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warnings and cautions
5 WARNINGS AND PRECAUTIONS Increased gastrointestinal toxicities with fluorouracil: Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur ( 5.1 , 7 ) Drug interaction with trimethoprim-sulfamethoxazole: Increased rates of treatment failure and morbidity with concomitant use of d,l- leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV. ( 5.2 ) 5.1 Increased Gastrointestinal Toxicities with Fluorouracil Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions ( 7 )] . Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l- leucovorin and fluorouracil. Do not initiate or continue therapy with KHAPZORY and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur. 5.2 Drug Interaction with Trimethoprim-Sulfamethoxazole Concomitant use of d,l- leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection increased treatment failure and morbidity.
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.1 )] Drug-interaction with trimethoprim-sulfamethoxazole [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥ 20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue were stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer were stomatitis, diarrhea, and nausea. ( 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. 6.1 Clinical Trials Experience Because 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. High-Dose Methotrexate Therapy Table 2 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 rescue, for osteosarcoma, in 16 patients, ages 6-21 years. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Adverse Reaction Levoleucovorin n=16 (%) All Grades Grade 3-4 Gastrointestinal Stomatitis 38 6 Vomiting 38 0 Nausea 19 0 Diarrhea 6 0 Dyspepsia 6 0 Typhlitis 6 6 Respiratory Dyspnea 6 0 Skin and Appendages Dermatitis 6 0 Other Confusion 6 0 Neuropathy 6 0 Renal function abnormal 6 0 Taste perversion 6 0 Combination with Fluorouracil in Colorectal Cancer Table 3 presents the frequency of adverse reactions which occurred in 2 arms of a randomized trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l -leucovorin. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 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, then every 5 weeks until disease progression or unacceptable toxicity. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reaction Levoleucovorin/fluorouracil n=318 (%) d,l -Leucovorin/fluorouracil n=307 (%) Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Gastrointestinal Disorders Stomatitis 72 12 72 14 Diarrhea 70 19 65 17 Nausea 62 8 61 8 Vomiting 40 5 37 6 Abdominal Pain Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 14 3 19 3 General Disorders Asthenia/Fatigue/Malaise 29 5 32 11 Metabolism and Nutrition Anorexia/Decreased Appetite 24 4 25 2 Skin Disorders Dermatitis 29 1 28 1 Alopecia 26 0.3 28 1 6.2 Postmarketing Experience The following adverse reactions were identified during post approval use of levoleucovorin. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following have been reported: Respiratory : dyspnea Dermatologic : pruritus, rash Other Clinical Events : temperature change, rigors, allergic reactions