2.1 Important Use Information

KHAPZORY is indicated for intravenous administration only . Do not administer intrathecally.

2.2 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy

The recommended dosage for KHAPZORY is based on a methotrexate dose of 12 grams/m 2 administered as intravenous infusion over 4 hours in adult and pediatric patients. Twenty-four hours after starting the methotrexate infusion, initiate KHAPZORY at a dose of 7.5 mg (approximately 5 mg/m 2) as an intravenous infusion every 6 hours.

Monitor serum creatinine and methotrexate levels at least once daily. Continue KHAPZORY, 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 dose or extend the duration as recommended in Table 1.

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 are observed, in subsequent courses extend KHAPZORY 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 KHAPZORY or prolonged administration may be indicated.

2.3 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination

Start KHAPZORY in adult and pediatric patients 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 KHAPZORY increases, the effectiveness of KHAPZORY to diminish methotrexate toxicity may decrease. Administer KHAPZORY 7.5 mg (approximately 5 mg/m 2) as an 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 dose of KHAPZORY to 50 mg/m 2 intravenously every 3 hours until the methotrexate level is less than 5 x 10 -8 M for the following:

• if the 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 bicarbonate dose to maintain urine pH at 7 or greater.

2.4 Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer

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

• KHAPZORY at 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m 2, once daily for 5 consecutive days
• KHAPZORY at 10 mg/m 2 by intravenous injection, followed by fluorouracil at 425 mg/m 2, once daily for 5 consecutive days

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

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

2.5 Preparation

Reconstitute the 175 mg and 300 mg vial contents with 3.6 mL and 6.2 mL of 0.9% Sodium Chloride Injection, USP, respectively to obtain a clear, colorless to yellowish solution (resultant concentration 50 mg per mL levoleucovorin). Reconstitution with a sodium chloride solution with preservatives (e.g., benzyl alcohol) has not been studied. Do not store reconstituted solution for more than 12 hours at room temperature. Protect from light.

Dilute reconstituted solution immediately (if possible), 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 diluted reconstituted solution for more than 12 hours at room temperature. Protect from light.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

5.1 Increased Gastrointestinal Toxicities with Fluorouracil

Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions ( 7)] . Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l-leucovorin and fluorouracil. Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur.

5.2 Drug Interaction with Trimethoprim-Sulfamethoxazole

Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection increased treatment failure and morbidity.

6.1 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.

High-Dose Methotrexate Therapy

Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m 2 followed by levoleucovorin rescue, for osteosarcoma, in 16 patients, ages 6-21 years. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration.

Combination with Fluorouracil in Colorectal Cancer

Table 3 presents the frequency of adverse reactions which occurred in 2 arms of a randomized 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. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l-leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, then every 5 weeks until disease progression or unacceptable toxicity.

6.2 Postmarketing Experience

The following adverse reactions were identified during post approval use of levoleucovorin. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following have been reported:

• Respiratory: dyspnea
• Dermatologic: pruritus, rash
• Other Clinical Events: temperature change, rigors, allergic reactions

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 2-4% and 15-20%, 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 KHAPZORY 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 KHAPZORY 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 years and over to determine whether they respond differently from younger patients.

In the NCCTG clinical trial of levoleucovorin in combination with fluorouracil in the treatment of metastatic colorectal cancer, adverse reactions were consistent with fluorouracil related toxicity and were similar for patients age 65 years and older and patients younger than 65 [see Clinical Studies ( 14.2)] .

12.1 Mechanism of Action

High-dose methotrexate therapy

Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid (THF). Levoleucovorin does not require reduction by dihydrofolate reductase 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 then acts to stabilize the binding of FdUMP to thymidylate synthase, thereby enhancing the inhibition of thymidylate synthase.

12.3 Pharmacokinetics

Distribution

The pharmacokinetics of levoleucovorin after intravenous injection of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentration was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentration was 275 ng/mL (CV 18%) observed around 0.9 hours post injection.

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

A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m 2/day IV bolus) was administered in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l-leucovorin (500 mg/m 2 as a continuous IV infusion for 5.5 days, N=6).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

14.1 Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma

The efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients, ages 6-21 years, who received 58 courses of chemotherapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m 2 IV over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m 2 IV over 6 hours, followed by levoleucovorin 7.5 mg 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 adverse reaction profile [see Adverse Reactions ( 6.1)].

14.2 Metastatic Colorectal Cancer

In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with metastatic colorectal cancer comparing d,l‑leucovorin (LV) 200 mg/m 2 and fluorouracil 370 mg/m 2 versus LV 20 mg/m 2 and fluorouracil 425 mg/m 2 versus fluorouracil 500 mg/m 2, 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 LV 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 LV 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 Mayo/NCCTG randomized clinical study the fluorouracil alone arm was replaced by sequentially administered methotrexate (MTX), fluorouracil, and LV. Response rates with LV 200 mg/m 2 and fluorouracil 370 mg/m 2 versus LV 20 mg/m 2 and fluorouracil 425 mg/m 2 versus sequential MTX and fluorouracil and LV were 31% (p≤0.01), 42% (p≤0.01), and 14%, respectively. 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 between the treatment arms.

A randomized controlled trial conducted by the 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/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l-leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, then every 5 weeks until disease progression or unacceptable toxicity.