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Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin, present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin].
Fusilev for Injection and Fusilev Injection contain levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate. The molecular weight is 601.6 and the structural formula is:
 |
Its molecular formula is: C20H21CaN7O7• 5H2O.
Fusilev for Injection is supplied as a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol per 50 mg vial. Sodium hydroxide and/or hydrocholoric acid are used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 5.3 mL of sterile 0.9% Sodium Chloride Injection, USP [See DOSAGE AND ADMINISTRATION]
Fusilev Injection is supplied as a sterile solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5).
Fusilev is indicated for:
Fusilev is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.
Fusilev is indicated for intravenous administration only. Do not administer intrathecally.
Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture.
The recommended dosage for Fusilev is based on a methotrexate dose of 12 grams/m² administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate Fusilev at a dose of 7.5 mg (approximately 5 mg/m²) as an intravenous infusion every 6 hours. Â Monitor serum creatinine and methotrexate levels at least once daily. Continue Fusilev administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Adjust the Fusilev dose or extend the duration as recommended in Table 1.
Table 1 : Recommended Dosage for Fusilev based on Serum Methotrexate and Creatinine Levels
| CLINICAL SITUATION | LABORATORY FINDINGS | RECOMMENDATION |
| 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 | Administer 7.5 mg by intravenous infusion every 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 7.5 mg by intravenous infusion every 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). | Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar. |
| *These patients are likely to develop reversible renal failure. In addition to appropriate Fusilev therapy, continue hydration and urinary alkalinization and monitoring fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. | ||
Decreased methotrexate elimination or renal impairment which are clinically important but less severe than the abnormalities described in Table 1 can occur following methotrexate administration. If toxicity associated with methotrexate is observed, in subsequent courses extend Fusilev rescue for an additional 24 hours (total of 14 doses over 84 hours).
Third-Space Fluid Collection and Other Causes of Delayed Methotrexate Elimination Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration can delay methotrexate elimination. Under such circumstances, higher doses of Fusilev or prolonged administration may be indicated.
Start Fusilev as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and Fusilev increases, the effectiveness of Fusilev to diminish methotrexate toxicity may decrease. Administer Fusilev 7.5 mg (approximately 5 mg/m²) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10-8 M (0.05 micromolar).
Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of Fusilev to 50 mg/m² intravenously every 3 hours and continue Fusilev at this dosage until the methotrexate level is less than 5 x 10-8 M for the following:
Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater.
The following regimens have been used for the treatment of colorectal cancer:
Administer Fluorouracil and Fusilev separately to avoid the formation of a precipitate.
This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from the toxicity from the prior course. Do not adjust Fusilev dosage for toxicity.
Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions.
Fusilev (levoleucovorin) for injection is a sterile white to pale yellow lyophilized powder in a single-dose vial available as:
50 mg per vial – NDC 72893-009-01
Store at 20°C to 25°C (68°F to 77°F) in carton until contents are used. Excursions permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from light.
Manufactured for Acrotech Biopharma Inc., East Windsor, NJ 08520. Revised: Mar 2023
The following clinically significant adverse reactions are described elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m² followed by Fusilev rescue for osteosarcoma in 16 patients aged 6 to 21 years. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration.
Table 2 : Adverse Reactions with High-Dose Methotrexate Therapy
| ADVERSE REACTIONS | FUSILEV N=16 |
|
| All Grades (%) | Grade 3-4 (%) | |
| Gastrointestinal | ||
| Stomatitis | 38 | 6 |
| Vomiting | 38 | 0 |
| Nausea | 19 | 0 |
| Diarrhea | 6 | 0 |
| Dyspepsia | 6 | 0 |
| Typhlitis | 6 | 6 |
| Respiratory | ||
| Dyspnea | 6 | 0 |
| Skin and Appendages | ||
| Dermatitis | 6 | 0 |
| Other | ||
| Confusion | 6 | 0 |
| Neuropathy | 6 | 0 |
| Renal function abnormal | 6 | 0 |
| Taste perversion | 6 | 0 |
Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l-leucovorin. Patients were randomized to fluorouracil 370 mg/m² intravenously and levoleucovorin 100 mg/m² intravenously, both daily for 5 days, or to fluorouracil 370 mg/m² intravenously and d,l-leucovorin 200 mg/m² intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.
