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DESCRIPTION: Leucovorin 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 -[[[(6 RS )-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 calcium is: C 20 H 21 CaN 7 O 7 M.W. 511.51 Leucovorin Calcium for Injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 200 mg vials. Each 200 mg vial of Leucovorin Calcium for Injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium. This lyophilized product contains no preservative. The inactive ingredient is sodium chloride added to adjust tonicity. Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS ), or with Sterile Water for Injection, USP. The inactive ingredient is sodium chloride 180 mg/vial for the 200 mg. Sodium hydroxide and/or hydrochloric acid may be added for pH adjustment. pH adjusted to approximately 7.8. There is 0.004 mEq of calcium per mg of leucovorin. Solution contains no bacteriostat or antimicrobial agents. structure

CLINICAL PHARMACOLOGY: Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)- I -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. I -Leucovorin ( I -5-formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to I ,5-methyltetrahydrofolate. I ,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 FADH 2 and NADPH. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin 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 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 were studied in male volunteers. After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1,259 ng/mL (range 897 to 1,625). 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 1,206 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 I -leucovorin, d -leucovorin and 5-methyltetrahydrofolate were 28.4 ± 3.5, 956 ± 97 and 129 ± 12 (mg/min/L ± S.E.). When a higher dose of d,I -leucovorin (200 mg/m 2 ) was used, similar results were obtained. The d -isomer persisted in plasma at concentrations greatly exceeding those of the I -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.

-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 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 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 is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 25 mg, almost 100% of the I -isomer but only 20% of the d -isomer is absorbed. 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. 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 (LV) 200 mg/m 2 and 5-fluorouracil (5-FU) 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 versus 5-FU 500 mg/m 2 . 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=0.05), 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/m 2 and 5-FU 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 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

INDICATIONS AND USAGE: Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin 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 calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

CONTRAINDICATIONS: Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12 . A hematologic remission may occur while neurologic manifestations continue to progress.

WARNINGS: In the treatment of accidental overdosages of folic acid antagonists, intravenous 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 toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally. LEUCOVORIN 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. 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. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m 2 are administered, Leucovorin 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 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). Leucovorin 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 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/m 2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin. 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/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%. Therapy with leucovorin 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, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.

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, 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, 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 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 placebo-controlled study.

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 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 enhances the toxicity of fluorouracil, leucovorin/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/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/mm 3 Nadir Platelets/mm 3 Nadir 5-FU Dose Moderate Severe 1,000 to 1,900 <1,000 25 to 75,000 <25,000 decrease 20% decrease 30% If no toxicity occurs, the 5-fluorouracil dose may increase 10%. Treatment should be deferred until WBCs are 4,000/mm 3 and platelets 130,000/mm 3 . 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. 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 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 may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS ). Pregnancy Teratogenic Effects: Pregnancy Category C. Adequate 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 PRECAUTIONS , Drug Interactions .

rin 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 PRECAUTIONS , Drug Interactions . General Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit and not absorb the leucovorin. Leucovorin 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 enhances the toxicity of fluorouracil, leucovorin/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/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/mm 3 Nadir Platelets/mm 3 Nadir 5-FU Dose Moderate Severe 1,000 to 1,900 <1,000 25 to 75,000 <25,000 decrease 20% decrease 30% If no toxicity occurs, the 5-fluorouracil dose may increase 10%. Treatment should be deferred until WBCs are 4,000/mm 3 and platelets 130,000/mm 3 . 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.

. 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. 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 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 may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS ). Pregnancy Teratogenic Effects: Pregnancy Category C. Adequate 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 PRECAUTIONS , Drug Interactions .

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Diarrhea and/or Stomatitis </td><td styleCode="Rrule" align="left" valign="top">WBC/mm³ Nadir </td><td styleCode="Rrule" align="left" valign="top">Platelets/mm³ Nadir </td><td styleCode="Rrule" align="left" valign="top">5-FU Dose </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top">Moderate Severe </td><td styleCode="Rrule" align="left" valign="top">1,000 to 1,900 &lt;1,000 </td><td styleCode="Rrule" align="left" valign="top">25 to 75,000 &lt;25,000 </td><td styleCode="Rrule" align="left" valign="top">decrease 20% decrease 30% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Diarrhea and/or Stomatitis </td><td styleCode="Rrule" align="left" valign="top">WBC/mm³ Nadir </td><td styleCode="Rrule" align="left" valign="top">Platelets/mm³ Nadir </td><td styleCode="Rrule" align="left" valign="top">5-FU Dose </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top">Moderate Severe </td><td styleCode="Rrule" align="left" valign="top">1,000 to 1,900 &lt;1,000 </td><td styleCode="Rrule" align="left" valign="top">25 to 75,000 &lt;25,000 </td><td styleCode="Rrule" align="left" valign="top">decrease 20% decrease 30% </td></tr></tbody></table>

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+ (%) 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 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity Grade 3 or higher

<table cellspacing="0" cellpadding="0" border="0" width=" 710px"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">(High LV) /5-FU (N=155) </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">(Low LV) /5-FU (N=161) </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">5-FU Alone (N=70) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"> </td><td styleCode="Rrule" align="center" valign="bottom">Any (%) </td><td styleCode="Rrule" align="center" valign="bottom">Grade 3+ (%) </td><td styleCode="Rrule" align="center" valign="bottom">Any (%) </td><td styleCode="Rrule" align="center" valign="bottom">Grade 3+ (%) </td><td styleCode="Rrule" align="center" valign="bottom">Any (%) </td><td styleCode="Rrule" align="center" valign="bottom">Grade 3+ (%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Leukopenia </td><td styleCode="Rrule" align="center" valign="bottom">69 </td><td styleCode="Rrule" align="center" valign="bottom">14 </td><td styleCode="Rrule" align="center" valign="bottom">83 </td><td styleCode="Rrule" align="center" valign="bottom">23 </td><td styleCode="Rrule" align="center" valign="bottom">93 </td><td styleCode="Rrule" align="center" valign="bottom">48 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Thrombocytopenia </td><td styleCode="Rrule" align="center" valign="bottom">8 </td><td styleCode="Rrule" align="center" valign="bottom">2 </td><td styleCode="Rrule" align="center" valign="bottom">8 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">18 </td><td styleCode="Rrule" align="center" valign="bottom">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Infection </td><td styleCode="Rrule" align="center" valign="bottom">8 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">3 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">7 </td><td styleCode="Rrule" align="center" valign="bottom">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Nausea </td><td styleCode="Rrule" align="center" valign="bottom">74 </td><td styleCode="Rrule" align="center" valign="bottom">10 </td><td styleCode="Rrule" align="center" valign="bottom">80 </td><td styleCode="Rrule" align="center" valign="bottom">9 </td><td styleCode="Rrule" align="center" valign="bottom">60 </td><td styleCode="Rrule" align="center" valign="bottom">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Vomiting </td><td styleCode="Rrule" align="center" valign="bottom">46 </td><td styleCode="Rrule" align="center" valign="bottom">8 </td><td styleCode="Rrule" align="center" valign="bottom">44 </td><td styleCode="Rrule" align="center" valign="bottom">9 </td><td styleCode="Rrule" align="center" valign="bottom">40 </td><td styleCode="Rrule" align="center" valign="bottom">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Diarrhea </td><td styleCode="Rrule" align="center" valign="bottom">66 </td><td styleCode="Rrule" align="center" valign="bottom">18 </td><td styleCode="Rrule" align="center" valig

td styleCode="Rrule" align="center" valign="bottom">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Diarrhea </td><td styleCode="Rrule" align="center" valign="bottom">66 </td><td styleCode="Rrule" align="center" valign="bottom">18 </td><td styleCode="Rrule" align="center" valig n="bottom">67 </td><td styleCode="Rrule" align="center" valign="bottom">14 </td><td styleCode="Rrule" align="center" valign="bottom">43 </td><td styleCode="Rrule" align="center" valign="bottom">11 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Stomatitis </td><td styleCode="Rrule" align="center" valign="bottom">75 </td><td styleCode="Rrule" align="center" valign="bottom">27 </td><td styleCode="Rrule" align="center" valign="bottom">84 </td><td styleCode="Rrule" align="center" valign="bottom">29 </td><td styleCode="Rrule" align="center" valign="bottom">59 </td><td styleCode="Rrule" align="center" valign="bottom">16 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Constipation </td><td styleCode="Rrule" align="center" valign="bottom">3 </td><td styleCode="Rrule" align="center" valign="bottom">0 </td><td styleCode="Rrule" align="center" valign="bottom">4 </td><td styleCode="Rrule" align="center" valign="bottom">0 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">- </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Lethargy/Malaise/Fatigue </td><td styleCode="Rrule" align="center" valign="bottom">13 </td><td styleCode="Rrule" align="center" valign="bottom">3 </td><td styleCode="Rrule" align="center" valign="bottom">12 </td><td styleCode="Rrule" align="center" valign="bottom">2 </td><td styleCode="Rrule" align="center" valign="bottom">6 </td><td styleCode="Rrule" align="center" valign="bottom">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Alopecia </td><td styleCode="Rrule" align="center" valign="bottom">42 </td><td styleCode="Rrule" align="center" valign="bottom">5 </td><td styleCode="Rrule" align="center" valign="bottom">43 </td><td styleCode="Rrule" align="center" valign="bottom">6 </td><td styleCode="Rrule" align="center" valign="bottom">37 </td><td styleCode="Rrule" align="center" valign="bottom">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Dermatitis </td><td styleCode="Rrule" align="center" valign="bottom">21 </td><td styleCode="Rrule" align="center" valign="bottom">2 </td><td styleCode="Rrule" align="center" valign="bottom">25 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">13 </td><td styleCode="Rrule" align="center" valign="bottom">- </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top">Anorexia </td><td styleCode="Rrule" align="center" valign="bottom">14 </td><td styleCode="Rrule" align="center" valign="bottom">1 </td><td styleCode="Rrule" align="center" valign="bottom">22 </td><td styleCode="Rrule" align="center" valign="bottom">4 </td><td styleCode="Rrule" align="center" valign="bottom">14 </td><td styleCode="Rrule" align="center" valign="bottom">- </td></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top">Hospitalization for Toxicity </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">5% </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">15% </td><td styleCode="Rrule" colspan="2" align="center" valign="bottom">7% </td></tr></tbody></table>

DOSAGE AND ADMINISTRATION: Advanced Colorectal Cancer Either of the following two regimens is recommended: Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 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 dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity. Several other doses and schedules of leucovorin/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/5-fluorouracil treatment regimens. Leucovorin Rescue After High-Dose Methotrexate Therapy The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m 2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). 4 Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m 2 ) 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 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 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.

ing 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; 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 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 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 a delayed excretion (see WARNINGS ). Leucovorin 10 mg/m 2 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 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 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 100 mg/m 2 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 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL. Leucovorin Calcium for Injection contains no preservative.

jection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg 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/m 2 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.

