Fusilev (Page 2 of 4)

3 DOSAGE FORMS AND STRENGTHS

• For Injection: 50 mg of levoleucovorin as a sterile white to pale yellow lyophilized powder in a single-dose vial for reconstitution.

4 CONTRAINDICATIONS

Fusilev is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

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

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.
Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with Fusilev 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) ]

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/m2 followed by Fusilev rescue for osteosarcoma in 16 patients aged 6 to 21 years. Most patients received Fusilev 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 Fusilev 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 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 Pain1 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

1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

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