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warnings and cautions
5 WARNINGS AND PRECAUTIONS Due to Ca ++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. (5.1) Levoleucovorin injection 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) 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 Levoleucovorin injection 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. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of levoleucovorin injection and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination. In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-FU alone or 5-FU in combination with 200 mg/m 2 of d,l -leucovorin and 20% when treated with 5-FU in combination with 20 mg/m 2 of d,l -leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose d,l -leucovorin/5-FU combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with levoleucovorin injection and 5-FU must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-FU and d,l -leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving d,l -leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established. 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.
6 ADVERSE REACTIONS Allergic reactions were reported in patients receiving Levoleucovorin injection. (6.3) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Levoleucovorin injection as rescue after high-dose methotrexate therapy. (6.1) The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Levoleucovorin injection in combination with 5-FU were diarrhea, nausea and stomatitis. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies in High-Dose Methotrexate Therapy 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/m 2 followed by Levoleucovorin injection rescue for osteosarcoma in 16 patients age 6 to 21. Most patients received levoleucovorin injection 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Body System/ Adverse Reactions Number (%) of Patients with Adverse Reactions (N =16) Number (%) of Courses with Adverse Reactions (N = 58) All Grade 3+ All Grade 3+ 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 Typhlitis 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 levoleucovorin injection rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Clinical Studies in Combination with 5-FU in Colorectal Cancer A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l -leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reaction Levoleucovorin/5FU n=318 d,l -Leucovorin/5FU n=307 Adverse Event N (%) Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Gastrointestinal Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%) Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%) Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%) Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%) Abdominal Pain 1 45 (14%) 10 (3%) 57 (19%) 10 (3%) General Disorders Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%) Metabolism and Nutrition Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%) Skin Disorders Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%) Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%) 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 6.3 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 reactions.” In an analysis where calcium levoleucovorin injection was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events).