NDC 68152-114 Khapzory

Levoleucovorin

NDC Product Code 68152-114

NDC 68152-114-01

Package Description: 1 VIAL in 1 CARTON > 6 mL in 1 VIAL

NDC Product Information

Khapzory with NDC 68152-114 is a a human prescription drug product labeled by Spectrum Pharmaceuticals, Inc.. The generic name of Khapzory is levoleucovorin. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Spectrum Pharmaceuticals, Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Khapzory Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LEVOLEUCOVORIN DISODIUM 300 mg/6mL

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Folate Analog - [EPC] (Established Pharmacologic Class)
  • Folic Acid - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Spectrum Pharmaceuticals, Inc.
Labeler Code: 68152
FDA Application Number: NDA211226 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-02-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Khapzory Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

  • KHAPZORY is indicated for: •rescue after high-dose methotrexate therapy in patients with osteosarcoma. •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 UseKHAPZORY 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.

2.1 Important Use Information

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

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 LevelsClinical SituationLaboratory FindingsRecommendationNormal methotrexate eliminationSerum 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 eliminationSerum 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 injuryThese 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 has resolved.Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR100% 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.Impaired Methotrexate Elimination or Renal ImpairmentDecreased 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 EliminationAccumulation 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.

  • 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 10-6 M •if the methotrexate level at 48-hours is greater than 9 x 10-7 MContinue 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/m2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m2, once daily for 5 consecutive days •KHAPZORY at 10 mg/m2 by intravenous injection, followed by fluorouracil at 425 mg/m2, once daily for 5 consecutive daysThis 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.

3 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 reconstitution.

4 Contraindications

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. 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 Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labeling: •Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions (5.1)] •Drug-interaction with trimethoprim-sulfamethoxazole [see Warnings and Precautions (5.2)]

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 TherapyTable 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m2 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.Table 2 Adverse Reactions with High-Dose Methotrexate TherapyAdverse ReactionLevoleucovorinn=16(%)All GradesGrade 3-4GastrointestinalStomatitis386Vomiting380Nausea190Diarrhea60Dyspepsia60Typhlitis66RespiratoryDyspnea60Skin and AppendagesDermatitis60OtherConfusion60Neuropathy60Renal function abnormal60Taste perversion60Combination with Fluorouracil in Colorectal CancerTable 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/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, then every 5 weeks until disease progression or unacceptable toxicity.Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either ArmAdverse ReactionLevoleucovorin/fluorouracil n=318(%)d,l-Leucovorin/fluorouracil n=307(%)Grade 1-4Grade 3-4Grade 1-4Grade 3-4Gastrointestinal DisordersStomatitis 7212 7214Diarrhea 70 19 6517Nausea 62 8 61 8Vomiting 40 5 37 6Abdominal PainIncludes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 14 3 19 3General DisordersAsthenia/Fatigue/Malaise 29 5 32 11Metabolism and NutritionAnorexia/Decreased Appetite 24 4 25 2Skin DisordersDermatitis 29 1 28 1Alopecia 26 0.3 28 1

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

7 Drug Interactions

Effect of leucovorin products on fluorouracilLeucovorin products increase the toxicity of fluorouracil [see Warnings and Precautions (5.1)].

8.1 Pregnancy

Risk SummaryThere 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 SummaryThere 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)].

11 Description

  • KHAPZORY is a folate analog and the pharmacologically active levo-isomer of d,l-leucovorin. The chemical name is (2S)-2-[[4-[[(6S)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6- yl] methylamino] benzoyl] amino] pentanedioate. The molecular formula is C20H23N7O7 and the molecular weight is 473.45. The chemical structure is: •Levoleucovorin is a slightly hygroscopic, crystalline, yellow powder which is soluble in water when pH is at or above 8.KHAPZORY 175 mg is a sterile lyophilized powder consisting of 175 mg levoleucovorin, 29.6 mg sodium hydroxide, and 105 mg mannitol in each vial. Additional sodium hydroxide and/or hydrochloric acid may be used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 3.6 mL of sterile 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)].KHAPZORY 300 mg is a sterile lyophilized powder consisting of 300 mg levoleucovorin, 50.7 mg sodium hydroxide, and 180 mg mannitol in each vial. Additional sodium hydroxide and/or hydrochloric acid may be used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 6.2 mL of sterile 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)].

12.1 Mechanism Of Action

High-dose methotrexate therapyLevoleucovorin 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 CancerLevoleucovorin 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

DistributionThe 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.EliminationThe 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 StudiesA 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/m2/day IV bolus) was administered in combination with levoleucovorin (250 mg/m2 and 1000 mg/m2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l-leucovorin (500 mg/m2 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/m2 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/m2 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/m2 and fluorouracil 370 mg/m2 versus LV 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 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/m2 and fluorouracil 370 mg/m2 versus LV 20 mg/m2 and fluorouracil 425 mg/m2 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/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, then every 5 weeks until disease progression or unacceptable toxicity.

16 How Supplied/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 92618KHAPZORY is a trademark of Spectrum Pharmaceuticals, Inc.

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