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. Advanced Colorectal Cancer Either of the following two regimens is recommended: Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 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 dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity. Several other doses and schedules of leucovorin/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/5-fluorouracil treatment regimens.

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/5-fluorouracil treatment regimens. Leucovorin Rescue After High-Dose Methotrexate Therapy The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m 2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). 4 Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m 2 ) 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 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 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; 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 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 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.

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 a delayed excretion (see WARNINGS ). Leucovorin 10 mg/m 2 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 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 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 100 mg/m 2 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.

the dose of leucovorin should be increased to 100 mg/m 2 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 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL. Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg 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/m 2 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 is supplied as follows: Product No. NDC No. Strength NP701050 63323-710-59 200 mg per vial Packaged individually. Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light (keep in outer carton). The container closure is not made with natural rubber latex.

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left" valign="top"><content styleCode="italics"> </content> <content styleCode="bold">Product</content> <content styleCode="bold"> No.</content> </td><td styleCode="Rrule" align="left" valign="top"> <content styleCode="bold">NDC</content> <content styleCode="bold">No.</content> </td><td styleCode="Rrule" align="left" valign="bottom"> <content styleCode="bold">Strength</content> </td><td styleCode="Rrule" align="left" valign="top"/></tr><tr><td styleCode="Lrule Rrule" align="left" valign="top"> NP701050 </td><td styleCode="Rrule" align="left" valign="top"> 63323-710-59 </td><td styleCode="Rrule" align="left" valign="top"> 200 mg per vial </td><td styleCode="Rrule" align="left" valign="top"> Packaged individually. </td></tr></tbody></table>

REFERENCES: 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. Poon, MA, et al. Biochemical Modulation of Fluorouracil with Leucovorin: Confirmatory Evidence of Improved Therapeutic Efficacy in Advanced Colorectal Cancer, J Clin Oncol 1991;9,11:1967-1972. 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 Plus 5-Fluorouracil for Colorectal Carcinoma", Cancer Treat Rep 71:1122,1987. Link, MP, 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. Meropol NJ, Creaven PJ, White RM, et al. "Seizures Associated With Leucovorin Administration in Cancer Patients." JNCL 1995;87(1):56-58. NOVAPLUS is a registered trademark of Vizient, Inc.

1 INDICATIONS AND USAGE Leucovorin calcium tablets are a folate analog indicated: To reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. ( 1.1 ) For the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). ( 1.2 ) Limitations of Use Leucovorin calcium tablets are not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate. ( 1.2 ) Limitations of Use Leucovorin calcium tablets are not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1.3 ) 1.1 Reduction of Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Leucovorin calcium tablets are indicated to reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. 1.2 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant Leucovorin calcium tablets are indicated for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). Limitations of Use Leucovorin calcium tablets are not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate (5-MTHF) [see Clinical Pharmacology (12.3) ] . 1.3 Limitations of Use Leucovorin calcium tablets are not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.

2 DOSAGE AND ADMINISTRATION Leucovorin calcium tablets are for oral administration only and can be taken with or without food. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. ( 2.1 ) Administer leucovorin calcium tablets as soon as possible after a folic acid antagonist or dihydrofolate reductase (DHFR) inhibitor overdose and within 24 hours of methotrexate use when there is impaired methotrexate elimination. ( 2.2 ) Recommended Dosage to Reduce Methotrexate Toxicity in Patients with Impaired Methotrexate Elimination 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). If a dosage greater than 25 mg every 6 hours is needed, an injectable formulation of leucovorin should be administered parenterally. ( 2.2 ) Recommended Dosage to Reduce the Toxicity of Folic Acid Antagonists or DHFR Inhibitors in Patients Following an Overdosage 5 mg to 15 mg per day. ( 2.2 ) For patients with impaired methotrexate elimination and following a methotrexate overdose, administer intravenous fluids (3 L/day) and alkalinize the urine to maintain the urine pH at 7.0 or greater. ( 2.2 ) Recommended Dosage to Treat FOLR1-CFTD Initiate oral leucovorin calcium tablets as follows based on body weight: Less than 40 kg: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 8.5 mg/kg/day. ( 2.3 ) 40 kg or more: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 330 mg/day. ( 2.3 ) Administer the total daily dosage once daily or in divided doses up to 6 times per day. ( 2.3 ) Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. ( 2.3 ) 2.1 Important Administration Instructions Each indication has a different method for calculating the dosage (i.e., fixed dosage, body surface area-based dosage, or body weight-based dosage). Ensure that the correct method for calculating the dosage is used [see Dosage and Administration (2.2 , 2.3) ]. Leucovorin calcium tablets are for oral administration only and can be taken with or without food [see Clinical Pharmacology (12.3) ]. Crushing of leucovorin tablets and mixing with food or liquid (e.g., water, breastmilk, infant formula) has been reported in literature. If administering via this method, administer immediately after mixing. 2.2 Recommended Dosage to Reduce the Toxicity of Methotrexate in Patients with Impaired Methotrexate Elimination or to Reduce the Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Following Overdose Administer leucovorin calcium tablets as soon as possible after a folic acid antagonist or DHFR inhibitor overdose and within 24 hours of methotrexate administration when there is impaired methotrexate elimination. The effectiveness of leucovorin calcium tablets decreases as the time interval between leucovorin calcium tablets administration and the folic acid antagonist or DHFR inhibitor increases. For patients with impaired methotrexate elimination, monitor serum methotrexate concentrations and serum creatinine to determine the recommended dosage and duration of leucovorin calcium tablets. For patients with impaired methotrexate elimination and in patients following a methotrexate overdose, administer intravenous fluids (3 Liters per day) and alkalinize the urine to maintain a urine pH of 7.0 or greater.

and serum creatinine to determine the recommended dosage and duration of leucovorin calcium tablets. For patients with impaired methotrexate elimination and in patients following a methotrexate overdose, administer intravenous fluids (3 Liters per day) and alkalinize the urine to maintain a urine pH of 7.0 or greater. The recommended leucovorin calcium tablets dosage to reduce methotrexate toxicity in patients with impaired methotrexate elimination: 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). When a dosage greater than 25 mg every 6 hours is needed for this use, leucovorin calcium tablets are not recommended because this dosage and the formulation may be inadequate to treat significant methotrexate toxicity, resulting in possible methotrexate toxicity fatalities. Refer to the prescribing information for leucovorin injection for dosage recommendations. 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, higher doses of leucovorin are needed; discontinue oral administration of leucovorin calcium tablets and administer leucovorin intravenously or intramuscularly. Refer to the prescribing information for leucovorin injection for the appropriate dosage and duration. In patients who experience non-oliguric renal failure, continue leucovorin, hydration and alkalinization of the urine (pH of 7.0 or greater) until the methotrexate level is 0.05 micromolar. Extend the duration of leucovorin calcium tablets administration for an additional 24 hours in subsequent courses of methotrexate in patients who experience significant methotrexate toxicities, impaired methotrexate elimination including third-space fluid accumulation and inadequate hydration, or renal impairment. The recommended leucovorin calcium tablets dosage to reduce the toxicity of folic acid antagonists or DHFR inhibitors (trimethoprim or pyrimethamine) following an overdose: 5 mg to 15 mg orally once daily. 2.3 Recommended Dosage for Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant The recommended oral dosage of leucovorin calcium tablets for patients with FOLR1-CFTD is based on the patient's weight (see Table 1). Adjust dosage based on clinical response [see Clinical Studies (14.1) ] . Table 1. Recommended Leucovorin Calcium Tablets Dosage for Patients with FLOR1-CFTD Patient Weight Initial Total Daily Dosage * Maximum Total Daily Dosage Round doses to the nearest tablet strength or combination of strengths. Frequency of Administration Bioavailability is reduced with individual leucovorin doses above 25 mg in adults [see Clinical Pharmacology (12.3) ]. Less than 40 kg 1 to 2 mg/kg/day 8.5 mg/kg/day Administer the total daily dosage once daily or in divided doses up to 6 times per day. Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. 40 kg or more 1 to 2 mg/kg/day 330 mg/day

