KHAPZORY is indicated for:
- rescue after high-dose methotrexate therapy in patients
- diminishing the toxicity associated with overdosage of
folic acid antagonists or impaired methotrexate elimination.
- the treatment of patients with metastatic colorectal
cancer in combination with fluorouracil.
Limitations Of Use
KHAPZORY is not indicated for the treatment of pernicious
anemia and megaloblastic anemia secondary to lack of vitamin B12 because of the
risk of progression of neurologic manifestations despite hematologic remission.
DOSAGE AND ADMINISTRATION
Important Use Information
KHAPZORY is indicated for intravenous administration only.
Do not administer intrathecally.
Recommended Dosage For Rescue After High-Dose
The recommended dosage for KHAPZORY is based on a
methotrexate dose of 12 grams/m² 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/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 or extend the duration as recommended in Table 1.
Table 1 : Recommended Dosage for KHAPZORY based on
Serum Methotrexate and Creatinine Levels
|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,
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, continuing hydration and
urinary alkalinization, and monitoring of fluid and electrolyte status, until
the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure
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
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 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/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 dose of KHAPZORY to 50 mg/m² 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
- if the methotrexate level at 48-hours is greater than 9 x
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.
Dosage In Combination With Fluorouracil For Metastatic
The following regimens have been used for the treatment
of colorectal cancer:
- KHAPZORY at 100 mg/m² by intravenous injection over a
minimum of 3 minutes, followed by fluorouracil at 370 mg/m², once daily for 5
- KHAPZORY at 10 mg/m² by intravenous injection, followed
by fluorouracil at 425 mg/m², 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.
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.
Dosage Forms And Strengths
For Injection: 175 mg and 300 mg of levoleucovorin as a
sterile, white to yellowish lyophilized powder in a single-dose vial for
Storage And Handling
KHAPZORY (levoleucovorin) for injection is a sterile,
preservative-free, white to yellowish lyophilized powder in a single-dose vial.
It is available as:
175 mg vial - NDC 68152-112-01.
300 mg vial - NDC 68152-114-01.
Store at 20°C to 25°C (68°F to 77°F); excursions
permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room
Temperature]. Store vial in original carton until contents are used.
Protect solutions from light.
Distributed by: Spectrum Pharmaceuticals, Inc., Irvine,
CA 92618. Revised: Oct 2018