Leucovorin Calcium: Package Insert and Label Information (Page 2 of 2)

Geriatric Use

Clinical studies of leucovorin calcium did not show differences in safety or effectiveness between subjects over 65 and younger subjects. Other clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be excreted by the kidney and the risk of toxic reactions to the drug may be greater in patients with impaired renal function. Because elder patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

ADVERSE REACTIONS

Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. No other adverse reactions have been attributed to the use of leucovorin per se.

The following table summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.

PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY

	(High LV) /5-FU (N = 155)		(Low LV) /5-FU (N = 161)		5-FU Alone (N = 70)
	Any	Grade 3+	Any	Grade 3+	Any	Grade 3+
	(%)	(%)	(%)	(%)	(%)	(%)
High LV = Leucovorin 200 mg/m2
Low LV = Leucovorin 20 mg/m2
Any = percentage of patients reporting toxicity of any severity
Grade 3+ = percentage of patients reporting toxicity of grade 3 or higher
Leukopenia	69	14	83	23	93	48
Thrombocytopenia	8	2	8	1	18	3
Infection	8	1	3	1	7	2
Nausea	74	10	80	9	60	6
Vomiting	46	8	44	9	40	7
Diarrhea	66	18	67	14	43	11
Stomatitis	75	27	84	29	59	16
Constipation	3	0	4	0	1	—
Lethargy/Malaise/Fatigue	13	3	12	2	6	3
Alopecia	42	5	43	6	37	7
Dermatitis	21	2	25	1	13	—
Anorexia	14	1	22	4	14	—
Hospitalization for Toxicity	5%		15%		7%

To report SUSPECTED ADVERSE EVENTS, contact Teva Pharmaceuticals USA, Inc., at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ medwatch for voluntary reporting of adverse reactions.

OVERDOSAGE

Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

DOSAGE AND ADMINISTRATION

Advanced Colorectal Cancer

Either of the following two regimens is recommended:

1. Leucovorin is administered at 200 mg/m² by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m² by intravenous injection.
2. Leucovorin is administered at 20 mg/m² by intravenous injection followed by 5-fluorouracil at 425 mg/m² by intravenous injection.

5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28 day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests). For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosages may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

Leucovorin Rescue After High-Dose Methotrexate Therapy

The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m² administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).

Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalinization (pH of 7 or greater) should be continued until the methotrexate level is below 5 × 10^-8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

Clinical Situation	Laboratory Findings	Leucovorin Dosage and Duration
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.	15 mg PO, IM, or IV q 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 15 mg PO, IM, or IV q 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; a 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).	150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage

Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS). Leucovorin 10 mg/m² should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10^-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 × 10^-6 M or the 48 hour level is greater than 9 × 10^-7 M, the dose of leucovorin should be increased to 100 mg/m² IV every 3 hours until the methotrexate level is less than 10^-8 M.

Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7 or greater.

Megaloblastic Anemia Due to Folic Acid Deficiency

Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

Each 100 mg vial of leucovorin calcium for injection when reconstituted with 10 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 350 mg vial of leucovorin calcium for injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg leucovorin per mL. Leucovorin calcium for injection contains no preservative. Reconstitute the lyophilized vial products with bacteriostatic water for injection, USP, (benzyl alcohol preserved), or sterile water for injection, USP. When reconstituted with bacteriostatic water for injection, USP, the resulting solution must be used within 7 days. If the product is reconstituted with sterile water for injection, USP, use immediately and discard any unused portion.

Because of the benzyl alcohol contained in bacteriostatic water for injection, USP, when doses greater than 10 mg/m² are administered, leucovorin calcium for injection should be reconstituted with sterile water for injection, USP, and used immediately (see WARNINGS). Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

HOW SUPPLIED

Leucovorin Calcium for Injection, USP is supplied in sterile, single-dose vials.

NDC Number	Strength
0703-5140-01	100 mg vial packaged individually
0703-5145-01	350 mg vial packaged individually

Store at room temperature, 15° to 30°C (59° to 86°F).

Protect from light. Discard unused portion. Store in carton until contents are used.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Distributed by:

Teva Pharmaceuticals USA, Inc.

Parsippany, NJ 07054

Rev. C 5/2020

PRINCIPAL DISPLAY PANEL

NDC 0703-5140-01 Rx only

Leucovorin Calcium for Injection, USP

equivalent to leucovorin100 mg/vial

For Intramuscular or

Intravenous Use

STERILE

Single-Dose Vial

Discard Unused Portion.

TEVA

PRINCIPAL DISPLAY PANEL

NDC 0703-5145-01 Rx only

Leucovorin Calcium for Injection

equivalent to leucovorin350 mg/vial

For Intramuscular or

Intravenous Use

STERILE

Single-Dose Vial

Discard Unused Portion.

TEVA

LEUCOVORIN CALCIUM leucovorin calcium injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-5140 Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEUCOVORIN CALCIUM (LEUCOVORIN) LEUCOVORIN 100 mg in 10 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:0703-5140-01 1 VIAL, SINGLE-USE in 1 CARTON contains a VIAL, SINGLE-USE 1 10 mL in 1 VIAL, SINGLE-USE This package is contained within the CARTON (0703-5140-01)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA081277 02/01/1994

LEUCOVORIN CALCIUM leucovorin calcium injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0703-5145 Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEUCOVORIN CALCIUM (LEUCOVORIN) LEUCOVORIN 350 mg in 17.5 mL

Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE SODIUM HYDROXIDE HYDROCHLORIC ACID

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:0703-5145-01 1 VIAL, SINGLE-USE in 1 CARTON contains a VIAL, SINGLE-USE 1 17.5 mL in 1 VIAL, SINGLE-USE This package is contained within the CARTON (0703-5145-01)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040174 06/12/1997

Labeler — Teva Parenteral Medicines, Inc. (794362533)

Revised: 09/2020 Teva Parenteral Medicines, Inc.