Prescription Drugs

CLINICAL PHARMACOLOGY Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)-L-isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of "one-carbon" moieties. Following oral administration, leucovorin is rapidly absorbed and enters the general body pool of reduced folates. The increase in plasma and serum folate activity (determined microbiologically with Lactobacillus casei) seen after oral administration of leucovorin is predominantly due to 5-methyltetrahydrofolate. Twenty normal men were given a single, oral 15 mg dose (7.5 mg/m2) of leucovorin calcium and serum folate concentrations were assayed with L. casei. Mean values observed (± one standard error) were: Time to peak serum folate concentration: 1.72 ± 0.08 hours, Peak serum folate concentration achieved: 268 ± 18 ng/mL, Serum folate half-disappearance time: 3.5 hours. Oral tablets yielded areas under serum folate concentration-time curves (AUCs) that were 12% greater than equal amounts of leucovorin given intramuscularly and equal to the same amounts given intravenously. Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg and 37% for 100 mg.

CLINICAL PHARMACOLOGY Leucovorin (leucovorin calcium) is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin (leucovorin calcium) does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. l-Leucovorin (leucovorin calcium) (l-5-formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to l,5-methyltetrahydrofolate. l,5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH. Administration of leucovorin (leucovorin calcium) can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, leucovorin (leucovorin calcium) can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin (leucovorin calcium) does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication). Leucovorin (leucovorin calcium) is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme. The pharmacokinetics after intravenous, intramuscular and oral administration of a 25 mg dose of leucovorin (leucovorin calcium) were studied in male volunteers. After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/mL (range 897 to 1625). The mean time to peak was 10 minutes. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1206 ng/mL at 10 minutes. A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug. The mean peak of 5-methyl-THF was 258 ng/mL and occurred at 1.3 hours. The terminal half-life for total reduced folates was 6.2 hours. The area under the concentration versus time curves (AUCs) for l-leucovorin (leucovorin calcium) , d-leucovorin (leucovorin calcium) and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.). When a higher dose of d,l-leucovorin (leucovorin calcium) (200 mg/m2) was used, similar results were obtained. The d-isomer persisted in plasma at concentrations greatly exceeding those of the l-isomer. After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/mL (range 240 to 725) and occurred at 52 minutes. Similar to IV administration, the initial sharp rise was due to the parent compound. The mean peak of 5-formyl-THF was 360 ng/mL and occurred at 28 minutes. The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates. The mean peak of 5-methyl-THF was 226 ng/mL at 2.8 hours. The terminal half-life of total reduced folates was 6.2 hours. There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF, or 5-methyl-THF. After oral administration of leucovorin (leucovorin calcium) reconstituted with aromatic elixir, the mean peak concentration of serum total reduced folates was 393 ng/mL (range 160 to 550). The mean time to peak was 2.3 hours and the terminal half-life was 5.7 hours. The major component was the metabolite 5-methyltetrahydrofolate to which leucovorin (leucovorin calcium) is primarily converted in the intestinal mucosa. The mean peak of 5-methyl-THF was 367 ng/mL at 2.4 hours. The peak level of the parent compound was 51 ng/mL at 1.2 hours. The AUC of total reduced folates after oral administration of the 25 mg dose was 92% of the AUC after intravenous administration. Following oral administration, leucovorin (leucovorin calcium) is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the l-isomer but only 20% of the d-isomer is absorbed. Oral absorption of leucovorin (leucovorin calcium) is saturable at doses above 25 mg. The apparent bioavailability of leucovorin (leucovorin calcium) was 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg. 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: Leucovorin (leucovorin calcium) (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 (leucovorin calcium) , low dose leucovorin (leucovorin calcium) 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.1 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= < .01), 42% (p= < .01), and 14%. Respective median survival times were 12.7 months (p= < .04), 12.7 months (p= < .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.2 REFERENCES 1. Poon, MA, et al. Biochemical Modulation of Fluorouracil: Evidence of Significant Improvement of Survival and Quality of Life in Patients with Advanced Colorectal Carcinoma, J Clin Oncol 1989; 7:1407-1418. 2. Poon, MA, et al. Biochemical Modulation of Fluorouracil with Leucovorin (leucovorin calcium) : Confirmatory Evidence of Improved Therapeutic Efficacy in Advanced Colorectal Cancer, J Clin Oncol 1991; 9, 11:1967-1972.

