Product
Fusilev
Approval Date
March 7, 2008
Release Date
Mid-August 2008
Company
Spectrum Pharmaceuticals, Inc.
Class
Folate analogue
Indication
In osteosarcoma, to reducetoxicity of high-dose methotrexate (MTX) therapy. To reduce toxicity and counteracteffects of impaired MTX elimination and of inadvertent overdose of folic acidantagonists.
Active Ingredient
Levoleucovorin (as calcium pentahydrate) 50mg/vial; pwd forIV inj after reconstitution; contains mannitol 50mg/vial.
Agency Roster
LehmanMillet
Marketing Strategy/Execution
FUSILEV(TM) is indicated after high-dosemethotrexate therapy in patients with osteosarcoma, and to diminish thetoxicity and counteract the effects of impaired methotrexate elimination orinadvertent overdose of folic acid antagonists. FUSILEV(TM) is the onlycommercially available formulation comprised only of the pharmacologicallyactive enantiomer of leucovorin (levoleucovorin or (6S)-leucovorin. FUSILEVwill be supplied in 50-mg vials of freeze-dried powder.
Also in the Pipeline(courtesy of Adis R&D Insight)
Drug: CGP 19835
Manufacturer: IDM Pharma
Indication: Osteosarcoma
Active Ingredient: Mifamurtide
Phase: Preregistration
Source: Wolters Kluwer Health
Pharmacology
Levoleucovorin is the pharmacologically active isomer of theracemic drug d,l-leucovorin, a derivative of folic acid. It can counteract thetherapeutic and toxic effects of folic acid antagonists such as MTX whichinhibit the activity of the enzyme dihydrofolate reductase. Levoleucovorin isdosed at 1/2 the usual dose for racemic leucovorin.
Clinical Trials
The safety and efficacy of levoleucovorin rescue followinghigh-dose MTX was studied in 16 patients 6–21years of age who received 58courses of therapy for osteogenic sarcoma. High-dose MTX was used as onecomponent of several different combination chemotherapy regimens evaluatedacross several trials. Thirteen patients received MTX 12g/m2 IV over4 hours and levoleucovorin 7.5mg every 6 hours for 60 hours or longer beginning24 hours after the completion of MTX. Three patients received MTX 12.5g/m2IV over 6 hours, then levoleucovorin 7.5mg every 3 hours for 18 doses starting12 hours after completion of MTX therapy. The efficacy of levoleucovorin wasbased on the adverse reaction profile. Six patients (37.5%) reportedstomatitis, with one (6.3%) having grade 3 or higher. Six patients (37.5%)reported vomiting while nausea occurred in 3 patients (18.8%). The number ofpatients who had other adverse reactions such as dyspnea, neuropathy, anddermatitis was reported as one. In the 58 courses of therapy, there was a totalof 10 occurrences for stomatitis, 14 for vomiting, 3 for nausea, and 3 forabnormal renal function.
Adverse Reactions
Stomatitis, vomiting, nausea.
Adults and Children
<6years: see literature. =6years: Give by IV inj; maxrate 160mg/min. High-dose MTX rescue: Start 24hrs after the beginning of MTXinfusion (based on MTX dose of 12g/m2 over 4hrs). Normal MTXelimination: give levoleucovorin 7.5mg (approximately 5mg/m2) every6hrs for 10 doses. Delayed late MTX elimination: continue levoleucovorin 7.5mg every6hrs until MTX <0.05micromolar; delayed early MTX elimination and/orevidence of acute renal injury: levoleucovorin 75mg every 3hrs until MTX<1micromolar, then 7.5mg every 3hrs until MTX <0.05micromolar. Maycontinue another 24hrs for subsequent courses in cases of significant clinicaltoxicity. Inadvertent MTX overdose: Start as soon as possible or within 24hrsif delayed MTX excretion. Levoleucovorin 7.5mg every 6hrs until MTX<0.05micromolar. See literature.
Contraindications
Not applicable.
Precautions
Not for treating pernicious anemia and megaloblastic anemia.Monitor serum creatinine and MTX levels every 24hrs. Delayed early MTXelimination may cause reversible renal failure; provide hydration, alkalinizeurine with sodium bicarbonate, closely monitor fluid and electrolytes untilserum MTX <0.05 micromolar and renal failure resolves. Pregnancy (Cat.C).Nursing mothers.
Interactions
Potentiates 5-fluorouracil toxicity. Antagonizes TMP/SMZ.Antagonizes anticonvulsants (eg, phenobarbital, primidone, phenytoin). May beaffected by drugs that affect MTX elimination.
