Baseline studies indicated; see Monitor. See Maternal/Child.
Levoleucovorin, when substituted for leucovorin calcium, is dosed at one-half the usual dose of the racemic form (leucovorin calcium).
Levoleucovorin rescue after high-dose methotrexate therapy:
Dose is based on a methotrexate dose of 12 Gm/M2 infused over 4 hours; see methotrexate monograph. Obtain serum creatinine and methotrexate levels at least once daily. Additional hydration and urinary alkalinization (pH 7 or greater) are indicated and should be continued until the methotrexate level is less than 0.05 micromolar. Twenty-four hours after starting the methotrexate infusion, initiate levoleucovorin rescue at a dose of 7.5 mg (approximately 5 mg/M2) as an IV infusion every 6 hours. Administer and/or adjust the levoleucovorin dose or extend rescue based on the following guidelines. See Dose Adjustments, Precautions, and Monitor.
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Treatment of folic acid antagonist overdose or impaired methotrexate elimination:
7.5 mg as an IV infusion every 6 hours (approximately 5 mg/M2) until the serum methotrexate level is less than 5 × 10–8 M (0.05 micromolar). Begin levoleucovorin rescue in adult and pediatric patients as soon as possible after an overdose of methotrexate or within 24 hours of methotrexate administration when there is impaired methotrexate elimination. The effectiveness of levoleucovorin in diminishing toxicity may decrease as the time interval between methotrexate administration and levoleucovorin rescue increases. See Dose Adjustments and Monitor.
Several regimens are in use. See fluorouracil (5-FU) monograph for 5-FU specific information. Administer 5-FU and levoleucovorin separately to avoid the formation of a precipitate.
Flush the IV line with NS between drugs.
Levoleucovorin 100 mg/M2 by IV injection over a minimum of 3 minutes (see Rate of Administration) followed by 5-FU 370 mg/M2 by IV injection or levoleucovorin 10 mg/M2 by IV injection followed by 5-FU at 425 mg/M2 by IV injection. Repeat either regimen daily for 5 days. This 5-day course is repeated at 4-week intervals for 2 courses and then at 4- to 5-week intervals provided that complete recovery from the toxic effects of the previous course has occurred. See Dose Adjustments.
See Usual Dose.
Levoleucovorin rescue after high-dose methotrexate therapy:
Decreased methotrexate elimination or renal impairment, which are clinically important but less severe than abnormalities described in the preceding chart, can occur after methotrexate administration. These abnormalities may or may not be associated with significant clinical toxicity. If toxicity is observed, extend levoleucovorin rescue for an additional 24 hours (a total of 14 doses over 84 hours) in subsequent courses. If lab abnormalities or clinical toxicities are observed, consider the possibility that the patient is taking other medications that interact with methotrexate (e.g., medications that may interfere with methotrexate elimination or binding to serum albumin [see methotrexate monograph]). ■ Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), inadequate hydration, or renal insufficiency can cause delayed methotrexate elimination. Higher doses of levoleucovorin or prolonged administration may be indicated.
Treatment of folic acid antagonist overdose or impaired methotrexate elimination:
Monitor serum creatinine and methotrexate levels at least every 24 hours. If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 × 10–6 M or the 48-hour level is greater than 9 × 10–7 M, increase the dose of levoleucovorin to 50 mg/M2 as an IV infusion every 3 hours until the methotrexate level is less than 10–8 M (0.01 micromolar). Hydrate with a minimum of 3 liters/day and use sodium bicarbonate for urinary alkalinization (adjust to maintain a urine pH of 7 or greater).
In subsequent courses, adjust the dose of 5-FU based on patient tolerance of the previous treatment course. Reduce 5-FU dose by 20% for patients who experienced moderate hematologic or GI toxicity in the previous course and 30% for patients who experienced severe toxicity. 5-FU dose may be increased by 10% if no toxicity was experienced in the previous course. Levoleucovorin doses are not adjusted for toxicity.
Available in a single-dose vial containing 50 mg of a lyophilized powder. Reconstitute each 50-mg vial with 5.3 mL of preservative-free NS (concentration equals 10 mg/mL). Do not use other diluents. A single dose may be further diluted immediately in NS or D5W to a concentration of 0.5 to 5 mg/mL.
Levoleucovorin for injection (generic):
Multiple manufacturers and strengths; consult individual prescribing information. Available in a single-dose vial containing 50 mg or 175 mg of a lyophilized powder. Reconstitute each 50-mg vial with 5.3 mL (175 mg with 17.7 mL) of preservative-free NS (concentration equals 10 mg/mL). Dilute immediately to a concentration of 0.5 to 5 mg/mL in NS or D5W. Also available as a solution in single-use vials containing 175 mg (17.5 mL) or 250 mg (25 mL). Concentration equals 10 mg/mL. A single dose may be further diluted to a concentration of 0.5 mg/mL in NS or D5W.
Available as a solution in single-use vials containing 175 mg (17.5 mL) or 250 mg (25 mL). Concentration equals 10 mg/mL. A single dose may be further diluted to a concentration of 0.5 mg/mL in NS or D5W.
Available in single-dose vials containing 175 mg or 300 mg of a lyophilized powder. Reconstitute each 175-mg vial with 3.6 mL (300-mg vial with 6.2 mL) of preservative-free NS. Concentration equals 50 mg/mL. Do not use other diluents. A single dose may be further diluted immediately in NS or D5W to a concentration of 0.5 to 5 mg/mL.
Do not use if solution is cloudy or if a precipitate is observed.
