Levoleucovorin (Page 2 of 4)

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

Levoleucovorin for Injection 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 Levoleucovorin for Injection 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 Levoleucovorin for Injection rescue for osteosarcoma in 16 patients aged 6 to 21 years. Most patients received Levoleucovorin for Injection 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

Levoleucovorin for Injection n = 16

All Grades (%)

Grades 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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