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Clinical Studies in High-Dose Methotrexate Therapy
Since 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. The following table 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 age 6-21. 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 (N =16)||Number (%) of Courses with Adverse Reactions (N = 58)|
|All||Grade 3+||All||Grade 3+|
|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)|
|Dyspnea||1 (6.3)||0||1 (1.7)||0|
|Skin and Appendages|
|Dermatitis||1 (6.3)||0||1 (1.7)||0|
|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 evaluable 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
|Levoleucovorin/5FU n=318||d,l-Leucovorin/5FU n=307|
|Grade 1-4||Grade 3-4||Grade 1-4||Grade 3-4|
|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||18 (6%)|
|Abdominal Pain1||45 (14%)||10 (3%)||57 (19%)||10 (3%)|
|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%)|
|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|
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 Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reactions.”
In an analysis where calcium levoleucovorin was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events).
Read the Fusilev (levoleucovorin) Side Effects Center for a complete guide to possible side effects
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects.
However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs.
Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration.
Read the Fusilev Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 6/6/2011
Additional Fusilev Information
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