Levofolinic acid (calcium levofolinate)

NO MAXIMUM DOSE IS STATED. The fetched section 4.2 contains no 'maximum' cue for levofolinic acid in either indication, so maxDose is deliberately left empty rather than inferred from the largest regimen figure. WHEN RESCUE IS INDICATED: 'Disodium levofolinate 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. Dose and duration of disodium levofolinate rescue primarily depend on the type and dose of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate.' ESCALATION BY 48-HOUR RESIDUAL METHOTREXATE LEVEL (verbatim table; 'Additional levofolinic acid to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 micromol/l'): residual methotrexate at or above 0.5 micromol/l - 7.5 mg/m2; at or above 1.0 micromol/l - 50 mg/m2; at or above 2.0 micromol/l - 100 mg/m2. 'Delayed methotrexate excretion may be seen in some patients... Under such circumstances, higher doses of disodium levofolinate or prolonged administration may be indicated.' COMBINATION WITH 5-FLUOROURACIL. The SPC stresses 'Different regimes and different doses are used, without any dose having been proven to be the optimal one' and that combined use 'is reserved for physicians experienced in the combination of folinates with 5-fluorouracil in cytotoxic therapy'. The example regimens given for adults and elderly in advanced or metastatic colorectal cancer are, verbatim: BIMONTHLY - '100 mg/m2 levofolinic acid (= 109.3 mg/m2 disodium levofolinate) by intravenous infusion over two hours, followed by bolus 400 mg/m2 of 5-fluorouracil and 22-hour infusion of 5-fluorouracil (600 mg/m2) for 2 consecutive days, every 2 weeks on days l and 2.' WEEKLY - '10 mg/m2 levofolinic acid (= 10.93 mg/m2 disodium levofolinate) by bolus i.v. injection or 100 to 250 mg/m2 levofolinic acid (= 109.3 mg/m2 to 273.25 mg/m2 disodium levofolinate) 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 disodium levofolinate infusion.' MONTHLY - '10 mg/m2 levofolinic acid (= 10.93 mg/m2 disodium levofolinate) by bolus i.v. injection or 100 to 250 mg/m2 levofolinic acid (= 109.3 mg/m2 to 273.25 mg/m2 disodium levofolinate) 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 5 consecutive days.' These 5-FU regimens are body-surface-area based and protocol-driven and are recorded here rather than in the dose field because the page's lead indication is methotrexate rescue. 'For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dose 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 disodium levofolinate dose is not required. The number of repeat cycles used is at the discretion of the clinician.' 'Disodium levofolinate can be safely mixed with 5-fluorouracil in a single infusion bag or pump without the risk of precipitation and catheter occlusion.' SUPPORTIVE MEASURES REQUIRED ALONGSIDE RESCUE (verbatim): 'a. Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites). b. Maintenance of urine output of 1800 - 2000 cc/m2/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy. c. Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4. These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1 microM).'

NOT WEIGHT-BASED, so dosePerKg is null. The SPC gives no separate paediatric dose for methotrexate rescue; it presents one regimen for all ages - 'The following guidelines may serve as an illustration of regimens used in adults, elderly and children' - and that regimen is a flat 7.5 mg first dose with a body-surface-area equivalent of 3-6 mg/m2, with all escalation expressed per m2 (7.5 / 50 / 100 mg/m2 by 48-hour residual methotrexate level). A per-kg figure therefore cannot be derived from this source. For the other indication the SPC is explicit: 'Paediatric population No data on the use of these combinations are available' (5-fluorouracil combination). Concentration 50 mg/ml is the levofolinic acid strength pinned by the product name 'Levofolinic acid 50 mg/ml Solution for injection or infusion'. Verify all paediatric dosing against a children's formulary and against the applied intermediate- or high-dose methotrexate protocol, which the SPC says 'will dictate the dose regimen', before prescribing.