LEVOLEUCOVORIN Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs 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. Monitor patients taking folinic acid in combination with antiepileptic drugs.

Fluorouracil

Leucovorin products increase the toxicity of fluorouracil. 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 the diarrhea has resolved, as rapid deterioration leading to death can occur [see Warnings and Precautions ( 5.2 )]. 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 in a placebo-controlled study [see Warnings and Precautions ( 5.3 )] .

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 )] . Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid or folinic acid. ( 4 )

AND PRECAUTIONS Due to Ca ++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute. ( 5.1 ) Levoleucovorin injection enhances the toxicity of fluorouracil. ( 5 . 2 , 7 ) Concomitant use of d,l-leucovorin with trimethoprim sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study. ( 5.3 ) 5 .1 Rate of Administration Because of the Ca ++ content of the levoleucovorin solution, no more than 16 mL (160 mg of levoleucovorin) should be injected intravenously per minute.

5.2 Potential for Enhanced Toxicity with 5-Fluorouracil Levoleucovorin injection enhances the toxicity of 5-fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly d,l-leucovorin and 5-fluorouracil. When these drugs are administered concurrently in the palliative treatment of advanced colorectal cancer, the dosage of 5-FU must be lower than usually administered. Although the toxicities observed in patients treated with the combination of levoleucovorin injection and 5-FU are qualitatively similar to those observed with 5-FU alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be of greater severity and of prolonged duration in patients treated with the combination. In the first Mayo/NCCTG controlled trial, toxicity, primarily gastrointestinal, resulted in 7% of patients requiring hospitalization when treated with 5-FU alone or 5-FU in combination with 200 mg/m 2 of d,l-leucovorin and 20% when treated with 5-FU in combination with 20 mg/m 2 of d,l-leucovorin. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose d,l-leucovorin/5-FU combination than in patients treated with the high dose combination – 11% versus 3%. Therapy with levoleucovorin injection and 5-FU must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In an additional study utilizing higher weekly doses of 5-FU and d,l-leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity. Seizures and/or syncope have been reported rarely in cancer patients receiving d,l-leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors. However, a causal relationship has not been established.

5.3 Potential for interaction with trimethoprim-sulfamethoxazole The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study.