and physical in use stability has been demonstrated for 72 hours at 20°C-25°C.
From a microbiological point of view the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C–8°C unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C–8°C). Keep the container in the outer carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
Colourless glass vials type 1 of 5, 10 or 20 ml.
Closure: bromobutyl rubber stopper with aluminium flip-off cap as seal.
Vials with 2 ml, 4 ml, 6 ml, 8 ml, 10 ml or 18 ml solution for injection/infusion.
Packs containing 1 vial or 5 vials. Not all pack sizes may be marketed.
Sodiofolin is administered intravenously, either undiluted by injection or by infusion after dilution. Preparation of solution for infusion must take place in aseptic conditions. The solution for injection/infusion may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection.
Sodiofolin is compatible with 5-fluorouracil.
Only clear solutions without visible particles should be used.
For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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