Table 3 : Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm
| ADVERSE REACTION | LEVOLEUCOVORIN /FLUOROURACIL N=318 |
D,L- LEUCOVORIN /FLUOROURACIL N=307 |
||
| Grades 1-4 (%) | Grades 3-4 (%) | Grades 1-4 (%) | Grades 3-4 (%) | |
| Gastrointestinal Disorders | ||||
| Stomatitis | 72 | 12 | 72 | 14 |
| Diarrhea | 70 | 19 | 65 | 17 |
| Nausea | 62 | 8 | 61 | 8 |
| Vomiting | 40 | 5 | 37 | 6 |
| Abdominal Pain1 | 14 | 3 | 19 | 3 |
| General Disorders | ||||
| Asthenia/Fatigue/Malaise | 29 | 5 | 32 | 11 |
| Skin Disorders | ||||
| Dermatitis | 29 | 1 | 28 | 1 |
| Alopecia | 26 | 0.3 | 28 | 1 |
| Metabolism and Nutrition | ||||
| Anorexia/Decreased Appetite | 24 | 4 | 25 | 2 |
| 1Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness | ||||
The following adverse reaction have been identified during postapproval use of levoleucovorin products.
Because these reactions are reported 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: temperature change, rigors, allergic reactions
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs.
Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with Fusilev and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur [see WARNINGS AND PRECAUTIONS].
The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study [see WARNINGS AND PRECAUTIONS].
Included as part of the PRECAUTIONS section.
Because of the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute.
Leucovorin products increase the toxicities of fluorouracil [see DRUG INTERACTIONS]. Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l-leucovorin and fluorouracil.
Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with Fusilev and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until resolved, as rapid deterioration leading to death can occur.
The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity [see DRUG INTERACTIONS].
No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.
There are limited data with Fusilev use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin.
Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryofetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information.
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.
There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production.
Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.
The safety and effectiveness of Fusilev have been established in pediatric patients for rescue after highdose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies].
The safety and effectiveness of Fusilev have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.
Clinical studies of Fusilev in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients.
In the NCCTG clinical trial of Fusilev in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.
No Information provided
Fusilev is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see ADVERSE REACTIONS].
Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5- fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase.
The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection.
Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.
The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8- tetrahydrofolate.
The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m²/day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m² and 1000 mg/m² as a continuous intravenous infusion for 5.5 days) or with d,l-leucovorin (500 mg/m² as a continuous intravenous infusion for 5.5 days).
The efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 grams/m² as an intravenous infusion over 4 hours was administered to 13 patients, who received Fusilev 7.5 mg by intravenous infusion every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 grams/m² intravenously over 6 hours, followed by Fusilev 7.5 mg by intravenous infusion every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Fusilev doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Fusilev rescue following high-dose methotrexate was based on the adverse reaction profile [See ADVERSE REACTIONS].
In a randomized clinical study conducted by Mayo Clinic and North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l leucovorin 200 mg/m² and fluorouracil 370 mg/m² versus d,l leucovorin 20 mg/m² and fluorouracil 425 mg/m² versus fluorouracil 500 mg/m², with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone) and 10%, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose d,l leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l leucovorin regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.
In a second randomized clinical study conducted by Mayo Clinic and NCCTG, the fluorouracil alone arm was replaced by a regimen of sequentially administered methotrexate , fluorouracil, and d,l leucovorin. Response rates with d,l leucovorin 200 mg/m² and fluorouracil 370 mg/m² versus d,l leucovorin 20 mg/m² and fluorouracil 425 mg/m² versus sequential methotrexate and fluorouracil and d,l leucovorin 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. There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms.
A randomized controlled trial conducted by NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l-leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m² intravenously and levoleucovorin 100 mg/m² intravenously, both daily for 5 days, or to fluorouracil 370 mg/m² intravenously and d,l-leucovorin 200 mg/m² intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.
No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.