Leucovorin Calcium Tablets DESCRIPTION Leucovorin Calcium Tablets contain either 5 mg or 25 mg leucovorin as the calcium salt of N-[4-[[(2-amino-5-formyl-1, 4, 5, 6, 7, 8-hexahydro-4-oxo-6-pteridinyl)-methyl]amino]benzoyl]-L-glutamic acid. This is equivalent to 5.40 mg or 27.01 mg of anhydrous leucovorin calcium (leucovorin calcium (leucovorin calcium (leucovorin calcium tablets) tablets) tablets) . In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 25mg tablet also contains D&C yellow no. 10 and FD&C blue no. 1. Leucovorin is a water soluble form of reduced folate in the folate group; it is useful as an antidote to drugs which act as folic acid antagonists. These tablets are intended for oral administration only. The structural formula of leucovorin calcium (leucovorin calcium (leucovorin calcium (leucovorin calcium tablets) tablets) tablets) is: C20H21CaN7O7........M.W.=511.51

Find Lowest Prices on LEUCOVORIN (leucovorin calcium) Calcium Injection USP DESCRIPTION Leucovorin (leucovorin calcium) is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N-[p-[[[(6RS)-2- amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1). The structural formula of leucovorin (leucovorin calcium) calcium is: C20H21CaN7O7...........................................M.W.=511.51 Leucovorin (leucovorin calcium) Calcium Injection USP is a sterile, preservative-free solution indicated for intramuscular (IM) or intravenous (IV) administration in a 50 mL single-dose vial. Each mL contains leucovorin (leucovorin calcium) calcium equivalent to 10 mg Leucovorin (leucovorin calcium) , USP; 8 mg sodium chloride; sodium hydroxide and/or hydrochloric acid for pH adjustment pH 7.8 (6.5 to 8.5). There is 0.004 mEq of calcium per mg of leucovorin (leucovorin calcium) . Solution contains no bacteriostat or antimicrobial agents. Leucovorin (leucovorin calcium) Calcium for Injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, and 350 mg vials. Each 50 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection, when reconstituted with 5 mL of sterile diluent, contains leucovorin (leucovorin calcium) (as the calcium salt) 10 mg/mL. Each 100 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection, when reconstituted with 10 mL of sterile diluent, contains leucovorin (leucovorin calcium) (as the calcium salt) 10 mg/mL. Each 200 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (leucovorin calcium) (as the calcium salt) 10 mg/mL. Each 350 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (leucovorin calcium) (as the calcium salt) 20 mg/mL. In each dosage form, one milligram of leucovorin (leucovorin calcium) calcium contains 0.002 mmol of leucovorin (leucovorin calcium) and 0.002 mmol of calcium. These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, USP, added to adjust tonicity. Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS), or with Sterile Water for Injection, USP.

INDICATIONS Leucovorin calcium tablets are indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. DOSAGE AND ADMINISTRATION Leucovorin calcium (leucovorin calcium (leucovorin calcium (leucovorin calcium tablets) tablets) tablets) tablets are intended for oral administration. Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended. 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 15 mg (10 mg/m2) should be administered IM, IV, or PO every 6 hours until serum methotrexate level is less than 10 -8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. 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 x 10 -6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 150 mg (100 mg/m2) IV every 3 hours until the methotrexate level is less than 10-8 M. Doses greater then 25 mg should be given parenterally (see CLINICAL PHARMACOLOGY). Hydration (3L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater. The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less and 5 to 15 mg of leucovorin per day has been recommended by some investigators. Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric 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 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. 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 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. HOW SUPPLIED Leucovorin Calcium (leucovorin calcium (leucovorin calcium (leucovorin calcium tablets) tablets) tablets) Tablets, USP are available as: White, round, unscored, biconvex tablets. Debossed with stylized b on one side and 484 on the other side. Available in bottles of: 20................................NDC 0555-0484-18 5 mg: 30................................NDC 0555-0484-01 100................................NDC 0505-0484-02 1000................................NDC 0555-0484-05 Pale green, round, unscored, biconvex tablets. Debossed with stylized b on one side and 485 on the other side. Available in bottles of: 25 mg: 25................................NDC 0555-0485-27 500................................NDC 0555-0485-04 Protect from light and moisture. Dispense with a child-resistant closure in a tight, light-resistant container. Store at controlled room temperature 15°-25°C (59°-77°F) [See USP]. REFERENCES 1. Grem JL, Shoemaker DD, Petrelli NJ, Douglas HO Jr: Severe and fatal toxic effects observed in treatment with high- and low-dose leucovorin plus 5-Fluorouracil for colorectal carcinoma. Cancer Treat Rep 1987;71:1122. 2. Link MP, Goorin AM, Miser AW et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986: 314:1600-1606. MANUFACTURED BY BARR LABORATORIES, INC. POMONA, NY 10970. OCTOBER 2002. FDA Rev date: 12/26/2000