3 DOSAGE FORMS AND STRENGTHS Leucovorin calcium tablets, USP: 5 mg: White to off-white, round, biconvex tablets debossed with “ING” above “181” on one side and scoreline on other side and free from physical defects. 10 mg: White to off-white, round, biconvex tablets debossed with “ING” above “182” on one side and score line on other side and free from physical defects. 15 mg: Peach colored, round, biconvex tablets debossed with “ING” above “183” on one side and score line on other side and free from physical defects. 25 mg: Peach colored, round, biconvex tablets debossed with “ING” above “184” on one side and scoreline on other side and free from physical defects. Tablets: 5 mg of leucovorin, 10 mg of leucovorin, 15 mg of leucovorin and 25 mg of leucovorin ( 3 )

4 CONTRAINDICATIONS Leucovorin calcium tablets are contraindicated in patients with a history of hypersensitivity reaction depending on indication as described below, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of leucovorin calcium tablets [see Description (11) ] : Folic acid antagonist or DHFR inhibitor toxicity: history of severe hypersensitivity reaction FOLR1-CFTD: history of any hypersensitivity reaction Reactions have included anaphylactic reactions [see Warnings and Precautions (5.1) ] . History of hypersensitivity reaction, depending on indication, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of leucovorin calcium tablets: folic acid antagonist or DHFR inhibitor toxicity: history of a severe hypersensitivity reaction FOLR1-CFTD: history of any hypersensitivity reaction. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Withhold or permanently discontinue leucovorin calcium tablets based on severity and indication. ( 4 , 5.1 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. Leucovorin calcium tablets are contraindicated for the treatment of folic acid antagonist or DHFR inhibitor toxicity in patients with a history of a severe hypersensitivity reaction and for the treatment of FOLR1-CFTD in patients with a history of any hypersensitivity reaction to leucovorin, levoleucovorin, folic acid, or any component of leucovorin calcium tablets [see Contraindications (4) ] . Withhold or permanently discontinue leucovorin calcium tablets based on the severity of hypersensitivity.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ]. The following adverse reactions have been identified during postapproval use of leucovorin (d,l-leucovorin) or levoleucovorin (l-leucovorin). Because these 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. Dermatologic: Pruritus, rash. Respiratory: Dyspnea. Other Clinical Events: Rigors, temperature change. Safety information for the treatment of FOLR1-CFTD with oral leucovorin is limited. The available evidence is based on published case reports [see Clinical Studies (14.1) ] . Adverse reactions included pruritus, rash, urticaria, dyspnea, hypersensitivity reactions, rigors, and temperature change. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Certain Antiepileptic Drugs : Increase monitoring for seizure activity in leucovorin calcium tablets-treated patients taking certain concomitant antiepileptic drugs. Certain antiepileptic drugs may reduce the effectiveness of leucovorin calcium tablets. ( 7.1 , 7.2 ) Trimethoprim-Sulfamethoxazole : Avoid concomitant use of leucovorin calcium tablets with trimethoprim-sulfamethoxazole. ( 7.1 ) Fluorouracil : Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients. ( 7.1 ) 7.1 Effects of Leucovorin on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in leucovorin calcium tablets-treated patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures in susceptible patients, including pediatric patients. It is not known whether folinic acid, including leucovorin calcium tablets, has the same effects; however, both folic and folinic acids, including leucovorin calcium tablets, share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of leucovorin calcium tablets with trimethoprim-sulfamethoxazole. The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with leucovorin calcium tablets, which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia. Fluorouracil 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. Concomitant granulocytopenia and fever were present in some but not all of the patients. 7.2 Effect of Other Drugs on Leucovorin Certain antiepileptic drugs may reduce folate absorption and metabolism leading to folate deficiency. As folic acid and folinic acid share common metabolic pathways, certain antiepileptic drugs may reduce the effectiveness of leucovorin calcium tablets.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the intermittent use of leucovorin for the treatment of folic acid antagonist or DHFR inhibitor toxicity during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no adequate data on the use of leucovorin for the treatment of FOLR1-CFTD in pregnant women. Adequate animal reproductive and developmental studies have not been conducted with leucovorin. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risks with Concomitant Use of Leucovorin Calcium Tablets and Chemotherapy Drugs administered in combination with leucovorin calcium tablets may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with leucovorin calcium tablets for additional information, as appropriate. 8.2 Lactation Risk Summary There are no data on the presence of leucovorin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for leucovorin calcium tablets and any potential adverse effects on the breastfed infant from leucovorin or from the underlying maternal condition. Refer to the Prescribing Information for chemotherapy administered in combination with leucovorin calcium tablets for breastfeeding recommendations, as appropriate. 8.4 Pediatric Use Leucovorin calcium tablets are indicated for the treatment of cerebral folate transport deficiency in pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD) [see Clinical Studies (14.1) ] . The safety and effectiveness of leucovorin calcium tablets have not been established to reduce the toxicity of methotrexate in pediatric patients with impaired methotrexate elimination or in pediatric patients to reduce the toxicity of folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose. 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 [see Drug Interactions (7.1) ] . 8.5 Geriatric Use There is insufficient information in patients 65 years of age and older on the use of leucovorin calcium tablets to reduce the toxicity of methotrexate, other folic acid antagonists, or DHFR inhibitors, and there is no information on the use of leucovorin calcium tablets to treat FOLR1-CFTD in patients 65 years of age and older to determine whether they respond differently from younger patients [see Clinical Studies (14.1) ] .

11 DESCRIPTION Leucovorin is a racemic mixture of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)- L -Levoisomer, known as Citrovorum factor , or (-)-folinic acid or levoleucovorin. Leucovorin is a water soluble form of reduced folate in the folate group. The chemical name of leucovorin, a folate analog, is 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. The molecular formula is C 20 H 21 CaN 7 O 7 and the molecular weight is 511.51 g/mol. The structural formula of leucovorin calcium is : Leucovorin calcium tablets, USP are for oral administration. Each 5 mg tablet contains 5 mg of leucovorin (equivalent to 5.4 mg of leucovorin calcium), each 10 mg tablet contains 10 mg of leucovorin (equivalent to 10.8 mg of leucovorin calcium), each 15 mg tablet contains 15 mg of leucovorin (equivalent to 16.2 mg of leucovorin calcium) and each 25 mg tablet contains 25 mg of leucovorin (equivalent to 27.01 mg of leucovorin calcium). The 5 mg, 10 mg, 15 mg and 25 mg tablets contain the following inactive ingredients: lactose monohydrate, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate. Additionally, the 15 mg and 25 mg tablets contains FD&C yellow #6. image description

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Levoleucovorin, a reduced folate and the pharmacologically active isomer of leucovorin (5-formyl­tetrahydrofolic acid), can mitigate the toxic effects of folate antagonists, including methotrexate and other agents that inhibit dihydrofolate reductase (DHFR). Inhibition of DHFR blocks the formation of tetrahydrofolate, an essential cofactor for DNA synthesis and repair. Levoleucovorin has been observed to increase levels of 5-MTHF, an active metabolite of folate, in case studies of FOLR1-CFTD [see Clinical Studies (14.1) ] . 12.2 Pharmacodynamics Levoleucovorin and its metabolites (5,10-methenyltetrahydrofolate, 5,10-methylenetetrahydrofolate, and 5-MTHF) serve as cofactors in “one carbon” metabolism. These reactions are involved in the generation of nucleic acids and the regulation of gene expression. 12.3 Pharmacokinetics Leucovorin is a racemic mixture of (l)-or levoleucovorin and (d)-or dextroleucovorin. Following oral administration of leucovorin to healthy adults, dextroleucovorin, levoleucovorin, and 5-MTHF exposures increased in a dose proportional manner with doses up to 25 mg, but in a less than dose proportional manner with doses greater than 25 mg. Absorption Following oral administration of leucovorin in adults, the apparent bioavailability of levoleucovorin is 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg, and dextroleucovorin is approximately 19% for 25 mg, 20% for 50 mg, and 7% for 100 mg. After a single oral 15 mg (7.5 mg/m 2 ) dose of leucovorin calcium tablets, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of leucovorin calcium tablets has not been evaluated. As leucovorin is a highly soluble and well absorbed drug, and different immediate-release oral formulations of leucovorin (oral tablet and oral solution) showed relatively higher bioavailability of total folates (>95%), food is not expected to have a clinically significant effect on the pharmacokinetics of leucovorin or 5-MTHF. Crushing of leucovorin and mixing with food or liquid has been reported in literature. Distribution Levoleucovorin is minimally bound to human serum albumin. The reported human serum albumin binding of 5-MTHF ranges from 42-49%. Leucovorin is not observed in cerebrospinal fluid (CSF) and 5-MTHF is reported to accumulate in CSF in children with leukemia. Elimination After intravenous administration of leucovorin in adults, the reported mean plasma elimination half-life in the literature was 0.5-1.3 hours for levoleucovorin and 3-7 hours for 5-MTHF. Metabolism: Following administration of oral leucovorin, levoleucovorin undergoes metabolism in intestinal cells via methenyltetrahydrofolate synthetase (MTHFS) and methylenetetrahydrofolate reductase (MTHFR) to its active metabolite, 5-MTHF. 5-MTHF is the main active metabolite in plasma after oral administration of leucovorin. Excretion: Leucovorin is mainly excreted by the kidney as unchanged dextroleucovorin, levoleucovorin, or as 5-MTHF, the metabolic product of levoleucovorin. Specific Populations Patients with Renal Impairment: The kidney is reported to contribute to the elimination of dextroleucovorin, levoleucovorin and its active metabolite, and plasma concentrations of dextroleucovorin, levoleucovorin, and 5-MTHF may be increased in patients with renal impairment. However, clinical studies on the impact of renal impairment have not been conducted.

y is reported to contribute to the elimination of dextroleucovorin, levoleucovorin and its active metabolite, and plasma concentrations of dextroleucovorin, levoleucovorin, and 5-MTHF may be increased in patients with renal impairment. However, clinical studies on the impact of renal impairment have not been conducted. Patients with Hepatic Impairment: The liver is reported to contribute to the metabolism of levoleucovorin, and plasma concentrations of levoleucovorin and 5-MTHF may be increased in patients with hepatic impairment. However, clinical studies on the impact of hepatic impairment have not been conducted.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies to assess the potential for carcinogenicity or genotoxicity, or for adverse effects on fertility have not been conducted for leucovorin.

