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warnings
Due to Ca superscript ++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. (5.1) Fusilev enhances the toxicity of fluorouracil. (5.2,7) 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. (5.3)
warnings and cautions
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.
Allergic reactions were reported in patients receiving Fusilev. (6.2) Vomiting (38 percent), stomatitis (38 percent) and nausea (19 percent) were reported in patients receiving Fusilev as rescue after high dose methotrexate therapy. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Spectrum Pharmaceuticals, Inc. at 1-877-387-4538 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
adverse reactions
6. ADVERSE REACTIONS 6.1 Clinical Studies Experience Since 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. The following table 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 age 6-21. Most patients received Fusilev 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions Body System/Adverse Reactions Number (%) of Patients with Adverse Reactions Number (%) of Courses with Adverse Reactions (N =16) (N = 58) All Grade 3 Plus All Grade 3 Plus Gastrointestinal Stomatitis 6 (37.5) 1 (6.3) 10 (17.2) 1 (1.7) Vomiting 6 (37.5) 0 14 (24.1) 0 Nausea 3 (18.8) 0 3 (5.2) 0 Diarrhea 1 (6.3) 0 1 (1.7) 0 Dyspepsia 1 (6.3) 0 1 (1.7) 0 Typlitis 1 (6.3) 1 (6.3) 1 (1.7) 1 (1.7) Respiratory Dyspnea 1 (6.3) 0 1 (1.7) 0 Skin and Appendages Dermatitis 1 (6.3) 0 1 (1.7) 0 Other Confusion 1 (6.3) 0 1 (1.7) 0 Neuropathy 1 (6.3) 0 1 (1.7) 0 Renal function abnormal 1 (6.3) 0 3 (5.2) 0 Taste perversion 1 (6.3) 0 1 (1.7) 0 Total number of patients 9 (56.3) 2 (12.5) Total number of courses 25 (43.1) 2 (3.4) The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reaction.”