INDICATIONS Leucovorin (leucovorin calcium) calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin (leucovorin calcium) calcium is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. Leucovorin (leucovorin calcium) calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. Leucovorin (leucovorin calcium) is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin (leucovorin calcium) should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. DOSAGE AND ADMINISTRATION Advanced Colorectal Cancer: Either of the following two regimens is recom-mended: Leucovorin (leucovorin calcium) 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. Leucovorin (leucovorin calcium) is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection. 5-Fluorouracil and leucovorin (leucovorin calcium) 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 dosage may be increased by 10%. Leucovorin (leucovorin calcium) dosages are not adjusted for toxicity. Several other doses and schedules of leucovorin (leucovorin calcium) /5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease. However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin (leucovorin calcium) /5-fluorouracil treatment regimens. Leucovorin (leucovorin calcium) Rescue After High-Dose Methotrexate Therapy: The recommendations for leucovorin (leucovorin calcium) 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).4 Leucovorin (leucovorin calcium) 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 (leucovorin calcium) should be administered parenterally. Do not administer leucovorin (leucovorin calcium) intrathecally. Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin (leucovorin calcium) administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The leucovorin (leucovorin calcium) dose should be adjusted or leucovorin (leucovorin calcium) rescue extended based on the following guidelines: GUIDELINES FOR LEUCOVORIN (leucovorin calcium) DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN (leucovorin calcium) 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 methotrexatelevel 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 (leucovorin calcium) therapy, these patients require continuing hydration and urinary alkalization, 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 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 (leucovorin calcium) 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 (leucovorin calcium) rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS). Leucovorin (leucovorin calcium) 10 mg/m2 should be administered IM, IV, 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 (leucovorin calcium) should be administered parenterally. Do not administer leucovorin (leucovorin calcium) 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 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin (leucovorin calcium) 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 7.0 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 50, 100, and 200 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection when reconstituted with 5, 10, and 20 mL, respectively, of sterile diluent yields a leucovorin (leucovorin calcium) concentration of 10 mg per mL. Each 350 mg vial of Leucovorin (leucovorin calcium) Calcium for Injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg per mL. Leucovorin (leucovorin calcium) 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 (leucovorin calcium) 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 (leucovorin calcium) solution, no more than 160 mg of leucovorin (leucovorin calcium) 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 (leucovorin calcium) should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate. HOW SUPPLIED Leucovorin (leucovorin calcium) Calcium Injection USP, 10 mg/mL, is supplied in sterile, single use vials as follows: NDC 55390-009-01..........................00 mg individually boxed. Store in refrigerator 2° to 8°C (36° to 46°F). Protect from light. Discard unused portion. Retain in carton until time of use. Leucovorin (leucovorin calcium) Calcium for Injection is supplied in sterile, single use vials as follows: NDC 55390-051-10..........................50 mg carton of 10. NDC 55390-052-10..........................100 mg carton of 10. NDC 55390-053-01..........................200 mg individually boxed. NDC 55390-054-01..........................350 mg individually boxed. Store at controlled room temperature 25°C (77° F). Protect from light. Retain in carton until time of use. REFERENCES 4. Link, M P, Goorin, AH, Miser, AW, et al. “The Effect of Adjuvant Chemotherapy on Relapse-Free Survival in Patients with Osteosarcoma of the Extremity,” N Engl J Med 1986; 314:1600-1606. MANUFACTURED BY: Ben Venue Laboratories, Inc. Bedford, Ohio 44146. MANUFACTURED FOR: Bedford Laboratories™ Bedford, Ohio 44146. July 2004.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists. CONTRAINDICATIONS Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurological manifestations continue to progress.

OVERDOSE Excessive amounts of leucovorin (leucovorin calcium) may nullify the chemotherapeutic effect of folic acid antagonists. CONTRAINDICATIONS Leucovorin (leucovorin calcium) is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress.

SIDE EFFECTS Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of fluorouracil (see WARNINGS).

SIDE EFFECTS Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin (leucovorin calcium) . No other adverse reactions have been attributed to the use of leucovorin (leucovorin calcium) per se. The following table summarizes significant adverse events occurring in 316 patients treated with the leucovorin (leucovorin calcium) /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 (leucovorin calcium) /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+ (%) 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% High LV = Leucovorin (leucovorin calcium) 200 mg/m2, Low LV = Leucovorin (leucovorin calcium) 20 mg/m2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher DRUG INTERACTIONS Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible pediatric patients. Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin (leucovorin calcium) enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin (leucovorin calcium) may reduce the efficacy of intrathecally administered methotrexate. Leucovorin (leucovorin calcium) may enhance the toxicity of 5-fluorouracil (see WARNINGS).

