21. Most patients received Fusilev 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 Number (%) of Courses with Adverse Reactions
(N =16) (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 eva luable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with Fusilev rescue because patients were receiving other myelosuppressive chemotherapy.
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/m2 intravenously and levoleucovorin 100 mg/m2 intravenously, both daily for 5 days, or with 5-FU 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. 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 Disorders
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 Pain1 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%)
1Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness
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