14 CLINICAL STUDIES 14.1 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant (FOLR1-CFTD) FOLR1-CFTD is a very rare neurological syndrome. No clinical trials have been conducted to examine the efficacy and safety of leucovorin in patients with FOLR1 variants. Evidence for the efficacy and safety of leucovorin in patients with FOLR1-CFTD was derived from the published literature. Forty-six patients with FOLR1-CFTD who received leucovorin treatment via various administration routes were identified in 26 published case reports and case reviews through 2024. Thirty cases were described in more than one publication. Of the 46 patients, a total of 27 (59%) were reported as having received leucovorin only via the oral administration route. These 27 patients ranged from approximately 2 months of age to 33 years of age at treatment initiation, and 25 of the patients had dosing information. The starting oral dose ranged from 0.5 to 3 mg/kg/day, and was 2 mg/kg/day in 14 of the 25 patients. Of the 20 patients with dose escalation reported, 17 had a maximum dose ≤6 mg/kg/day (reported range: 1.7 to 8.5 mg/kg/day). Information related to duration of use of leucovorin was limited, and there was no obvious relationship between the starting or maximum oral dose with patient demographics or disease severity. In some cases, it was reported that dose increase was based on clinical review of patient response. A range of clinical improvements in various neurological symptoms following treatment with oral leucovorin was reported for 24 of the 27 patients (e.g., reduction in severity or number of seizures; improvements in motor function, communication, and/or behavior). The remaining 3 patients showed either no change or no progression of symptoms; both the observed clinical improvements and the lack of disease progression are unexpected when compared to the progressive natural history of these patients with FOLR1-CFTD. CSF 5-MTHF measurements were collected at varying, unspecified time points across patients, with timing broadly categorized as before or after treatment initiation in most cases. In the subset of 27 FOLR1-CFTD patients who received oral leucovorin only, pre-treatment 5-MTHF levels were very low (<10 nmol/L in 17 of 21 patients with observed levels) compared to reported reference ranges from 40 up to 240 nmol/L. A subset of 7 patients had CSF 5-MTHF levels measured both before and after leucovorin initiation. All 7 patients experienced an increase in CSF 5-MTHF levels following treatment initiation, with 5 achieving normalization above 40 nmol/L.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Leucovorin calcium tablets, USP contain: 5 mg of leucovorin: White to off-white, round, biconvex tablet; debossed with “ING” above “181” on one side and scoreline on other side and free from any physical defects. NDC 50742-181-30: Bottle of 30 Tablets NDC 50742-181-01: Bottle of 100 Tablets 10 mg of leucovorin: White to off-white, round, biconvex tablet; debossed with “ING” above “182” on one side and scoreline on other side and free from any physical defects. NDC 50742-182-12: Bottle of 12 Tablets NDC 50742-182-24: Bottle of 24 Tablets 15 mg of leucovorin: Peach colored, round, biconvex tablet; debossed with “ING” above “183” on one side and scoreline on other side and free from any physical defects. NDC 50742-183-24: Bottle of 24 Tablets 25 mg of leucovorin: Peach colored, round, biconvex tablet; debossed with “ING” above “184” on one side and scoreline on other side and free from any physical defects. NDC 50742-184-25: Bottle of 25 Tablets 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION Administration Instructions Advise patients or caregivers that leucovorin tablets may be dissolved in an age-appropriate liquid (e.g., water, breastmilk, or infant formula) or crushed and mixed with soft food before administration. If leucovorin is to be administered in this manner, instruct patients or caregivers to administer the dissolved or mixed product immediately after mixing [see Dosage and Administration (2.1) ] . Hypersensitivity Reactions Advise patients to inform their healthcare provider if they develop a hypersensitivity reaction while taking leucovorin calcium tablets [see Warnings and Precautions (5.1) ] . Drug Interactions Advise patients to inform their healthcare providers of all concomitant drugs, including prescription drugs, nonprescription drugs, vitamins, and herbal products [see Drug Interactions (7) ] . Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811 Rx Only 554302 Revised: 03/2026 logo

<table cellspacing="1" cellpadding="0"><col/><col/><tbody><tr><td>Indications and Usage (<linkHtml href="#LINK_b2a1e6b0-849b-4c5b-90d3-73bdd1f3b847">1.2</linkHtml>)</td><td> 3/2026 </td></tr><tr><td>Dosage and Administration (<linkHtml href="#LINK_09641f43-4b0f-426c-b6be-eed76210bc1e">2.1</linkHtml>, <linkHtml href="#LINK_5f68c8a4-b033-42e7-87fe-6e41c3cd3c6d">2.3</linkHtml>)</td><td> 3/2026</td></tr><tr><td>Contraindications (<linkHtml href="#LINK_28e66f97-39e2-493a-bde5-03b3b8b399ba">4</linkHtml>)</td><td> 3/2026</td></tr><tr><td>Warnings and Precautions (<linkHtml href="#LINK_e5bc49fa-827d-4eaa-a38e-ddf3d032906c">5.1</linkHtml>)</td><td> 3/2026</td></tr></tbody></table>

1 INDICATIONS AND USAGE Leucovorin calcium tablets are a folate analog indicated: To reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. ( 1.1 ) For the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). ( 1.2 ) Limitations of Use Leucovorin calcium tablets are not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate. ( 1.2) Limitations of Use Leucovorin calcium tablets are not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1.3 ) 1.1 Reduction of Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Leucovorin calcium tablets are indicated to reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. 1.2 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant Leucovorin calcium tablets are indicated for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). Limitations of Use Leucovorin calcium tablets are not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate (5-MTHF) [see Clinical Pharmacology ( 12.3 )] . 1.3 Limitations of Use Leucovorin calcium tablets are not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.

2 DOSAGE AND ADMINISTRATION Leucovorin calcium tablets are for oral administration only and can be taken with or without food. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. ( 2.1 ) Administer leucovorin calcium tablets as soon as possible after a folic acid antagonist or dihydrofolate reductase (DHFR) inhibitor overdose and within 24 hours of methotrexate use when there is impaired methotrexate elimination. ( 2.2 ) Recommended Dosage to Reduce Methotrexate Toxicity in Patients with Impaired Methotrexate Elimination 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). If a dosage greater than 25 mg every 6 hours is needed, an injectable formulation of leucovorin should be administered parenterally. ( 2.2 ) Recommended Dosage to Reduce the Toxicity of Folic Acid Antagonists or DHFR Inhibitors in Patients Following an Overdosage 5 mg to 15 mg per day. ( 2.2 ) For patients with impaired methotrexate elimination and following a methotrexate overdose, administer intravenous fluids (3 L/day) and alkalinize the urine to maintain the urine pH at 7.0 or greater. ( 2.2 ) Recommended Dosage to Treat FOLR1-CFTD Initiate oral leucovorin calcium tablets as follows based on body weight: Less than 40 kg: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 8.5 mg/kg/day. ( 2.3 ) 40 kg or more: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 330 mg/day. ( 2.3 ) Administer the total daily dosage once daily or in divided doses up to 6 times per day. ( 2.3 ) Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. ( 2.3 ) 2.1 Important Administration Instructions Each indication has a different method for calculating the dosage (i.e., fixed dosage, body surface area-based dosage, or body weight-based dosage). Ensure that the correct method for calculating the dosage is used [see Dosage and Administration ( 2.2 , 2.3 )]. Leucovorin calcium tablets are for oral administration only and can be taken with or without food [see Clinical Pharmacology ( 12.3 )]. Crushing of leucovorin tablets and mixing with food or liquid (e.g., water, breastmilk, infant formula) has been reported in literature. If administering via this method, administer immediately after mixing. 2.2 Recommended Dosage to Reduce the Toxicity of Methotrexate in Patients with Impaired Methotrexate Elimination or to Reduce the Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Following Overdose Administer leucovorin calcium tablets as soon as possible after a folic acid antagonist or DHFR inhibitor overdose and within 24 hours of methotrexate administration when there is impaired methotrexate elimination. The effectiveness of leucovorin calcium tablets decreases as the time interval between leucovorin calcium tablets administration and the folic acid antagonist or DHFR inhibitor increases. For patients with impaired methotrexate elimination, monitor serum methotrexate concentrations and serum creatinine to determine the recommended dosage and duration of leucovorin calcium tablets. For patients with impaired methotrexate elimination and in patients following a methotrexate overdose, administer intravenous fluids (3 Liters per day) and alkalinize the urine to maintain a urine pH of 7.0 or greater.