Specific information not available.
Consult individual product instructions in the package insert. Some formulations can be stored at CRT protected from light; others require refrigeration also protected from light. All formulations may be further diluted in NS or D5W protected from light, but storage times at RT differ.
Manufacturer states, “Due to the risk of precipitation, do not coadminister levoleucovorin with other agents in the same admixture.” Dilute only with preservative-free NS; do not use other diluents or NS with preservatives.
Because of the calcium content of the solution, do not exceed a rate of administration of 16 mL/min of reconstituted solution (160 mg of levoleucovorin). When given in combination with 5-FU, flush the IV line with NS between drugs.
A folate analog and the pharmacologically active levo-isomer of d,l-leucovorin. A replacement for leucovorin calcium, which also contains the pharmacologically inactive dextro isomer. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase. Levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Also enhances the activity and toxicity of fluorouracil by stabilizing the binding of FdUMP (a fluorouracil metabolite) to thymidylate synthase (an enzyme important in DNA repair and replication), resulting in inhibition of this enzyme. Actively and passively transported across cell membranes. Terminal half-life is from 5.1 to 6.8 hours.
Rescue after high-dose methotrexate therapy in patients with osteosarcoma. ■ To diminish the toxicity associated with overdosage of folic acid antagonists (e.g., methotrexate, pemetrexed) or impaired methotrexate elimination. ■ Palliative treatment of patients with advanced metastatic colorectal cancer in combination with 5-fluorouracil.
Not indicated for the treatment of pernicious anemia or megaloblastic anemias secondary to vitamin B12 deficiency because of the risk of progression of neurologic manifestations despite hematologic remission.
Contraindicated in patients who have had severe hypersensitivity reactions to leucovorin products, folic acid, or folinic acid.
For IV use only; do not administer by any other route. ■ Contains calcium; limit rate of administration to no more than 16 mL/min (160 mg of levoleucovorin per minute). ■ Levoleucovorin enhances the toxicities of fluorouracil. Although toxicities during combination use with 5-fluorouracil (5-FU) are similar to those observed with 5-FU alone, GI toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe or of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of GI toxicity until those symptoms have resolved. ■ Seizures and/or syncope have been reported, usually in association with fluoropyrimidine administration and most commonly in patients with CNS metastases or other predisposing factors. ■ See Drug/Lab Interactions.
All situations with methotrexate:
Obtain baseline serum creatinine, electrolytes, and urine pH. Monitor SCr and methotrexate levels at least daily. ■ Adequate hydration and maintenance of a urinary pH of 7 or greater with sodium bicarbonate are indicated.
Levoleucovorin rescue after high-dose methotrexate therapy:
Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. Continuing hydration and urinary alkalinization and monitoring of fluid and electrolyte status are required until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.
Inadvertent methotrexate overdose:
See Dose Adjustments; hydration with a minimum of 3 liters/day and the use of sodium bicarbonate for urinary alkalinization (adjust to maintain a urine pH of 7 or greater) may be indicated.
Monitor for S/S of GI toxicity. Monitor patients with diarrhea until it has resolved, because rapid deterioration leading to death can occur. See the 5-fluorouracil monograph for hematologic monitoring requirements.
Use during pregnancy only if clearly needed. Levoleucovorin is administered in combination with methotrexate and fluorouracil, which can cause embryo-fetal harm. ■ Not known if levoleucovorin is excreted in human milk; has potential for harmful effects; discontinue breast-feeding. Levoleucovorin is administered in combination with methotrexate and fluorouracil. ■ Safety and effectiveness for use in pediatric patients have been established for rescue after high-dose methotrexate therapy in osteosarcoma and in diminishing toxicity associated with overdose of folic acid antagonists or impaired methotrexate elimination. Safety and effectiveness have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer; see literature.
Studies of levoleucovorin in the treatment of osteosarcoma did not include adults age 65 or older. ■ Deaths from severe dehydration, diarrhea, and severe enterocolitis have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
May ameliorate the hematologic toxicity associated with high-dose methotrexate, but levoleucovorin has no effect on other established toxicities of methotrexate, such as nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. ■ Folic acid in large amounts may counteract the antiepileptic effects of phenobarbital, phenytoin, and primidone. Seizure activity may be increased in susceptible patients. Levoleucovorin may or may not have the same effect due to shared metabolic pathways; use caution when administering concurrently with anticonvulsant drugs. ■ Leucovorin products increase the toxicities of fluorouracil; see Precautions. ■ Concomitant use with sulfamethoxazole/trimethoprim for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection may cause treatment failure and morbidity. ■ Small amounts of systemically administered levoleucovorin may enter the cerebrospinal fluid (CSF). High doses of levoleucovorin may reduce the effectiveness of intrathecally administered methotrexate.■ Levoleucovorin may enhance the toxic effects of capecitabine; monitor closely.
Nausea and vomiting and stomatitis were reported most commonly. Abnormal renal function, confusion, dermatitis, diarrhea, dyspepsia, dyspnea, hypersensitivity reactions, neuropathy, taste perversion, and typhlitis (inflammation of the cecum) have been reported. Serious side effects reported include hypercalcemia and increased GI toxicities in combination with fluorouracil.
Combination therapy with 5-fluorouracil (5-FU):
Abdominal pain, alopecia, anorexia, dermatitis, diarrhea, fatigue, nausea, stomatitis, vomiting. Hypersensitivity reactions have been reported.
Dyspnea, pruritus, rash, rigors, temperature change.