8 USE IN SPECIFIC POPULATIONS

8.1 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 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production.

Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.

8.4 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 [see Clinical Studies (14.1)].

The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

8.5 Geriatric Use

Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients.

In the NCCTG clinical trial of levoleucovorin in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

High-Dose Methotrexate Therapy

Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

Combination with Fluorouracil in Colorectal Cancer

Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'- deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase.

12.3 Pharmacokinetics

The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1,722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection.

Distribution

Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.

Elimination

The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate.

Drug Interaction Studies

The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m2/day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m2 and 1,000 mg/m2 as a continuous intravenous infusion for 5.5 days) or with d,l-leucovorin (500 mg/m2 as a continuous intravenous infusion for 5.5 days).

14 CLINICAL STUDIES

14.1 Rescue after High-Dose Methotrexate Therapy in Patients with

Osteosarcoma

The efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 grams/m2 as an intravenous infusion over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg by intravenous infusion every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 grams/m2 intravenously over 6 hours, followed by levoleucovorin 7.5 mg by intravenous infusion every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high-dose methotrexate was based on the adverse reaction profile [See Adverse Reactions (6.1)].

14.2 Metastatic Colorectal Cancer

In a randomized clinical study conducted by Mayo Clinic and North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l-leucovorin 200 mg/m2 and fluorouracil 370 mg/m2 versus d,l-leucovorin 20 mg/m2 and fluorouracil 425 mg/m2 versus fluorouracil 500 mg/m2, with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone) and 10%, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose d,l-leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l-leucovorin regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.

In a second randomized clinical study conducted by Mayo Clinic and NCCTG, the fluorouracil alone arm was replaced by a regimen of sequentially administered methotrexate , fluorouracil, and d,l-leucovorin. Response rates with d,l-leucovorin 200 mg/m2 and fluorouracil 370 mg/m2 versus d,l-leucovorin 20 mg/m2 and fluorouracil 425 mg/m2 versus sequential methotrexate and fluorouracil and d,l-leucovorin were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.

A randomized controlled trial conducted by NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l-leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m2 intravenously and d,l-leucovorin 200 mg/m2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.

2 DOSAGE AND ADMINISTRATION

2.1 Important Use Information

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

2.2 Co-administration of Levoleucovorin for Injection with other agents

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

2.3 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy

The recommended dosage for levoleucovorin for injection is based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate levoleucovorin for injection at a dose of 7.5 mg (approximately 5 mg/m2) as an intravenous infusion every 6 hours.

Monitor serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin for injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Adjust the levoleucovorin for injection dose or extend the duration as recommended in Table 1.

Table 1: Recommended Dosage forLevoleucovorin for Injection based on Serum Methotrexate and Creatinine Levels

Clinical Situation	Laboratory Findings	Recommendation
Normal Methotrexate Elimination	Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.	Administer 7.5 mg by intravenous infusion 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 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.	Continue 7.5 mg by intravenous infusion every 6 hours until methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury*	Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration. OR 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).	Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar.
These patients are likely to develop reversible renal failure. In addition to appropriate levoleucovorin for injection therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

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 for 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 for injection or prolonged administration may be indicated.

2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired

Methotrexate Elimination

Start levoleucovorin for 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 increases, the effectiveness of levoleucovorin to diminish methotrexate toxicity may decrease. Administer levoleucovorin for injection 7.5 mg (approximately 5 mg/m2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10-8 M (0.05 micromolar).

Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin for injection to 50 mg/m2 intravenously every 3 hours and continue levoleucovorin for injection at this dosage until the methotrexate level is less than 5 x 10-8 M for the following:

• if serum creatinine at 24-hours increases 50% or more compared to baseline
• if the methotrexate level at 24-hours is greater than 5 x 10-6 M
• if the methotrexate level at 48-hours is greater than 9 x 10-7 M,

Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater.

2.5 Dosage in Combination with Fluorouracil for Metastatic Colorectal

Cancer

The following regimens have been used for the treatment of colorectal cancer:

• Levoleucovorin for injection 100 mg/m2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m2 by intravenous injection, once daily for 5 consecutive days.
• Levoleucovorin for injection 10 mg/m2 by intravenous injection, followed by fluorouracil 425 mg/m2 by intravenous injection, once daily for 5 consecutive days.

Administer fluorouracil and levoleucovorin for injection separately to avoid the formation of a precipitate.

This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from the toxicity from the prior course. Do not adjust levoleucovorin for injection dosage for toxicity.

Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions.

2.6 Preparation for Administration

Levoleucovorin for Injection

• Prior to intravenous injection, reconstitute the 50 mg vial of levoleucovorin for Injection with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g., benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended.
• The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Discard unused portion.
• Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not store the reconstituted product or reconstituted product diluted using 0.9% Sodium Chloride Injection, USP for more than 12 hours at room temperature. Do not store reconstituted product diluted using 5% Dextrose Injection, USP for more than 4 hours at room temperature.
• Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. Do not use if cloudiness or precipitate is observed.
• Do not intravenously inject more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) per minute, because of the calcium content of the levoleucovorin solution.