and serum creatinine to determine the recommended dosage and duration of leucovorin calcium tablets. For patients with impaired methotrexate elimination and in patients following a methotrexate overdose, administer intravenous fluids (3 Liters per day) and alkalinize the urine to maintain a urine pH of 7.0 or greater. The recommended leucovorin calcium tablets dosage to reduce methotrexate toxicity in patients with impaired methotrexate elimination: 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). When a dosage greater than 25 mg every 6 hours is needed for this use, leucovorin calcium tablets are not recommended because this dosage and the formulation may be inadequate to treat significant methotrexate toxicity, resulting in possible methotrexate toxicity fatalities. Refer to the prescribing information for leucovorin injection for dosage recommendations. 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, higher doses of leucovorin are needed; discontinue oral administration of leucovorin calcium tablets and administer leucovorin intravenously or intramuscularly. Refer to the prescribing information for leucovorin injection for the appropriate dosage and duration. In patients who experience non-oliguric renal failure, continue leucovorin, hydration and alkalinization of the urine (pH of 7.0 or greater) until the methotrexate level is 0.05 micromolar. Extend the duration of leucovorin calcium tablets administration for an additional 24 hours in subsequent courses of methotrexate in patients who experience significant methotrexate toxicities, impaired methotrexate elimination including third-space fluid accumulation and inadequate hydration, or renal impairment. The recommended leucovorin calcium tablets dosage to reduce the toxicity of folic acid antagonists or DHFR inhibitors (trimethoprim or pyrimethamine) following an overdose: 5 mg to 15 mg orally once daily. 2.3 Recommended Dosage for Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant The recommended oral dosage of leucovorin calcium tablets for patients with FOLR1-CFTD is based on the patient’s weight (see Table 1). Adjust dosage based on clinical response [see Clinical Studies ( 14.1 )] . Table 1. Recommended Leucovorin calcium tablets Dosage for Patients with FOLR1-CFTD Patient Weight Initial Total Daily Dosage a Maximum Total Daily Dosage a Frequency of Administration b Less than 40 kg 1 to 2 mg/kg/day 8.5 mg/kg/day Administer the total daily dosage once daily or in divided doses up to 6 times per day. Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. 40 kg or more 1 to 2 mg/kg/day 330 mg/day a Round doses to the nearest tablet strength or combination of strengths. b Bioavailability is reduced with individual leucovorin doses above 25 mg in adults [see Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Leucovorin calcium tablets, USP: 5 mg: White, round, biconvex tablets, debossed with “stylized b” on one side and 484 on the other side 25 mg: Pale green, round, biconvex tablets, debossed with “stylized b” on one side and 485 on the other side Tablets: 5 mg of leucovorin, 25 mg of leucovorin ( 3 )

4 CONTRAINDICATIONS Leucovorin calcium tablets are contraindicated in patients with a history of hypersensitivity reaction depending on indication as described below, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of leucovorin calcium tablets [see Description ( 11 )]: Folic acid antagonist or DHFR inhibitor toxicity: history of severe hypersensitivity reaction FOLR1-CFTD: history of any hypersensitivity reaction Reactions have included anaphylactic reactions [see Warnings and Precautions ( 5.1 )] . History of hypersensitivity reaction, depending on indication, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of leucovorin calcium tablets: folic acid antagonist or DHFR inhibitor toxicity: history of a severe hypersensitivity reaction FOLR1-CFTD: history of any hypersensitivity reaction. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Withhold or permanently discontinue leucovorin calcium tablets based on severity and indication. ( 4 , 5.1 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. Leucovorin calcium tablets are contraindicated for the treatment of folic acid antagonist or DHFR inhibitor toxicity in patients with a history of a severe hypersensitivity reaction and for the treatment of FOLR1-CFTD in patients with a history of any hypersensitivity reaction to leucovorin, levoleucovorin, folic acid, or any component of leucovorin calcium tablets [see Contraindications ( 4 )] . Withhold or permanently discontinue leucovorin calcium tablets based on the severity of hypersensitivity.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )]. The following adverse reactions have been identified during postapproval use of leucovorin (d,l-leucovorin) or levoleucovorin (l-leucovorin). Because these 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. Dermatologic: Pruritus, rash. Respiratory: Dyspnea. Other Clinical Events: Rigors, temperature change. Safety information for the treatment of FOLR1-CFTD with oral leucovorin is limited. The available evidence is based on published case reports [see Clinical Studies ( 14.1 )] . Adverse reactions included pruritus, rash, urticaria, dyspnea, hypersensitivity reactions, rigors, and temperature change. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

7 DRUG INTERACTIONS Certain Antiepileptic Drugs : Increase monitoring for seizure activity in leucovorin-treated patients taking certain concomitant antiepileptic drugs. Certain antiepileptic drugs may reduce the effectiveness of leucovorin calcium tablets. ( 7.1 , 7.2 ) Trimethoprim-Sulfamethoxazole : Avoid concomitant use of leucovorin calcium tablets with trimethoprim-sulfamethoxazole. ( 7.1 ) Fluorouracil : Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients. ( 7.1 ) 7.1 Effects of Leucovorin on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in leucovorin-treated patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures in susceptible patients, including pediatric patients. It is not known whether folinic acid, including leucovorin calcium tablets, has the same effects; however, both folic and folinic acids, including leucovorin calcium tablets, share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of leucovorin calcium tablets with trimethoprim-sulfamethoxazole. The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with leucovorin calcium tablets, which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia. Fluorouracil 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. Concomitant granulocytopenia and fever were present in some but not all of the patients. 7.2 Effect of Other Drugs on Leucovorin Certain antiepileptic drugs may reduce folate absorption and metabolism leading to folate deficiency. As folic acid and folinic acid share common metabolic pathways, certain antiepileptic drugs may reduce the effectiveness of leucovorin calcium tablets.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the intermittent use of leucovorin for the treatment of folic acid antagonist or DHFR inhibitor toxicity during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no adequate data on the use of leucovorin for the treatment of FOLR1-CFTD in pregnant women. Adequate animal reproductive and developmental studies have not been conducted with leucovorin. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risks with Concomitant Use of Leucovorin calcium tablets and Chemotherapy Drugs administered in combination with leucovorin calcium tablets may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with leucovorin calcium tablets for additional information, as appropriate. 8.2 Lactation Risk Summary There are no data on the presence of leucovorin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for leucovorin calcium tablets and any potential adverse effects on the breastfed infant from leucovorin or from the underlying maternal condition. Refer to the Prescribing Information for chemotherapy administered in combination with leucovorin calcium tablets for breastfeeding recommendations, as appropriate. 8.4 Pediatric Use Leucovorin calcium tablets are indicated for the treatment of cerebral folate transport deficiency in pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD) [see Clinical Studies ( 14.1 )] . The safety and effectiveness of leucovorin calcium tablets have not been established to reduce the toxicity of methotrexate in pediatric patients with impaired methotrexate elimination or in pediatric patients to reduce the toxicity of folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose. 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 [see Drug Interactions ( 7.1 )] . 8.5 Geriatric Use There is insufficient information in patients 65 years of age and older on the use of leucovorin calcium tablets to reduce the toxicity of methotrexate, other folic acid antagonists, or DHFR inhibitors, and there is no information on the use of leucovorin calcium tablets to treat FOLR1-CFTD in patients 65 years of age and older to determine whether they respond differently from younger patients [see Clinical Studies ( 14.1 )] .

8.1 Pregnancy Risk Summary Available data on the intermittent use of leucovorin for the treatment of folic acid antagonist or DHFR inhibitor toxicity during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no adequate data on the use of leucovorin for the treatment of FOLR1-CFTD in pregnant women. Adequate animal reproductive and developmental studies have not been conducted with leucovorin. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risks with Concomitant Use of Leucovorin calcium tablets and Chemotherapy Drugs administered in combination with leucovorin calcium tablets may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with leucovorin calcium tablets for additional information, as appropriate.

8.4 Pediatric Use Leucovorin calcium tablets are indicated for the treatment of cerebral folate transport deficiency in pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD) [see Clinical Studies ( 14.1 )] . The safety and effectiveness of leucovorin calcium tablets have not been established to reduce the toxicity of methotrexate in pediatric patients with impaired methotrexate elimination or in pediatric patients to reduce the toxicity of folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose. 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 [see Drug Interactions ( 7.1 )] .

8.5 Geriatric Use There is insufficient information in patients 65 years of age and older on the use of leucovorin calcium tablets to reduce the toxicity of methotrexate, other folic acid antagonists, or DHFR inhibitors, and there is no information on the use of leucovorin calcium tablets to treat FOLR1-CFTD in patients 65 years of age and older to determine whether they respond differently from younger patients [see Clinical Studies ( 14.1 )] .

