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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hypercalcemia: Due to calcium content, inject no more than 16 mL (160 mg) of levoleucovorin solution intravenously per minute. ( 5.1 ) • Increased Gastrointestinal Toxicities with Fluorouracil: Do not initiate or continue therapy with levoleucovorin injection 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. ( 5.2 , 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. ( 5.3 ) 5.1 Hypercalcemia Because of the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute. 5.2 Increased Gastrointestinal Toxicities with Fluorouracil Levoleucovorin 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. Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with levoleucovorin injection and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until resolved, as rapid deterioration leading to death can occur. 5.3 Drug Interaction with Trimethoprim-Sulfamethoxazole The concomitant use of d,l -leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity [see Drug Interactions ( 7 )].
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypercalcemia [see Warnings and Precautions ( 5.1 )] • Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] • The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin injection rescue are stomatitis and vomiting. ( 6.1 ) • The most common adverse reactions (>50%) in patients receiving levoleucovorin injection in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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 aged 6 to 21 years. Most patients received levoleucovorin injection 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 Reactions Levoleucovorin Injection n=16 All Grades (%) Grades 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 reaction which occurred in 2 arms of a randomized controlled 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/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m2 intravenously and d,l -leucovorin 200 mg/m2 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. Table 3 Adverse Reactions Occurring in ≥10% of Patients in Either Arm Adverse Reaction Levoleucovorin/fluorouracil n=318 d,l- Leucovorin/fluorouracil n=307 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 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 Skin Disorders Dermatitis 29 1 28 1 Alopecia 26 0.3 28 1 Metabolism and Nutrition Anorexia/Decreased Appetite 24 4 25 2 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levoleucovorin products. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: pruritus, rash Respiratory: dyspnea Other: temperature change, rigors, allergic reactions