Sodium levofolinate

Risk Summary

There are limited data with sodium levofolinate use in pregnant women. Animal reproduction studies have not been conducted with sodium levofolinate.

Sodium levofolinate is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate or fluorouracil prescribing information for additional information.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Risk Summary

There are no data on the presence of sodium levofolinate in human milk or its effects on the breastfed infant or on milk production.

Sodium levofolinate is administered in combination with methotrexate or fluorouracil. Refer to methotrexate or fluorouracil prescribing information for additional information.

No studies have been conducted to evaluate the potential of sodium levofolinate for carcinogenesis, mutagenesis and impairment of fertility.

The following clinical significant adverse reactions are described elsewhere in the labeling:

• Increased gastrointestinal toxicities with fluorouracil

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 sodium levofolinate rescue, for osteosarcoma, in 16 patients aged 6 to 21 years. Most patients received sodium levofolinate 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:

Combination with Fluorouracil in Colorectal Cancer

Table 3 presents the frequency of adverse reactions 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 + sodium levofolinate compared to fluorouracil + d,l-leucovorin. Patients were randomized to fluorouracil 370 mg/m² intravenously and sodium levofolinate 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:

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of sodium levofolinate products. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following have been reported:

• Dermatologic: pruritus, rash
• Respiratory: dyspnea
• Other Clinical Events: temperature change, rigors, allergic reactions