Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom
Calcium levofolinate is used to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy. This procedure is known as Calcium Levofolinate Rescue.
Calcium levofolinate increases the thymine depleting effects of 5-FU resulting in enhanced cytotoxic activity. Combination regimens of 5-fluorouracil and levofolinate give greater efficacy compared to 5-FU given alone.
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 7.5 mg (approximately 5 mg/m²) every 6 hours for 10 doses by intramuscular injection, bolus intravenous injection or intravenous infusion, (see section below, 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 160 mg 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:
These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1 μM).
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 10 μM at 24 hours after administration, 1 μM at 48 hours and less than 0.2 μM at 72 hours. | 7.5 mg 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 0.2 μM at 72 hours, and more than 0.05 μM at 96 hours after administration. | Continue 7.5 mg IM or IV every 6 hours, until methotrexate level is less than 0.05 μM. |
| Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury | Serum methotrexate level of 50 μM or more at 24 hours or 5 μM or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration. | 75 mg IV every 3 hours, until methotrexate level is less than 1 μM; then 7.5 mg IV every 3 hours until methotrexate level is less than 0.05 μM. |
Administration: The 175 mg in 17.5 ml 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 175 mg contains 0.7 mEq (0.35 mmol) of calcium per vial and it is recommended that the solution is administered over not less than 3 minutes.
For intravenous infusion, the 175 mg in 17.5 ml 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 100 mg/m² by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370 mg/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 section 4.4).
There are no data available on the use of this combination in children.
For single use only.
There have been no reported sequelae in patients who have received significantly more calcium levofolinate than the recommended dosage. However, excessive amounts of calcium levofolinate may nullify the chemotherapeutic effect of folic acid antagonists.
Should overdose of the combination of 5-FU with calcium levofolinate occur, the overdose instructions for 5-FU should be followed.
2 years.
Store and transport refrigerated (2°C–8°C).
Keep vial in the outer carton in order to protect from light.
Type I amber glass vials each containing the equivalent of 25 mg, 50 mg or 175 mg of calcium levofolinate in 2.5 ml, 5 ml or 17.5 ml of solution respectively. Isovorin Solution for Injection is packed in boxes of 1 vial.
Not all pack sizes may be marketed.
For intravenous infusion, the 175 mg in 17.5 ml 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.
When Isovorin Solution for Injection is diluted with the recommended infusion fluids, the resulting solutions are intended for immediate use but may be stored for up to 24 hours under refrigerated conditions (2-8°C). Because of the risk of degradation, reconstituted solutions should be protected from light prior to use if necessary.
Prior to administration, calcium levofolinate should be inspected visually. The solution for injection or infusion should be a clear and yellowish solution. If cloudy in appearance, or if particles are observed, the solution should be discarded. Calcium levofolinate solution for injection or infusion is intended only for single use.
Any unused product or waste material should be disposed of in accordance with local requirements.
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