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Drug: Levoleucovorin - Fusilev™

Usual Diluents

NS, D5W

Dilution Data

Reconstitution and Infusion Instructions

Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended.
The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product.
Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours.
Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin ) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution

Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). Protect from light.

Stability / Miscellaneous

WARNINGS	CLINICAL PHARMACOLOGY	INDICATIONS
CONTRAINDICATIONS	DOSAGE AND ADMINISTRATION	RECONSTITUTION / DILUTION
	HOW SUPPLIED
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DESCRIPTION
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 contains 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.

CLINICAL PHARMACOLOGY
Mechanism Of Action
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 can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

Pharmacodynamics
Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.

Pharmacokinetics
The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8-tetrahydrofolate was 5.1 and 6.8 hours, respectively

1. INDICATIONS AND USAGE

Fusilev™ is a folate analog.
Fusilev rescue is indicated after high-dose methotrexate therapy in osteosarcoma.
Fusilev is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists

Limitations of Use

Fusilev is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B12. Improper use may cause a hematologic remission while neurologic manifestations continue to progress

2. DOSAGE AND ADMINISTRATION

2.1 Administration Guidelines
Fusilev is dosed at one-half the usual dose of the racemic form.

Fusilev is indicated for intravenous administration only. Do not administer intrathecally.

2.2 Co-administration of Fusilev with other agents
Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture.

2.3 Fusilev Rescue After High-Dose Methotrexate Therapy
The recommendations for Fusilev rescue are based on a methotrexate dose of 12 grams/m² administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Fusilev rescue at a dose of 7.5 mg (approximately 5 mg/m²) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

Serum creatinine and methotrexate levels should be determined at least once daily. Fusilev administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10^-8 M (0.05 micromolar). The Fusilev dose should be adjusted or rescue extended based on the following guidelines.

Table 1 Guidelines for Fusilev Dosage and Administration
Clinical Situation	Laboratory Findings	Fusilev 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	7.5 mg 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 7.5 mg 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).	75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 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 Fusilev therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, Fusilev 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.

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of Fusilev or prolonged administration may be indicated.

Although Fusilev may ameliorate the hematologic toxicity associated with high dose methotrexate, Fusilev has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage
Fusilev rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and Fusilev rescue increases, Fusilev’s effectiveness in counteracting toxicity may decrease. Fusilev 7.5 mg (approximately 5 mg/m² ) should be administered IV every 6 hours until the serum methotrexate level is less than 10^-8 M.

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 Fusilev should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10^-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

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2.5 Reconstitution and Infusion Instructions
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Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended.
The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product.
Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours.
Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed.
No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin ) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution

3. DOSAGE FORMS AND STRENGTHS
Fusilev is supplied in sterile, single-use vials containing 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin ) and 50 mg mannitol.

4. CONTRAINDICATIONS
Fusilev is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

5. WARNINGS AND PRECAUTIONS

5.1 Rate of Administration
Because of the Ca++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin ) should be injected intravenously per minute.

5.2 Potential for Enhanced Toxicity with 5-Fluorouracil
Fusilev enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil.

5.3 Potential for interaction with trimethoprim-sulfamethoxazole
The concomitant use of d,l-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.

HOW SUPPLIED/STORAGE AND HANDLING
Each 50 mg single-use vial of Fusilev for Injection contains a sterile lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol.

50 mg vial of freeze-dried powder – NDC 68152-101-00.

Store at 25° C (77 °F) in carton until contents are used. Excursions permitted from 15-30° C (59-86 °F). [See USP Controlled Room Temperature]. Protect from light.

Reference(s)

1) [PACKAGE INSERT DATA] : FUSILEV (levoleucovorin calcium) injection, powder, lyophilized, for solution. [Spectrum Pharmaceuticals, Inc.] Irvine, CA 92618. Revised: 09/2008.

Drug: Levoleucovorin - Fusilev™

Usual Diluents

Dilution Data

Stability / Miscellaneous

Reference(s)

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