Vykoura Drug Information

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 clinical practice. Table 2 summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.

Table 2: Percentage of Patients Treated with Leucovorin and Fluorouracil for Advanced Colorectal Carcinoma Reporting Adverse Experiences or Hospitalized for Toxicity High LV = Leucovorin 200 mg/m 2, Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher (High LV)/5-FU (N = 155) (Low LV)/5-FU (N = 161) 5-FU Alone (N = 70) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7%

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.

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.

Pregnancy Risk Summary Available data on the use of leucovorin during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Adequate animal reproduction studies have not been conducted with leucovorin. Agents administered in combination with VYKOURA may cause fetal harm.

Refer to the Prescribing Information for agents administered in combination with VYKOURA for additional information, as appropriate. 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.

Pediatric Use VYKOURA is indicated to reduce the toxicity of MTX in pediatric patients with impaired MTX elimination, and folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose.

is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid. 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.