11 DESCRIPTION Leucovorin is a racemic mixture of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)- L -Levoisomer, known as Citrovorum factor , or (-)-folinic acid or levoleucovorin. Leucovorin is a water soluble form of reduced folate in the folate group. The chemical name of leucovorin, a folate analog, is 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. The structural formula of leucovorin calcium is: C 20 H 21 CaN 7 O 7 M.W. 511.5 g/mol Leucovorin calcium tablets, USP are for oral administration. Each 5 mg tablet contains 5 mg of leucovorin (equivalent to 5.4 mg of leucovorin calcium, USP), and each 25 mg tablet contains 25 mg of leucovorin (equivalent to 27.01 mg of leucovorin calcium, USP). The 5 mg and 25 mg tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Additionally, the 25 mg tablet contains D&C yellow no.10 aluminum lake and FD&C blue no.1 aluminum lake. 1

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Levoleucovorin, a reduced folate and the pharmacologically active isomer of leucovorin (5-formyl- tetrahydrofolic acid), can mitigate the toxic effects of folate antagonists, including methotrexate and other agents that inhibit dihydrofolate reductase (DHFR). Inhibition of DHFR blocks the formation of tetrahydrofolate, an essential cofactor for DNA synthesis and repair. Levoleucovorin has been observed to increase levels of 5-MTHF, an active metabolite of folate, in case studies of FOLR1-CFTD [see Clinical Studies ( 14.1 )] . 12.2 Pharmacodynamics Levoleucovorin and its metabolites (5,10-methenyltetrahydrofolate, 5,10-methylenetetrahydrofolate, and 5-MTHF) serve as cofactors in “one carbon” metabolism. These reactions are involved in the generation of nucleic acids and the regulation of gene expression. 12.3 Pharmacokinetics Leucovorin is a racemic mixture of (l)- or levoleucovorin and (d)- or dextroleucovorin. Following oral administration of leucovorin to healthy adults, dextroleucovorin, levoleucovorin, and 5-MTHF exposures increased in a dose proportional manner with doses up to 25 mg, but in a less than dose proportional manner with doses greater than 25 mg. Absorption Following oral administration of leucovorin in adults, the apparent bioavailability of levoleucovorin is 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg, and dextroleucovorin is approximately 19% for 25 mg, 20% for 50 mg, and 7% for 100 mg. After a single oral 15 mg (7.5 mg/m 2 ) dose of leucovorin, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of leucovorin has not been evaluated. As leucovorin is a highly soluble and well absorbed drug, and different immediate-release oral formulations of leucovorin (oral tablet and oral solution) showed relatively higher bioavailability of total folates (>95%), food is not expected to have a clinically significant effect on the pharmacokinetics of leucovorin or 5-MTHF. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. Distribution Levoleucovorin is minimally bound to human serum albumin. The reported human serum albumin binding of 5-MTHF ranges from 42-49%. Leucovorin is not observed in cerebrospinal fluid (CSF) and 5-MTHF is reported to accumulate in CSF in children with leukemia. Elimination After intravenous administration of leucovorin in adults, the reported mean plasma elimination half-life in the literature was 0.5-1.3 hours for levoleucovorin and 3-7 hours for 5-MTHF. Metabolism: Following administration of oral leucovorin, levoleucovorin undergoes metabolism in intestinal cells via methenyltetrahydrofolate synthetase (MTHFS) and methylenetetrahydrofolate reductase (MTHFR) to its active metabolite, 5-MTHF. 5-MTHF is the main active metabolite in plasma after oral administration of leucovorin. Excretion: Leucovorin is mainly excreted by the kidney as unchanged dextroleucovorin, levoleucovorin, or as 5-MTHF, the metabolic product of levoleucovorin. Specific Populations Patients with Renal Impairment: The kidney is reported to contribute to the elimination of dextroleucovorin, levoleucovorin and its active metabolite, and plasma concentrations of dextroleucovorin, levoleucovorin, and 5-MTHF may be increased in patients with renal impairment. However, clinical studies on the impact of renal impairment have not been conducted.

12.1 Mechanism of Action Levoleucovorin, a reduced folate and the pharmacologically active isomer of leucovorin (5-formyl- tetrahydrofolic acid), can mitigate the toxic effects of folate antagonists, including methotrexate and other agents that inhibit dihydrofolate reductase (DHFR). Inhibition of DHFR blocks the formation of tetrahydrofolate, an essential cofactor for DNA synthesis and repair. Levoleucovorin has been observed to increase levels of 5-MTHF, an active metabolite of folate, in case studies of FOLR1-CFTD [see Clinical Studies ( 14.1 )] .

12.2 Pharmacodynamics Levoleucovorin and its metabolites (5,10-methenyltetrahydrofolate, 5,10-methylenetetrahydrofolate, and 5-MTHF) serve as cofactors in “one carbon” metabolism. These reactions are involved in the generation of nucleic acids and the regulation of gene expression.

12.3 Pharmacokinetics Leucovorin is a racemic mixture of (l)- or levoleucovorin and (d)- or dextroleucovorin. Following oral administration of leucovorin to healthy adults, dextroleucovorin, levoleucovorin, and 5-MTHF exposures increased in a dose proportional manner with doses up to 25 mg, but in a less than dose proportional manner with doses greater than 25 mg. Absorption Following oral administration of leucovorin in adults, the apparent bioavailability of levoleucovorin is 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg, and dextroleucovorin is approximately 19% for 25 mg, 20% for 50 mg, and 7% for 100 mg. After a single oral 15 mg (7.5 mg/m 2 ) dose of leucovorin, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of leucovorin has not been evaluated. As leucovorin is a highly soluble and well absorbed drug, and different immediate-release oral formulations of leucovorin (oral tablet and oral solution) showed relatively higher bioavailability of total folates (>95%), food is not expected to have a clinically significant effect on the pharmacokinetics of leucovorin or 5-MTHF. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. Distribution Levoleucovorin is minimally bound to human serum albumin. The reported human serum albumin binding of 5-MTHF ranges from 42-49%. Leucovorin is not observed in cerebrospinal fluid (CSF) and 5-MTHF is reported to accumulate in CSF in children with leukemia. Elimination After intravenous administration of leucovorin in adults, the reported mean plasma elimination half-life in the literature was 0.5-1.3 hours for levoleucovorin and 3-7 hours for 5-MTHF. Metabolism: Following administration of oral leucovorin, levoleucovorin undergoes metabolism in intestinal cells via methenyltetrahydrofolate synthetase (MTHFS) and methylenetetrahydrofolate reductase (MTHFR) to its active metabolite, 5-MTHF. 5-MTHF is the main active metabolite in plasma after oral administration of leucovorin. Excretion: Leucovorin is mainly excreted by the kidney as unchanged dextroleucovorin, levoleucovorin, or as 5-MTHF, the metabolic product of levoleucovorin. Specific Populations Patients with Renal Impairment: The kidney is reported to contribute to the elimination of dextroleucovorin, levoleucovorin and its active metabolite, and plasma concentrations of dextroleucovorin, levoleucovorin, and 5-MTHF may be increased in patients with renal impairment. However, clinical studies on the impact of renal impairment have not been conducted. Patients with Hepatic Impairment: The liver is reported to contribute to the metabolism of levoleucovorin, and plasma concentrations of levoleucovorin and 5-MTHF may be increased in patients with hepatic impairment. However, clinical studies on the impact of hepatic impairment have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies to assess the potential for carcinogenicity or genotoxicity, or for adverse effects on fertility have not been conducted for leucovorin.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Leucovorin calcium tablets, USP contain: 5 mg: White, round, biconvex tablets, debossed with “stylized b” on one side and 484 on the other side, packaged in bottles of 30 (NDC 0555-0484-01) and 100 (NDC 0555-0484-02) tablets. 25 mg: Pale green, round, biconvex tablets, debossed with “stylized b” on one side and 485 on the other side, packaged in bottles of 25 (NDC 0555-0485-27) tablets. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light and moisture. Keep this and all medications out of the reach of children.

17 PATIENT COUNSELING INFORMATION Administration Instructions Advise patients or caregivers that leucovorin tablets may be dissolved in an age-appropriate liquid (e.g., water, breastmilk, or infant formula) or crushed and mixed with soft food before administration. If leucovorin is to be administered in this manner, instruct patients or caregivers to administer the dissolved or mixed product immediately after mixing [see Dosage and Administration ( 2.1 )] . Hypersensitivity Reactions Advise patients to inform their healthcare provider if they develop a hypersensitivity reaction while taking leucovorin calcium tablets [see Warnings and Precautions ( 5.1 )] . Drug Interactions Advise patients to inform their healthcare providers of all concomitant drugs, including prescription drugs, nonprescription drugs, vitamins, and herbal products [see Drug Interactions ( 7 )] . Manufactured In Bulgaria By: Balkanpharma Dupnitsa AD Dupnitsa 2600, Bulgaria Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. D 3/2026

DESCRIPTION Leucovorin 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-[[[(6 RS )-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 calcium is: C 20 H 21 CaN 7 O 7 M.W=511.50 Leucovorin 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 calcium equivalent to 10 mg Leucovorin, USP; 8 mg sodium chloride; sodium hydroxide and/or hydrochloric acid for pH adjustment (pH 6.5 to 8.5). There is 0.004 mEq of calcium per mg of leucovorin. Solution contains no bacteriostat or antimicrobial agents. One milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium. leucovorin-stru

CLINICAL PHARMACOLOGY Leucovorin 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 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 (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 FADH 2 and NADPH. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin 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 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 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, d -leucovorin 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 (200 mg/m 2 ) 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.

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 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 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 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 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. 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 (LV) 200 mg/m 2 and 5-fluorouracil (5-FU) 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 versus 5-FU 500 mg/m 2 . 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/m 2 and 5-FU 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 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.

INDICATIONS & USAGE Leucovorin calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin 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 calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

CONTRAINDICATIONS Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12 . A hematologic remission may occur while neurologic manifestations continue to progress.

WARNINGS In the treatment of accidental overdosages of folic acid antagonists, intravenous 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 toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally. LEUCOVORIN 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. 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. 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). Leucovorin 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 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/m 2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin. 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/5-fluorouracil combination than in patients treated with the high dose combination -11% versus 3%. Therapy with leucovorin 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, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, 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. 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 morbidity in a placebo-controlled study.

