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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypercalcemia : Limit rate of infusion due to calcium content. ( 2.1 , 2.4 , 5.1 ) Increased gastrointestinal toxicities with fluorouracil ( 5.2 , 7 ) Drug interaction with trimethoprim-sulfamethoxazole : Increased rates of treatment failure with concomitant use of d,l -leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV. ( 5.3 ) 5.1 Hypercalcemia Due to the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute [see Dosage and Administration ( 2.1 and 2.4 )] . 5.2 Increased Gastrointestinal Toxicit ies with Fluorouracil Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions ( 7 )] . Gastrointestinal toxicities, (particularly stomatitis and diarrhea) occur more commonly, and may be of greater severity and prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l -leucovorin and fluorouracil. 5. 3 Drug- I nteraction with T rimethoprim- S ulfamethoxazole 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 in a placebo-controlled study.
6 ADVERSE REACTIONS The following serious 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 )] Drug-interaction with trimethoprim-sulfamethoxazole [s ee Warnings and Precautions ( 5.3 )] The most common adverse reactions (≥ 20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue were stomatitis and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-432-8534 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. 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 Body System/Adverse Reaction Number (%) of Patients (N = 16) All Grades ≥ Grade 3 Gastrointestinal Stomatitis 6 (37.5) 1 (6.3) Vomiting 6 (37.5) 0 Nausea 3 (18.8) 0 Diarrhea 1 (6.3) 0 Dyspepsia 1 (6.3) 0 Typhlitis 1 (6.3) 1 (6.3) Respiratory Dyspnea 1 (6.3) 0 Skin and Appendages Dermatitis 1 (6.3) 0 Other Confusion 1 (6.3) 0 Neuropathy 1 (6.3) 0 Renal function abnormal 1 (6.3) 0 Taste perversion 1 (6.3) 0 Total number of patients 9 (56.3) 6. 2 Postmarketing Experience The following adverse reactions were identified during postapproval use of levoleucovorin, administered in combination with a methotrexate or other regimen. Because these reactions are reported 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. The following have been reported: Respiratory : dyspnea Dermatologic : pruritus, rash Other Clinical Events : temperature change, rigors, allergic reactions