| For single use only. 4.2.1 Calcium Levofolinate Rescue Adults, Children and the Elderly: Calcium Levofolinate Rescue therapy should commence 24 hours after the beginning of methotrexate infusion. Dosage regimes vary depending upon the dose of methotrexate administered. In general, the calcium levofolinate should be administered at a dose of 7.5mg (approximately 5mg/m2) every 6 hours for 10 doses by intramuscular injection, bolus intravenous injection or intravenous infusion, (refer to 4.2.2 for information concerning use of calcium levofolinate with infusion fluids). Do not administer calcium levofolinate intrathecally.Where overdose of methotrexate is suspected, the dose of calcium levofolinate should be at least 50% of the offending dose of methotrexate and should be administered in the first hour. In the case of intravenous administration, no more than 160mg of calcium levofolinate should be injected per minute due to the calcium content of the solution.In addition to calcium levofolinate administration, measures to ensure the prompt excretion of methotrexate are important as part of Calcium Levofolinate Rescue therapy. These measures include: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 (0.1μM).Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of calcium levofolinate or prolonged administration may be indicated. Dosage and administration guidelines for these patients are given in Table 1. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.TABLE 1: Dosage and Administration Guidelines for Calcium Levofolinate Rescue Clinical Situation | Laboratory Findings | Levofolinate Dosage and Duration | Normal Methotrexate Elimination | Serum methotrexate level approximately 10μM at 24 hours after administration, 1μM at 48 hours and less than 0.2μM at 72 hours. | 7.5mg IM or IV every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). | Delayed Late Methotrexate Elimination | Serum methotrexate level remaining above 0.2μM at 72 hours, and more than 0.05μM at 96 hours after administration. | Continue 7.5mg IM or IV every 6 hours, until methotrexate level is less than 0.05μM. | Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury | Serum methotrexate level of 50μM or more at 24 hours or 5μM or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration. | 75mg IV every 3 hours, until methotrexate level is less than 1μM; then 7.5mg IV every 3 hours until methotrexate level is less than 0.05μM. |
4.2.2 Colorectal Cancer: Enhancement of 5-FU Cytotoxicity Adults and the Elderly: Administration: The 175mg in 17.5ml vial of Calcium Levofolinate Solution for Injection should be used to administer the high doses of calcium levofolinate required in combination regimens. When used in combination regimens with 5-FU, calcium levofolinate should only be given by the intravenous route. The agents should not be mixed together. Each vial of calcium levofolinate 175mg contains 0.7mEq (0.35mmol) of calcium per vial and it is recommended that the solution is administered over not less than 3 minutes.For intravenous infusion, the 175mg in 17.5ml Solution for Injection may be diluted with any of the following infusion fluids before use: Sodium Chloride 0.9%; Glucose 5%; Glucose 10%; Glucose 10% and Sodium Chloride 0.9% Injection; Compound Sodium Lactate Injection.Calcium levofolinate should not be mixed together with 5-FU in the same infusion and, because of the risk of degradation, the giving set should be protected from light.Dosage: Based on the available clinical evidence, the following regimen is effective in advanced colorectal carcinoma:Calcium levofolinate given at a dose of 100mg/m2 by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370mg/m2 by intravenous injection. The injection of levofolinate should not be given more rapidly than over 3 minutes because of the calcium content of the solution. This treatment is repeated daily for 5 consecutive days. Subsequent courses may be given after a treatment-free interval of 21-28 days.For the above regimen, modification of the 5-FU dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity. A reduction of calcium levofolinate dosage is not required. The number of repeat cycles used is at the discretion of the clinician. On the basis of the available data, no specific dosage modifications are recommended in the use of the combination regimen with 5-FU in the elderly. However, particular care should be taken when treating elderly or debilitated patients as these patients are at increased risk of severe toxicity with this therapy (See 'Warnings and Precautions'). Children: There are no data available on the use of this combination in children. | |