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 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 enhances the toxicity of fluorouracil, leucovorin/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/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 (Table 1), based on the most severe toxicities: Table 1: Dosage modifications for fluorouracil Diarrhea and/or Stomatitis WBC/mm 3 Nadir Platelets/mm 3 Nadir 5-FU dose Moderate 1,000 to 1,900 25 to 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/mm 3 and platelets 130,000/mm 3 . 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. 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 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 may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS ). Pregnancy Teratogenic Effects: Pregnancy Category C. Adequate 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 PRECAUTIONS , Drug Interactions . Geriatric Use Clinical studies of leucovorin calcium did not show differences in safety or effectiveness between subjects over 65 and younger subjects.

y drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother. Pediatric Use See PRECAUTIONS , Drug Interactions . 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 elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this patient population.

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">Diarrhea and/or Stomatitis </td><td styleCode="Rrule" align="center" valign="top">WBC/mm³Nadir </td><td styleCode="Rrule" align="center" valign="top">Platelets/mm³ Nadir </td><td styleCode="Rrule" align="center" valign="top">5-FU dose </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top">Moderate </td><td styleCode="Rrule" align="center" valign="top">1,000 to 1,900 </td><td styleCode="Rrule" align="center" valign="top">25 to 75,000 </td><td styleCode="Rrule" align="center" valign="top">decrease 20% </td></tr><tr><td styleCode="Lrule Rrule" align="center" valign="top">Severe </td><td styleCode="Rrule" align="center" valign="top">&lt;1,000 </td><td styleCode="Rrule" align="center" valign="top">&lt;25,000 </td><td styleCode="Rrule" align="center" valign="top">decrease 30% </td></tr></tbody></table>

Laboratory Tests Patients being treated with the leucovorin/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 (Table 1), based on the most severe toxicities: Table 1: Dosage modifications for fluorouracil Diarrhea and/or Stomatitis WBC/mm 3 Nadir Platelets/mm 3 Nadir 5-FU dose Moderate 1,000 to 1,900 25 to 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/mm 3 and platelets 130,000/mm 3 . 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.

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 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 may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS ).

Pregnancy Teratogenic Effects: Pregnancy Category C. Adequate 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.

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 elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this patient population.

ADVERSE REACTIONS Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. Anaphylactic reactions, including shock, have been reported. No other adverse reactions have been attributed to the use of leucovorin per se . Table 2 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. TABLE 2: 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+ (%) 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 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines (Table 3): TABLE 3: 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 micro-molar 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.

<table cellspacing="0" cellpadding="0" border="0" width="849.87"><colgroup><col width="30.2034428794992%"/><col width="9.70266040688576%"/><col width="15.0234741784038%"/><col width="9.54616588419405%"/><col width="14.8669796557121%"/><col width="8.1377151799687%"/><col width="12.5195618153365%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">(High LV) /5-FU (N=155) </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">(Low LV) /5-FU (N=161) </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">5-FU Alone (N=70) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> </td><td styleCode="Rrule" align="center" valign="middle">Any (%) </td><td styleCode="Rrule" align="center" valign="middle">Grade 3+ (%) </td><td styleCode="Rrule" align="center" valign="middle">Any (%) </td><td styleCode="Rrule" align="center" valign="middle">Grade 3+ (%) </td><td styleCode="Rrule" align="center" valign="middle">Any (%) </td><td styleCode="Rrule" align="center" valign="middle">Grade 3+ (%) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Leukopenia </td><td styleCode="Rrule" align="center" valign="middle">69 </td><td styleCode="Rrule" align="center" valign="middle">14 </td><td styleCode="Rrule" align="center" valign="middle">83 </td><td styleCode="Rrule" align="center" valign="middle">23 </td><td styleCode="Rrule" align="center" valign="middle">93 </td><td styleCode="Rrule" align="center" valign="middle">48 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Thrombocytopenia </td><td styleCode="Rrule" align="center" valign="middle">8 </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">8 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Infection </td><td styleCode="Rrule" align="center" valign="middle">8 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">7 </td><td styleCode="Rrule" align="center" valign="middle">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Nausea </td><td styleCode="Rrule" align="center" valign="middle">74 </td><td styleCode="Rrule" align="center" valign="middle">10 </td><td styleCode="Rrule" align="center" valign="middle">80 </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">60 </td><td styleCode="Rrule" align="center" valign="middle">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Vomiting </td><td styleCode="Rrule" align="center" valign="middle">46 </td><td styleCode="Rrule" align="center" valign="middle">8 </td><td styleCode="Rrule" align="center" valign="middle">44 </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">40 </td><td styleCode="Rrule" align="center" valign="middle">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td>

Code="Rrule" align="center" valign="middle">44 </td><td styleCode="Rrule" align="center" valign="middle">9 </td><td styleCode="Rrule" align="center" valign="middle">40 </td><td styleCode="Rrule" align="center" valign="middle">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Diarrhea </td> <td styleCode="Rrule" align="center" valign="middle">66 </td><td styleCode="Rrule" align="center" valign="middle">18 </td><td styleCode="Rrule" align="center" valign="middle">67 </td><td styleCode="Rrule" align="center" valign="middle">14 </td><td styleCode="Rrule" align="center" valign="middle">43 </td><td styleCode="Rrule" align="center" valign="middle">11 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Stomatitis </td><td styleCode="Rrule" align="center" valign="middle">75 </td><td styleCode="Rrule" align="center" valign="middle">27 </td><td styleCode="Rrule" align="center" valign="middle">84 </td><td styleCode="Rrule" align="center" valign="middle">29 </td><td styleCode="Rrule" align="center" valign="middle">59 </td><td styleCode="Rrule" align="center" valign="middle">16 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Constipation </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">0 </td><td styleCode="Rrule" align="center" valign="middle">4 </td><td styleCode="Rrule" align="center" valign="middle">0 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">- </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Lethargy/Malaise/Fatigue </td><td styleCode="Rrule" align="center" valign="middle">13 </td><td styleCode="Rrule" align="center" valign="middle">3 </td><td styleCode="Rrule" align="center" valign="middle">12 </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">6 </td><td styleCode="Rrule" align="center" valign="middle">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Alopecia </td><td styleCode="Rrule" align="center" valign="middle">42 </td><td styleCode="Rrule" align="center" valign="middle">5 </td><td styleCode="Rrule" align="center" valign="middle">43 </td><td styleCode="Rrule" align="center" valign="middle">6 </td><td styleCode="Rrule" align="center" valign="middle">37 </td><td styleCode="Rrule" align="center" valign="middle">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Dermatitis </td><td styleCode="Rrule" align="center" valign="middle">21 </td><td styleCode="Rrule" align="center" valign="middle">2 </td><td styleCode="Rrule" align="center" valign="middle">25 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">13 </td><td styleCode="Rrule" align="center" valign="middle">- </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle">Anorexia </td><td styleCode="Rrule" align="center" valign="middle">14 </td><td styleCode="Rrule" align="center" valign="middle">1 </td><td styleCode="Rrule" align="center" valign="middle">22 </td><td styleCode="Rrule" align="center" valign="middle">4 </td><td styleCode="Rrule" align="center" valign="middle">14 </td><td styleCode="Rrule" align="center" valign="middle">- </td></tr><tr><td styleCode="Lrule Rrule" valign="middle">Hospitalization for Toxicity </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">5% </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">15% </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">7% </td></tr></tbody></table>

><td styleCode="Lrule Rrule" valign="middle">Hospitalization for Toxicity </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">5% </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">15% </td><td styleCode="Rrule" colspan="2" align="center" valign="middle">7% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="667"><colgroup><col width="29.7859571914383%"/><col width="42.3084616923385%"/><col width="27.9055811162232%"/></colgroup><thead><tr><th styleCode="Lrule Rrule Toprule" align="center"><content styleCode="bold">Clinical</content> <content styleCode="bold">Situation</content><content styleCode="bold"/> </th><th styleCode="Lrule Rrule Toprule" align="center"><content styleCode="bold">Laboratory Findings</content> </th><th styleCode="Lrule Rrule Toprule" align="center"><content styleCode="bold">Leucovorin Dosage</content> <content styleCode="bold">and Duration</content> </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Normal Methotrexate Elimination </td><td styleCode="Rrule" valign="top">Serum methotrexate level approximately 10 micro-molar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. </td><td styleCode="Rrule" valign="top">15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Delayed Late Methotrexate Elimination </td><td styleCode="Rrule" valign="top">Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. </td><td styleCode="Rrule" valign="top">Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury </td><td styleCode="Rrule" valign="top">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). </td><td styleCode="Rrule" valign="top">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. </td></tr></tbody></table>

DOSAGE & ADMINISTRATION Advanced Colorectal Cancer Either of the following two regimens is recommended: 1. Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. 2. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 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 dosage 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/m 2 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/m 2 ) 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 alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10 -8 M (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 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 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.