WARNINGS In the treatment of accidental overdosage of folic acid antagonists, leucovorin should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin's effectiveness in counteracting hematologic toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin. Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously. Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.1 Concomitant granulocytopenia and fever were present in some but not all of the patients. The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo controlled study. PRECAUTIONS General Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb the leucovorin. Leucovorin has no effect on other established toxicities of methotrexate, such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. Pregnancy Teratogenic Effects Pregnancy Category C. Animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother. Pediatric Use See DRUG INTERACTIONS.

WARNINGS In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin (leucovorin calcium) should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin (leucovorin calcium) rescue increases, leucovorin (leucovorin calcium) 's effectiveness in counteracting toxicity decreases. In the treatment of accidental overdosages of intrathecally adminstered folic acid antagonists, do not adminster leucovorin (leucovorin calcium) intrathecally. LEUCOVORIN (leucovorin calcium) MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin (leucovorin calcium) . Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin (leucovorin calcium) or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin (leucovorin calcium) Calcium for Injection, when doses greater than 10 mg/m2 are administered, Leucovorin (leucovorin calcium) Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see DOSAGE AND ADMINISTRATION). Because of the calcium content of the leucovorin (leucovorin calcium) solution, no more than 160 mg of leucovorin (leucovorin calcium) should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute). Leucovorin (leucovorin calcium) enhances the toxicity of 5-fluorouracil. When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered. Although the toxicities observed in patients treated with the combination of leucovorin (leucovorin calcium) plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination. In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-fluorouracil alone or 5-fluorouracil in combination with 200 mg/m2 of leucovorin (leucovorin calcium) and 20% when treated with 5-fluorouracil in combination with 20 mg/m2 of leucovorin (leucovorin calcium) . In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose leucovorin (leucovorin calcium) /5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%. Therapy with leucovorin (leucovorin calcium) and 5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-fluorouracil and leucovorin (leucovorin calcium) , elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.3 Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin (leucovorin calcium) , usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a causal relationship has not been established.5 The concomitant use of leucovorin (leucovorin calcium) with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a place-bo-controlled study. REFERENCES 3. Grem, J.L., Shoemaker, D.D., Petrelli, N.J., Douglas, H.O., "Severe and Fatal Toxic Effects Observed in Treatment with High- and Low-Dose Leucovorin (leucovorin calcium) Plus 5- Fluorouracil for Colorectal Carcinoma", Cancer Treat Rep 71:1122, 1987. 5. Meropol NJ, Creaven PJ, White RM, et al. "Seizures Associated With Leucovorin (leucovorin calcium) Administration in Cancer Patients," JNCL 1995; 87 (1):56-58. PRECAUTIONS General Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit and not absorb the leucovorin (leucovorin calcium) . Leucovorin (leucovorin calcium) has no effect on non-hematologic toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. Since leucovorin (leucovorin calcium) enhances the toxicity of fluorouracil, leucovorin (leucovorin calcium) /5-fluorouracil combination therapy for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy. Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity. Laboratory Tests Patients being treated with the leucovorin (leucovorin calcium) /5-fluorouracil combination should have a CBC with differential and platelets prior to each treatment. During the first two courses a CBC with differential and platelets has to be repeated weekly and thereafter once each cycle at the time of anticipated WBC nadir. Electrolytes and liver function tests should be performed prior to each treatment for the first three cycles then prior to every other cycle. Dosage modifications of fluorouracil should be instituted as follows, based on the most severe toxicities: Diarrhea and/or Stomatitis WBC/mm3 Nadir Platelets/mm3 Nadir 5-FU Dose Moderate 1,000 - 1,900 25-75,000 decrease 20% Severe < 1,000 < 25,000 decrease 30% If no toxicity occurs, the 5-fluorouracil dose may increase 10%. Treatment should be deferred until WBCs are 4,000/mm3 and platelets 130,000/mm3. If blood counts do not reach these levels within two weeks, treatment should be discontinued. Patients should be followed up with physical examination prior to each treatment course and appropriate radiological examination as needed. Treatment should be discontinued when there is clear evidence of tumor progression. Pregnancy Teratogenic Effects Pregnancy Category C. Adequate animal reproduction studies have not been conducted with leucovorin (leucovorin calcium) . It is also not known whether leucovorin (leucovorin calcium) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin (leucovorin calcium) should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin (leucovorin calcium) is administered to a nursing mother. Pediatric Use See PRECAUTIONS: DRUG INTERACTIONS.