LEUCOVORIN Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Effects of Other Drugs on VYKOURA Glucarpidase Administer VYKOURA at least 2 hours before or 2 hours after the glucarpidase dose when administering concomitantly. Glucarpidase can decrease leucovorin concentrations, which may decrease the effect of leucovorin rescue.

7.2 Effects of VYKOURA on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures. It is not known whether folinic acid, including VYKOURA, has the same effects; however, both folic and folinic acids, including VYKOURA share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of VYKOURA with trimethoprim-sulfamethoxazole . The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with VYKOURA which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia.

VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid [see Warnings and Precautions (5.1) ]. Reactions have included anaphylactic reactions. VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid. ( 4 )

WARNINGS In the treatment of accidental overdosages of folic acid antagonists, intravenous leucovorin calcium should be administered as promptly as possible. As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin calcium's effectiveness in counteracting toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin calcium intrathecally. LEUCOVORIN CALCIUM MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin calcium. Delayed methotrexate excretion may be caused by a third space fluid accumulation (ie, ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of leucovorin calcium or prolonged administration may be indicated. Doses higher than those recommended for oral use must be given intravenously. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m 2 are administered, leucovorin calcium for injection should be reconstituted with Sterile Water for Injection, USP, and used immediately. (See DOSAGE AND ADMINISTRATION .) Because of the calcium content of the leucovorin calcium solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg per mL, or 8 mL of a 20 mg per mL solution per minute). Leucovorin calcium enhances the toxicity of 5-fluorouracil. When these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered. Although the toxicities observed in patients treated with the combination of leucovorin calcium plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe 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-fluorouracil alone or 5-fluorouracil in combination with 200 mg/m 2 of leucovorin calcium and 20% when treated with 5-fluorouracil in combination with 20 mg/m 2 of leucovorin calcium. In the second Mayo/NCCTG trial, hospitalizations related to treatment toxicity also appeared to occur more often in patients treated with the low dose leucovorin calcium/5-fluorouracil combination than in patients treated with the high dose combination — 11% versus 3%. Therapy with leucovorin calcium and 5-fluorouracil 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-fluorouracil and leucovorin calcium, 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 leucovorin calcium, 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. The concomitant use of leucovorin calcium 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.