Khapzory

Name: Khapzory

Indications

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 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.

Side effects

The following serious adverse reactions are described elsewhere in the labeling:

  • Increased gastrointestinal toxicities with fluorouracil [see WARNINGS AND PRECAUTIONS]
  • Drug-interaction with trimethoprim-sulfamethoxazole [see WARNINGS AND PRECAUTIONS]

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/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 Therapy

Adverse Reaction Levoleucovorin
n=16 (%)
All Grades Grade 3-4
Gastrointestinal
Stomatitis 38 6
Vomiting 38 0
Nausea 19 0
Diarrhea 6 0
Dyspepsia 6 0
Typhlitis 6 6
Respiratory
Dyspnea 6 0
Skin and Appendages
Dermatitis 6 0
Other
Confusion 6 0
Neuropathy 6 0
Renal function abnormal 6 0
Taste perversion 6 0

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/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 Arm

Adverse Reaction Levoleucovorin/ fluorouracil
n=318 (%)
dl-Leucovorin/ fluorouracil
n=307 (%)
Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Gastrointestinal Disorders
Stomatitis 72 12 72 14
Diarrhea 70 19 65 17
Nausea 62 8 61 8
Vomiting 40 5 37 6
Abdominal Pain* 14 3 19 3
General Disorders
Asthenia/Fatigue/Malaise 29 5 32 11
Metabolism and Nutrition
Anorexia/Decreased Appetite 24 4 25 2
Skin Disorders
Dermatitis 29 1 28 1
Alopecia 26 0.3 28 1
*Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

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

Warnings

Included as part of the PRECAUTIONS section.

Overdose

No Information provided

Clinical pharmacology

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.

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/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).

Clinical Studies

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].

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.

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