LEVOLEUCOVORIN CALCIUM - Side Effects Levoleucovorin

Side Effects for LEVOLEUCOVORIN CALCIUM (levoleucovorin injection, solution) are also known as adverse reactions. Below is a summary of known side effects for LEVOLEUCOVORIN CALCIUM. If you experience side effects when taking LEVOLEUCOVORIN CALCIUM, be sure to tell your doctor.

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 levoleucovorin rescue for osteosarcoma in 16 patients age 6-21. Most patients received levoleucovorin 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+

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 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 levoleucovorin 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/5-FU
n = 318

d,l-Leucovorin/5-FU
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 Pain

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

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%)

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).

This drug label information is as submitted to the Food and Drug Administration (FDA) and is intended for informational purposes only. If you think you may have a medical emergency, immediately call your doctor or dial 911. 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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