May 26, 2016
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Fusilev Side Effects Center

Medical Editor: William C. Shiel Jr., MD, FACP, FACR

Fusilev (levoleucovorin) is indicated for the treatment of metastatic colorectal cancer and bone cancer (after methotrexate therapy). Seizures and fainting, though rare, have been reported in patients taking Fusilev. Gastrointestinal disorders such as nausea, vomiting, and diarrhea are commonly reports as a side effect of Fusilev.

It is not known whether Fusilev can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Fusilev should be given to a pregnant woman only if clearly needed. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Fusilev, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Our Fusilev Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Patient Information in Detail?

Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.

Fusilev in Detail - Patient Information: Side Effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your doctor or caregivers at once if you have a serious side effect such as:

  • white patches or sores inside your mouth or on your lips;
  • urinating more or less than usual;
  • severe or ongoing diarrhea;
  • feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
  • fever, chills;
  • confusion; or
  • trouble breathing.

Less serious side effects may include:

  • nausea, vomiting, diarrhea;
  • stomach pain, upset stomach;
  • numbness or tingling;
  • loss of appetite, unusual or unpleasant taste in your mouth;
  • weakness, tired feeling;
  • hair loss; or
  • mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Fusilev (levoleucovorin)

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Fusilev FDA Prescribing Information: Side Effects
(Adverse Reactions)


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

Adverse Reaction
Adverse Event
N (%)
Levoleucovorin/5FU n=318 d,l-Leucovorin/5FU n=307
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 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 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 entire FDA prescribing information for Fusilev (levoleucovorin)

Report Problems to the Food and Drug Administration


You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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