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 a delayed excretion (see WARNINGS ). Leucovorin 10 mg/m 2 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 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 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 100 mg/m 2 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. 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 drug 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 Injection USP, 10 mg per mL, is supplied in sterile, single use vials as follows: Product No. NDC No. Strength 603150 63323-631-50 500 mg per 50 mL (10 mg per mL) 50 mL ready-to-use vial,packaged individually. Store in refrigerator 2° to 8°C (36° to 46°F). Protect from light . Discard unused portion. Retain in carton until time of use. The container closure is not made with natural rubber latex. Manufactured for: Fresenius Kabi USA, LLC Lake Zurich, IL 60047 Made in Austria For Product Inquiry: 1-800-551-7176 or www.fresenius-kabi.com/us 451386A/Revised: April 2018 logo.1

<table cellspacing="0" cellpadding="0" border="0" width="690"><colgroup><col width="13.6231884057971%"/><col width="19.1304347826087%"/><col width="16.3768115942029%"/><col width="50.8695652173913%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Product No.</content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">NDC No.</content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Strength</content> </td><td styleCode="Rrule" valign="top"> </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top">603150 </td><td styleCode="Rrule" align="justify" valign="top">63323-631-50 </td><td styleCode="Rrule" align="center" valign="top">500 mg per 50 mL (10 mg per mL) </td><td styleCode="Rrule" align="justify" valign="top">50 mL ready-to-use vial,packaged individually. </td></tr></tbody></table>

DESCRIPTION Leucovorin 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-[[[(6 RS )-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 calcium is: - C 20 H 21 CaN 7 O 7 M.W.=511.51 Leucovorin Calcium for Injection, USP is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 350 mg vial. Each 350 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL. In each dosage form, one milligram of leucovorin calcium, USP contains 0.002 mmol of leucovorin and 0.002 mmol of calcium. This lyophilized product contain no preservative. The inactive ingredient is Sodium Chloride, added to adjust tonicity. Sodium hydroxide may be added for pH adjustment. pH adjusted to 7.0 to 8.5. Reconstitute with Bacteriostatic Water for Injection, which contains benzyl alcohol (see WARNINGS section), or with Sterile Water for Injection. structure

CLINICAL PHARMACOLOGY Leucovorin 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 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 ( 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 FADH 2 and NADPH. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin 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 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 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, d -leucovorin 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 (200 mg/m 2 ) 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.

-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 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 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 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 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. 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 (LV) 200 mg/m 2 and 5-fluorouracil (5-FU) 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 versus 5-FU 500 mg/m 2 . 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/m 2 and 5-FU 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 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. The pharmacokinetics of 200 mg doses of leucovorin administered intravenously and orally (reconstituted powder, not tablets) have been evaluated in healthy male subjects. The serum clearance corrected for bioavailability, terminal half-life, and apparent volume of distribution of total folate were not significantly different between routes of administration. The oral bioavailability of the 200 mg dose was 31%. Eighty-three percent of the biologically active IV dose was recovered in the urine within 24 hours, 31% as 5-methyltetrahydrofolate. Twenty percent of the same oral dose was excreted in 24 hours, 16% as 5-methyltetrahydrofolate.

INDICATIONS AND USAGE Leucovorin Calcium rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin 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 Calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. 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 should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

WARNINGS In the treatment of accidental overdosages of folic acid antagonists, intravenous 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 toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not adminster leucovorin intrathecally. LEUCOVORIN 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. 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. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m 2 are administered, Leucovorin 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 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). Leucovorin 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 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/m 2 of leucovorin and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin. 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/5-fluorouracil combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with leucovorin 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, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.

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, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving leucovorin, 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. 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 morbidity in a placebo- controlled study.

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 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 enhances the toxicity of fluorouracil, leucovorin/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/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/mm 3 Nadir Platelets/mm 3 Nadir 5-FU Dose Moderate 1,000 to 1,900 25 to 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/mm 3 and platelets 130,000/mm 3 . 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. 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 lquantities of systemically administered leucovorin 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 may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS). Pregnancy Teratogenic Effects: Adequate 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 PRECAUTIONS, Drug Interactions. Geriatric Use: Clinical studies of leucovorin calcium did not show differences in safety or effectiveness between subjects over 65 and younger subjects.

y drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother. Pediatric Use: See PRECAUTIONS, Drug Interactions. 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.

<table width="100%" cellspacing="0pt" cellpadding="0pt"><col width="24%"/><col width="24%"/><col width="25%"/><col width="24%"/><tbody><tr><td align="center" valign="middle" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Diarrhea and/or Stomatitis</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold">WBC/mm³</content> <content styleCode="bold">Nadir</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold">Platelets/mm³</content> <content styleCode="bold">Nadir</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold">5-FU Dose</content> </paragraph></td></tr><tr><td align="center" valign="bottom" styleCode="Rrule Lrule Botrule "><paragraph>Moderate </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>1,000 to 1,900 </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>25 to 75,000 </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>decrease 20% </paragraph></td></tr><tr><td align="center" valign="bottom" styleCode="Rrule Botrule Lrule "><paragraph>Severe </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>&lt;1,000 </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>&lt;25,000 </paragraph></td><td align="center" valign="bottom" styleCode="Rrule Botrule "><paragraph>decrease 30% </paragraph></td></tr></tbody></table>

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+ § (%) (%) (%) (%) (%) (%) 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 200 mg/m 2 † Low LV = Leucovorin 20 mg/m 2 ‡ Any = percentage of patients reporting toxicity of any severity § Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="100%" cellspacing="0pt" cellpadding="0pt"><col width="30%"/><col width="10%"/><col width="14%"/><col width="9%"/><col width="13%"/><col width="8%"/><col width="14%"/><tbody><tr><td valign="middle" styleCode="Rrule Botrule Lrule Toprule "><paragraph> </paragraph></td><td colspan="2" align="center" valign="top" styleCode="Rrule Botrule Toprule "><paragraph>(High LV^*) /5-FU (N=155) </paragraph></td><td colspan="2" align="center" valign="top" styleCode="Rrule Botrule Toprule "><paragraph>(Low LV^&#x2020;)/5-FU (N=161) </paragraph></td><td colspan="2" align="center" valign="top" styleCode="Rrule Botrule Toprule "><paragraph>5-FU Alone (N=70) </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Any^&#x2021; </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Grade 3+ ^&#xA7; </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Any^&#x2021; </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Grade 3+^&#xA7; </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Any^&#x2021; </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>Grade 3+ ^&#xA7; </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph><content styleCode="underline">(%)</content> </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Leukopenia </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>69 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>14 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>83 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>23 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>93 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>48 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Thrombocytopenia </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>2 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </par

tyleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>2 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </par agraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>18 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>3 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Infection </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>3 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>7 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>2 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Nausea </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>74 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>10 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>80 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>9 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>60 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>6 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Vomiting </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>46 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>8 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>44 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>9 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>40 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>7 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Diarrhea </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>66 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>18 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>67 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>14 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>43 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>11 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Stomatitis </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>75 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>27 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>84 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>29 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>59 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>16 </paragraph></td></tr><tr><td valign="middle"

ragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>29 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>59 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>16 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Constipation </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>3 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>0 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>4 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>0 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>- </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Lethargy/Malaise/Fatigue </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>13 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>3 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>12 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>2 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>6 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>3 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Alopecia </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>42 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>5 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>43 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>6 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>37 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>7 </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Dermatitis </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>21 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>2 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>25 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>13 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>- </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Lrule Botrule "><paragraph>Anorexia </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>14 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>1 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>22 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>4 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>14 </paragraph></td><td align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>- </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Botrule Lrule "><paragraph>Hospitalization for Toxicity </paragraph></td><td colspan="2" align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>5% </paragraph></td><td colspan="2"

enter" valign="middle" styleCode="Rrule Botrule "><paragraph>- </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Botrule Lrule "><paragraph>Hospitalization for Toxicity </paragraph></td><td colspan="2" align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>5% </paragraph></td><td colspan="2" align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>15% </paragraph></td><td colspan="2" align="center" valign="middle" styleCode="Rrule Botrule "><paragraph>7% </paragraph></td></tr></tbody></table>

DOSAGE AND ADMINISTRATION Advanced Colorectal Cancer Either of the following two regimens is recommended: • 1.Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. • 2.Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5- fluorouracil at 425 mg/m 2 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/m 2 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/m 2 ) 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 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 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).

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 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 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/m 2 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 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 100 mg/m 2 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 350 mg vial of Leucovorin Calcium for Injection when reconstituted with 17.5 mL of sterile diluent yields a leucovorin concentration of 20 mg per mL. Leucovorin Calcium for Injection contains no preservative. Reconstitute the lyophilized vial product with Bacteriostatic Water for Injection (benzyl alcohol preserved), or Sterile Water for Injection. When reconstituted with Bacteriostatic Water for Injection, the resulting solution must be used within 7 days. If the product is reconstituted with Sterile Water for Injection, use immediately and discard any unused portion.

Bacteriostatic Water for Injection (benzyl alcohol preserved), or Sterile Water for Injection. When reconstituted with Bacteriostatic Water for Injection, the resulting solution must be used within 7 days. If the product is reconstituted with Sterile Water for Injection, use immediately and discard any unused portion. Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, when doses greater than 10 mg/m 2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, 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 (White to yellow color lyophilized cake or powder) is supplied as a sterile lyophilized powder as follows: NDC Leucovorin Calcium for Injection, USP Package Factor 68462-767-35 350 mg Single-Dose Vial 1 vial per carton Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light . Retain in carton until time of use. Discard unused portion. For Product Inquiry call 1 (888) 721-7115. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Revised: May 2025 glenmarklogo

<table width="100%" cellspacing="0pt" cellpadding="0pt"><col width="21%"/><col width="44%"/><col width="33%"/><tbody><tr><td valign="middle" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">NDC</content> </paragraph></td><td valign="middle" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold">Leucovorin Calcium for Injection, USP</content> </paragraph></td><td valign="middle" styleCode="Rrule Botrule Toprule "><paragraph><content styleCode="bold">Package Factor</content> </paragraph></td></tr><tr><td valign="middle" styleCode="Rrule Botrule Lrule "><paragraph>68462-767-35 </paragraph></td><td valign="middle" styleCode="Rrule Botrule "><paragraph>350 mg Single-Dose Vial </paragraph></td><td valign="middle" styleCode="Rrule Botrule "><paragraph>1 vial per carton </paragraph></td></tr></tbody></table>