Levoleucovorin Calcium Drug Information

Important Use Information

Levoleucovorin injection is indicated for intravenous administration only. Do not administer intrathecally.

Co-administration of Levoleucovorin Injection with other agents Due to the risk of precipitation, do not co-administer levoleucovorin injection with other agents in the same admixture.

Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for levoleucovorin injection is based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Monitor serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below micromolar.

Adjust the levoleucovorin injection dose or extend the duration as recommended in Table 1. Table 1: Recommended Dosage for Levoleucovorin Injection based on Serum Methotrexate and Creatinine Levels Impaired Methotrexate Elimination or Renal Impairment Decreased methotrexate elimination or renal impairment which are clinically important but less severe than the abnormalities described in Table 1 can occur following methotrexate administration. If toxicity associated with methotrexate is observed, in subsequent courses extend levoleucovorin injection rescue for an additional 24 hours (total of 14 doses over 84 hours).

Third-Space Fluid Collection and Other Causes of Delayed Methotrexate Elimination Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration can delay methotrexate elimination. Under such circumstances, higher doses of levoleucovorin injection or prolonged administration may be indicated.

Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Monitor serum creatinine and methotrexate levels at least every 24 hours.

Administer fluorouracil and levoleucovorin injection separately to avoid the formation of a precipitate. Do not adjust levoleucovorin injection dosage for toxicity. Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions.

Preparation for Administration Levoleucovorin Injection

Levoleucovorin injection contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Discard unused portion.

Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not store the product diluted using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP for more than 4 hours at room temperature. Visually inspect the diluted solution for particulate matter and discoloration prior to administration.

Do not use if cloudiness or precipitate is observed. Inject no more than 16 mL of levoleucovorin Injection (160 mg of levoleucovorin) intravenously per minute, because of the calcium content of the levoleucovorin solution.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Table 2: 6 0 Combination with Fluorouracil in Colorectal Cancer Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l -leucovorin.

Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. Table 3: Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm

Postmarketing Experience

The following adverse reaction have been identified during postapproval use of levoleucovorin products. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: pruritus, rash Respiratory: dyspnea Other: temperature change, rigors, allergic reactions

Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs.

Fluorouracil Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur.

Trimethoprim-Sulfamethoxazole The concomitant use of d,l -leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.

Pregnancy Risk Summary There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm.

Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Pediatric Use The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature. The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

Levoleucovorin injection is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid.