Fusilev

Cytoprotectant Agents

Administer via intravenous route only; do NOT give intrathecally.
Dilution is required prior to administration.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

50-mg powder vial
Reconstitution
Add 5.3 mL of 0.9% Sodium Chloride Injection to the 50-mg vial for a final levoleucovorin concentration of 10 mg/mL.
Reconstitution with a Sodium Chloride solution that contains preservatives (e.g., benzyl alcohol) has not been evaluated.
Further dilute the reconstituted vial immediately.
Dilution
Add the calculated dose/volume to 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a diluted admixture final concentration between 0.5 mg/mL and 5 mg/mL.
Storage: Solutions diluted in 0.9% Sodium Chloride Injection are stable at room temperature for up to 12 hours; solutions diluted in 5% Dextrose Injection are stable at room temperature for up to 4 hours. Protect from light.[44212] [62333] [62334] [63479]
175-mg powder vial
Reconstitution
Add 17.7 mL of 0.9% Sodium Chloride Injection to the 175-mg vial for a final levoleucovorin concentration of 10 mg/mL.
Reconstitution with a Sodium Chloride solution that contains preservatives (e.g., benzyl alcohol) has not been evaluated.
Further dilute the reconstituted vial immediately. Protect from light and do not store the reconstituted vial for more than 24 hours at room temperature.
Dilution
Add the calculated dose/volume to 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a diluted admixture final concentration between 0.5 mg/mL and 5 mg/mL.
Storage: Solutions diluted in 0.9% Sodium Chloride Injection are stable at room temperature for up to 24 hours; solutions diluted in 5% Dextrose Injection are stable at room temperature for up to 4 hours. Protect from light.[59344]
175-mg Khapzory powder vial
Reconstitution
Add 3.6 mL of 0.9% Sodium Chloride Injection to the 175-mg vial for a final levoleucovorin concentration of 50 mg/mL.
Reconstitution with a Sodium Chloride solution that contains preservatives (e.g., benzyl alcohol) has not been evaluated.
Further dilute the reconstituted vial immediately if possible. Protect from light and do not store the reconstituted vial for more than 12 hours at room temperature.
Dilution
Add the calculated dose/volume to 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a diluted admixture final concentration between 0.5 mg/mL and 5 mg/mL.
Storage: Do not store the diluted solution for more than 12 hours at room temperature. Protect from light.
300-mg Khapzory powder vial
Reconstitution
Add 6.2 mL of 0.9% Sodium Chloride Injection to the 300-mg vial for a final levoleucovorin concentration of 50 mg/mL.
Reconstitution with a Sodium Chloride solution that contains preservatives (e.g., benzyl alcohol) has not been evaluated.
Further dilute the reconstituted vial immediately if possible. Protect from light and do not store the reconstituted vial for more than 12 hours at room temperature.
Dilution
Add the calculated dose/volume to 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a diluted admixture final concentration between 0.5 mg/mL and 5 mg/mL.
Storage: Do not store the diluted solution for more than 12 hours at room temperature. Protect from light.
10 mg/mL Solution Vials
Dilution
Add the calculated dose/volume to 0.9% Sodium Chloride Injection or 5% Dextrose Injection for a diluted admixture final concentration of 0.5 mg/mL.
Storage: Solutions diluted in 0.9% Sodium Chloride Injection or 5% Dextrose Injection are stable at room temperature for up to 4 hours. Protect from light.[44212] [62331] [62332] [63477] [63478]
 
Intravenous Injection
Administer the diluted solution IV at a rate not to exceed 16 mL/minute (160 mg/minute) because of the calcium content in the levoleucovorin solution.
Do not administer other agents in the same admixture due to the risk of precipitation.[44212] [59344] [62331] [62332] [62333] [62334] [63477] [63478] [63479]

diarrhea / Early / 19.0-19.0
stomatitis / Delayed / 6.3-12.0
nausea / Early / 0-8.0
typhlitis / Delayed / 6.3-6.3
vomiting / Early / 5.0-5.0
fatigue / Early / 0-5.0
malaise / Early / 0-5.0
asthenia / Delayed / 0-5.0
anorexia / Delayed / 4.0-4.0
abdominal pain / Early / 3.0-3.0
atopic dermatitis / Delayed / 1.0-1.0
alopecia / Delayed / 0.3-0.3
seizures / Delayed / Incidence not known

dyspnea / Early / 6.3-6.3
confusion / Early / 6.3-6.3
peripheral neuropathy / Delayed / 6.3-6.3

dyspepsia / Early / 6.3-6.3
dysgeusia / Early / 6.3-6.3
fever / Early / Incidence not known
chills / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
rash / Early / Incidence not known
syncope / Early / Incidence not known

Fusilev, KHAPZORY

Rx

Active isomer of 5-formyl tetrahydrofolic acid; counteracts the therapeutic and toxic effects of folic acid antagonists; enhances the therapeutic and toxic effects of 5-FU
For rescue after high-dose methotrexate for osteosarcoma, to reduce the toxicity and effects of overdose of folic acid antagonists or impaired methotrexate elimination, and used in combination chemotherapy with 5-FU in the palliative treatment of patients with advanced metastatic colorectal cancer
Because of the calcium content of the levoleucovorin solution, no more than 160 mg of levoleucovorin should be injected intravenously per minute

7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starting 24 hours after the beginning of the methotrexate infusion. The levoleucovorin dosage may need to be increased or therapy may need to be extended based on methotrexate levels. If significant clinical toxicity is observed, extend the levoleucovorin rescue for an additional 24 hours (i.e., 7.5 mg IV every 6 hours for a total of 14 doses over 84 hours). Administer levoleucovorin therapy, hydration, and urinary alkalinization (i.e., maintain a urinary pH of 7 or higher) until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar).

7.5 mg (approximately 5 mg/m2) IV every 6 hours for 10 doses starting 24 hours after the beginning of the methotrexate infusion. The levoleucovorin dosage may need to be increased or therapy may need to be extended based on methotrexate levels. If significant clinical toxicity is observed, extend the levoleucovorin rescue for an additional 24 hours (i.e., 7.5 mg IV every 6 hours for a total of 14 doses over 84 hours). Administer levoleucovorin therapy, hydration, and urinary alkalinization (i.e., maintain a urinary pH of 7 or higher) until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar).

7.5 mg (approximately 5 mg/m2) IV every 6 hours until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar); begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. If 24-hour serum creatinine concentration increases 50% or more from baseline or the serum methotrexate concentration is higher than 5 x 10-6 Molar at 24 hours or higher than 9 x 10-7 Molar at 48 hours, increase the levoleucovorin dosage to 50 mg/m2 IV every 3 hours until the serum methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar). Administer hydration (3 L/day) and urinary alkalinization with sodium bicarbonate; adjust the bicarbonate dose to maintain a urine pH 7 or higher.

7.5 mg (approximately 5 mg/m2) IV every 6 hours until the methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar); begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. If 24-hour serum creatinine concentration increases 50% or more from baseline or the serum methotrexate concentration is higher than 5 x 10-6 Molar at 24 hours or higher than 9 x 10-7 Molar at 48 hours, increase the levoleucovorin dosage to 50 mg/m2 IV every 3 hours until the serum methotrexate level is less than 5 x 10-8 Molar (0.05 micromolar). Administer hydration (3 L/day) and urinary alkalinization with sodium bicarbonate; adjust the bicarbonate dose to maintain a urine pH 7 or higher.

Two regimens have been studied: 1) levoleucovorin 100 mg/m2 by slow IV injection over at least 3 minutes followed by 5-fluorouracil 370 mg/m2 by IV injection; and 2) levoleucovorin 10 mg/m2 by IV injection followed by 5-fluorouracil 425 mg/m2 by IV injection; administer levoleucovorin and 5-fluorouracil separately to avoid precipitation. Either regimen is given daily for 5 days repeated every 4 weeks for 2 cycles; subsequent cycles may be given at 4 to 5 week intervals once the patient has recovered from the toxic effects of the previous cycle. Levoleucovorin doses are not adjusted for toxicity. Reduce the 5-fluorouracil daily dose by 20% in patients who experience moderate hematologic or gastrointestinal toxicity in the prior treatment course; reduce 5-fluorouracil daily dose by 30% in patients who have severe toxicity. The 5-fluorouracil dosage may be increased by 10% in patients who do not have toxicity in the prior cycle of therapy.[44212] [63785]

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Amobarbital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Barbiturates: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Butabarbital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Butalbital; Acetaminophen: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Butalbital; Acetaminophen; Caffeine: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Capecitabine: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with leucovorin is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Floxuridine: (Major) Calcium leucovorin provides reduced folates, which enhance binding of fluorouracil to thymidylate synthetase. This increases both the therapeutic efficacy and the toxicity of fluorouracil. In particular, patients can experience increased diarrhea and stomatitis. Floxuridine is metabolized to fluorouracil, so a similar interaction can occur.
Fluorouracil, 5-FU: (Major) Administration of leucovorin concurrently with fluorouracil, 5-FU can be therapeutically advantageous, but it can also potentiate the adverse effects associated with 5-FU therapy (e.g., gastrointestinal toxicities, myelosuppression). The dosage of 5-FU must be decreased when given in combination with leucovorin. Closely monitor for gastrointestinal toxicities (e.g., stomatitis, diarrhea) and myelosuppression including leukopenia and thrombocytopenia. Stop use of these medications in patients who develop gastrointestinal toxicities, and do not reinitiate treatment until symptoms have resolved. A similar interaction is anticipated with levoleucovorin.
Fosphenytoin: (Moderate) Limited data suggest that leucovorin/levoleucovorin may interfere with the activity of anticonvulsants such as phenytoin (and fosphenytoin). Because folic acid can decrease serum concentrations of these agents, leucovorin/levoleucovorin may interact similarly. Phenytoin is known to interfere with folic acid absorption, but whether leucovorin/levoleucovorin absorption is altered is unknown. Clinicians should consider careful monitoring of patients when leucovorin or levoleucovorin is added to these anticonvulsants or when they are added to leucovorin/levoleucovorin therapy.
Glucarpidase: (Major) Continue to administer leucovorin after glucarpidase, but do not administer leucovorin within 2 hours before or after a glucarpidase dose because leucovorin is a substrate for glucarpidase. For example, intravenous administration of 50 Units/kg glucarpidase 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52% and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93%. For the first 48 hours after glucarpidase administration, administer the same leucovorin dose as given before glucarpidase. Beyond 48 hours after glucarpidase, administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Continue leucovorin until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days; use of a chromatographic method to determine methotrextae concentrations is needed for the first 48 hours after glucarpidase receipt. Also, continue hydration and alkalinization of the urine as indicated. Levoleucovorin is the l-isomer of leucovorin and a similar interaction is expected.
Methohexital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Pentobarbital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Phenobarbital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Phenytoin: (Moderate) Limited data suggest that leucovorin may interfere with the activity of anticonvulsants such as phenytoin. Because folic acid can decrease serum concentrations of these agents, leucovorin may interact similarly. Phenytoin is known to interfere with folic acid absorption, but whether leucovorin absorption is altered is unknown. Clinicians should consider careful monitoring of patients when leucovorin is added to these anticonvulsants or when they are added to leucovorin therapy. Because levoleucovorin is the l-isomer of leucovorin, levoleucovorin also shares metabolic pathways with folic acid, and a similar interaction with anticonvulsants is expected.
Primidone: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Secobarbital: (Minor) Limited data suggest that leucovorin and levoleucovorin may interfere with the activity of anticonvulsants such as barbiturates. Folic acid can decrease serum concentrations of anticonvulsants in children. Leucovorin shares metabolic pathways with folic acid. Clinicians should consider careful monitoring of patients.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Racemic leucovorin may be used to offset the toxicity of folate antagonists such as trimethoprim; however, the concomitant use of leucovorin with sulfamethoxazole; trimethoprim for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect. (Minor) The concomitant use of leucovorin with sulfamethoxazole; trimethoprim, for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect.
Trimethoprim: (Minor) Racemic leucovorin may be used to offset the toxicity of folate antagonists such as trimethoprim; however, the concomitant use of leucovorin with sulfamethoxazole; trimethoprim for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with an increased risk of treatment failure and morbidity. Levoleucovorin may result in the same effect.

Fusilev/KHAPZORY/Levoleucovorin Intravenous Inj Pwd F/Sol: 50mg, 175mg, 300mg
Levoleucovorin Intravenous Inj Sol: 1mL, 10mg

Maximum doses have not been established and may vary depending on therapeutic goals.

Maximum doses have not been established and may vary depending on therapeutic goals.

Maximum doses have not been established and may vary depending on therapeutic goals. Safety and efficacy for advanced metastatic colorectal cancer have not been established.

6 years and older: Maximum doses have not been established and may vary depending on therapeutic goals. Safety and efficacy for advanced metastatic colorectal cancer have not been established.
Younger than 6 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Mechanism of Action: Levoleucovorin is a reduced folate, and does not function as a cytotoxic chemotherapy agent. It is the calcium salt of the levo isomeric form of racemic d,l-leucovorin, which is the pharmacologically active isomer of leucovorin. Due to the increased potency of levoleucovorin, doses are one-half the usual dose of the racemic form (d,l-leucovorin).Levoleucovorin acts as a replacement therapy to rescue cells from the effects of folate antagonists such as methotrexate. Levoleucovorin does not require reduction by dihydrofolate reductase to act as a folate cofactor, and is actively and passively transported across cell membranes. In vivo, levoleucovorin is rapidly converted to 5-methytetrahydrofolic acid (MTHF), the primary circulating form of active reduced folate, and 5,10-methylenetetrahydrofolate (mTHF). These reduced folates replete the folate pool and continue the folic acid cycle. The reduced folates are polyglutamated by folylpolyglutamate synthetase, which increases the size and electronegative charge of the folate and helps retain it inside the cell.

Levoleucovorin is administered intravenously. It is the levo isomeric form of racemic (d,l)-leucovorin and the pharmacologically active isomer of 5-formyl tetrahydrofolic acid (folinic acid). Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase; it forms 5-methyltetrahydrofolate (5-MTHF), a reduced (active) folate. When administered by intravenous injection, small quantities of leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite (5-MTHF); however, the CSF concentration of 5-MTHF remains 1- to 3-orders of magnitude lower than the usual methotrexate concentration following intrathecal administration. The mean terminal half-lives for tetrahydrofolate (THF) and 5-MTHF were 5.1 hours and 6.8 hours, respectively, following a single 15 mg levoleucovorin intravenous dose in healthy male volunteers.
 
Affected cytochrome P450 isoenzymes: none

The mean total tetrahydrofolate (THF) Cmax was 1,722 nanograms (ng)/mL following a single IV levoleucovorin 15-mg dose in healthy male volunteers; the mean Cmax for 5-methyltetrahydrofolate (5-MTHF) was 275 ng/mL, observed approximately 0.9 hours post injection. In 40 healthy subjects, the geometric mean ratio for AUC(0-inf) and Cmax values were within the standard limit of 80% to 125% for both levoleucovorin and 5-MTHF following a single IV dose of levoleucovorin 200 mg/m2 and racemic (d,l)-leucovorin 400 mg/m2 in a pharmacokinetic crossover study. Following the IV administration of levoleucovorin in this study, the geometric mean AUC(0-inf) was 30,719 ng x hour/mL and the geometric mean Cmax was 10,895 ng/mL. The geometric mean AUC(0-inf) and Cmax values were 52,105 ng x hour/mL and 4930 ng/mL, respectively, for 5-MTHF after levoleucovorin administration. In another study, the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-MTHF were comparable following treatment with 5-fluorouracil in combination with 5.5 days of levoleucovorin given as a continuous IV infusion (n = 9) or d,l-leucovorin given as a continuous IV infusion (n = 6).

Data are limited regarding use of levoleucovorin during human pregnancy; animal reproduction studies have not been conducted. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embyro-fetal harm.

There are no data on the presence of levoleucovorin in human breast milk or its effects on the breast-fed infant or on milk production. Levoleucovorin is a derivative of folic acid, and according to the American Academy of Pediatrics (AAP), folic acid is considered to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.