KHAPZORY — levoleucovorin disodium injection, powder, lyophilized, for solution
Acrotech Biopharma Inc


KHAPZORY is indicated for:

  • rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
  • diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination adult and pediatric patients.
  • The treatment of adults with metastatic colorectal cancer in combination with fluorouracil.

Limitations of Use

KHAPZORY is not indicated for pernicious anemia and megaloblastic anemia secondary to lack the of vitamin B12 because of the risk of progression of neurologic manifestations despite hematologic remission.


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/m2 administered as intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate KHAPZORY 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 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 KHAPZORY or extend the duration as recommended in Table 1.

Table 1 Recommended Dosage for KHAPZORY 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 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.

2.3 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. Administer KHAPZORY 7.5 mg (approximately 5 mg/m2) 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 dosage of KHAPZORY to 50 mg/m2 intravenously every 3 hours and continue KHAPZORY at this dosage 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 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
KHAPZORY at 10 mg/m2 by intravenous injection, followed by fluorouracil at 425 mg/m2 ,by intravenous injection once daily for 5 consecutive days

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 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 the diluted reconstituted solution for more than 12 hours at room temperature. Protect from light.

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


For Injection: 175 mg and 300 mg of levoleucovorin as a sterile, white to yellowish lyophilized powder in a single-dose vial for reconstitution.


KHAPZORY is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid, or folinic acid [see Adverse Reactions (6.2)].


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.

Monitor patients for gastrointestinal toxicities. 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.

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