Khapzory Drug Information

Important Use Information KHAPZORY is indicated for intravenous administration only. Do not administer intrathecally. KHAPZORY consists of levoleucovorin in the form of a disodium salt, which makes it compatible with fluorouracil.

This allows KHAPZORY and fluorouracil to be combined in the same infusion bag for intravenous administration without catheter occlusion or precipitation for up to 72 hours at 20°C to 25°C (68°F to 77°F).

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. 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 micromolar.

Adjust the dose KHAPZORY or extend the duration as recommended in Table 1. Table 1 Recommended Dosage for KHAPZORY based on Serum Methotrexate and Creatinine Levels *These patients are likely to develop reversible renal failure. In addition to appropriate KHAPZORY therapy, continue hydration and urinary alkalinization, and monitoring 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 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.

Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start KHAPZORY 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. Monitor serum creatinine and methotrexate levels at least every 24 hours.

Do not adjust KHAPZORY dosage for toxicity. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear, colorless to slight yellow and free of visible particles.

Discard the reconstituted solution with visible particulate matter or discoloration. If not used immediately, store the reconstituted solution for up to 12 hours at room temperature at 20°C to 25°C (68°F to 77°F). Protect from light.

Dilution Withdraw the required volume of the reconstituted solution from the vial and dilute with 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP to a final concentration of 0.5 mg/mL to 5 mg/mL. Discard any unused portion remaining in the single-dose vial(s). Protect from light.

Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

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 reactions 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 2 *Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of levoleucovorin products. 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: • Dermatologic: pruritus, rash • Respiratory: dyspnea • Other Clinical Events: 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 Khapzory 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 or 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.

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