LEVOLEUCOVORIN (Page 4 of 4)

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.

13.2 Animal Pharmacology and/or Toxicology

The acute intravenous LD50 values in adult mice and rats were 575 mg/kg (1725 mg/m2) and 378 mg/kg (2268 mg/m2), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m2 for high-dose methotrexate therapy which represents a 3-log safety margin.

14 CLINICAL STUDIES

14.1 High-Dose Methotrexate Therapy

The safety and efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients age 6 to 21 who received 58 courses of therapy 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 the adverse reaction profile. [See Adverse Reactions (6)]

14.2 Combination with 5-FU in Colorectal Cancer

In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer, three treatment regimens were compared: d,l-leucovorin (LV) 200 mg/m2 and 5-fluorouracil (5-FU) 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus 5-FU 500 mg/m2. All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups, 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 gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave 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 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m2 and 5-FU 370 mg/m2 versus LV 20 mg/m2 and 5-FU 425 mg/m2 versus sequential MTX and 5-FU and LV were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.

A randomized controlled trial conducted by the NCCTG in patients with advanced metastatic colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l-leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 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, and then every 5 weeks until disease progression or unacceptable toxicity.

Levoleucovorin is dosed at one-half the usual dose of racemic d,l-leucovorin.

16 HOW SUPPLIED/STORAGE AND HANDLING

Levoleucovorin Injection, 175 mg contains 17.5 mL sterile clear pale yellow color solution in a single-dose vial.

Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

175 mg/17.5 mL solution – NDC 16714-890-01

Levoleucovorin Injection, 250 mg contains 25 mL sterile clear pale yellow color solution in a single-dose vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride.

250 mg/25 mL solution – NDC 16714-915-01

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used.

Trademarks are the property of their respective owners.

Manufactured for: Northstar Rx LLC

Memphis, TN 38141.

Manufactured by: GLAND PHARMA LIMITED

Pashamylaram,

Hyderabad-502 307, INDIA.

Issued: 0918

175 mg/17.5 mL -Vial

175vial
(click image for full-size original)

Unvarnished Area Consists of: 2D Barcode, Lot Number, Expiry Date and Serial Number

175carton
(click image for full-size original)

250 mg/25 mL- Vial

250vial
(click image for full-size original)

Unvarnished Area Consists of: 2D Barcode, Lot Number, Expiry Date and Serial Number

250carton
(click image for full-size original)

LEVOLEUCOVORIN
levoleucovorin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16714-890
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Levoleucovorin Calcium (Levoleucovorin) Levoleucovorin 175 mg in 17.5 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Hydroxide
Sodium Chloride
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:16714-890-01 1 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 17.5 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (16714-890-01)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA210892 09/26/2018
LEVOLEUCOVORIN
levoleucovorin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16714-915
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Levoleucovorin Calcium (Levoleucovorin) Levoleucovorin 250 mg in 25 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Hydroxide
Sodium Chloride
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:16714-915-01 1 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 25 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (16714-915-01)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA210892 09/26/2018
Labeler — NorthStar RxLLC (830546433)
Establishment
Name Address ID/FEI Operations
GLAND PHARMA LIMITED 918601238 analysis (16714-890), manufacture (16714-890), analysis (16714-915), manufacture (16714-915)

Revised: 12/2017 NorthStar RxLLC

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