IMPORTANT SAFETY INFORMATION

Contraindications
• FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

Warnings and Precautions
• Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute
• FUSILEV enhances the toxicity of fluorouracil.
• Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

Adverse Reactions
Allergic reactions were reported in patients receiving FUSILEV.
Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high dose methotrexate therapy.
The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Fusilev in combination with 5-FU were diarrhea, nausea and stomatitis.

Drug Interactions
FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

Reporting of Suspected Adverse Reactions
You are encouraged to report side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see the FUSILEV (levoleucovorin) for injection full prescribing information for complete safety information.

IMPORTANT SAFETY INFORMATION

Leukemia and Myelodysplastic Syndrome: Among 204 patients receiving Y-90-ZEVALIN following first-line chemotherapy, two patients (1%) were diagnosed with AML within 3 years of receiving ZEVALIN.

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to diagnosis of MDS or AML was 1.9 years following treatment with the ZEVALIN therapeutic regimen; however, the cumulative incidence continues to increase.

Embryo-fetal Toxicity: May cause fetal harm if given during pregnancy.

Extravasation: Monitor for extravasation and terminate infusion if it occurs. Resume infusion in another limb.

Immunization: Do not administer live viral vaccines to patients who recently received ZEVALIN.

Laboratory Monitoring: Obtain complete blood counts (CBC) and platelet counts at least weekly.

Radionuclide Precautions: During and after radiolabeling ZEVALIN with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.

Creutzfeldt-Jakob Disease (CJD): The ZEVALIN therapeutic regimen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, ZEVALIN carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of CJD also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Impairment of Fertility: There is a potential risk that the ZEVALIN therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the ZEVALIN therapeutic regimen.

Nursing Mothers: Patients should be advised to discontinue nursing during and after ZEVALIN treatment.

Adverse Reactions: The most common adverse reactions of ZEVALIN are cytopenias, fatigue, abdominal pain, nausea, nasopharyngitis, asthenia, diarrhea, cough, and pyrexia. Common adverse reactions (≥40%) in clinical trials were: neutropenia, leukopenia, thrombocytopenia, anemia, infection, asthenia, musculoskeletal symptoms, and gastrointestinal symptoms. The most serious adverse reactions of ZEVALIN are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies.

When administered following first-line chemotherapy, grade 3/4 adverse reactions of ZEVALIN include prolonged and severe cytopenias (thrombocytopenia [51%], neutropenia [41%], leukopenia [36%], lymphopenia [18%], and anemia [5%]) and secondary malignancies. Cytopenias were more severe and more prolonged among eleven (5%) patients who received ZEVALIN after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non–fludarabine-containing regimens. Grade 3/4 infections occurred in 8% of ZEVALIN-treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection.

Grade 3/4 adverse reactions of ZEVALIN in relapsed or refractory NHL patients include prolonged and severe cytopenias (thrombocytopenia [63%], neutropenia [60%], anemia [17%], and ecchymosis [<1%]) and secondary malignancies. Serious infections occurred in 3% of patients (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% of patients (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis).

Please click here to see the full Prescribing Information, including BOXED WARNINGS, for ZEVALIN. Because the ZEVALIN therapeutic regimen includes the use of rituximab, please also consult Prescribing Information for rituximab (www.rituxan.com).