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warnings and cautions
5 WARNINGS AND PRECAUTIONS Elevated Liver Transaminase Levels : Obtain baseline liver transaminase (ALT, AST) and total bilirubin levels prior to treatment initiation with KYGEVVI. If signs or symptoms consistent with liver injury are observed, interrupt treatment. Consider permanently discontinuing KYGEVVI if signs/symptoms consistent with liver injury persist or worsen. Monitor patients yearly and as clinically indicated. ( 5.1 ) Gastrointestinal Adverse Reactions : Reduce KYGEVVI dosage or interrupt treatment based on severity of diarrhea and/or vomiting. If persistent severe diarrhea and/or vomiting occurs, consider discontinuing KYGEVVI permanently. ( 5.2 ) 5.1 Elevated Liver Transaminase Levels Elevated liver transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] levels were reported in patients treated with KYGEVVI [see Adverse Reactions (6.1) ] . In Study 1, two patients permanently discontinued treatment with KYGEVVI upon recurrence of elevated liver enzymes after a rechallenge at a reduced dose. Obtain baseline liver transaminase (ALT, AST) and total bilirubin levels in patients prior to treatment initiation with KYGEVVI. If signs or symptoms consistent with liver injury are observed, interrupt treatment with KYGEVVI until liver transaminase (ALT, AST) and total bilirubin levels have either returned to baseline or stabilized at a new baseline value. Consider permanently discontinuing KYGEVVI if signs or symptoms consistent with liver injury persist or worsen. Monitor liver transaminases and total bilirubin levels yearly and as clinically indicated [see Dosage and Administration (2.3) ] . 5.2 Gastrointestinal Adverse Reactions Diarrhea and vomiting leading to hospitalization, dose reduction, and permanent discontinuation were reported in patients treated with KYGEVVI [see Adverse Reactions (6.1) ] . Based on the severity of the diarrhea and/or vomiting, reduce the dosage of KYGEVVI or interrupt treatment until diarrhea and/or vomiting improves or returns to baseline. Consider restarting KYGEVVI at the last tolerated dose, and increase the dose as tolerated. For persistent or recurring diarrhea and/or vomiting, consider discontinuing KYGEVVI permanently and provide supportive care with electrolyte repletion as clinically indicated.
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Elevated Liver Transaminase Levels [see Warnings and Precautions (5.1) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥5%) are diarrhea, abdominal pain (including abdominal pain upper), vomiting, alanine aminotransferase increased (ALT), and aspartate aminotransferase increased (AST). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. The safety of KYGEVVI was evaluated in a prospective, open-label, single-arm study in pediatric and adult patients with genetically confirmed TK2d previously treated with pyrimidine nucleosides (Trial 1). Additional safety information was derived from retrospective chart review studies (Study 1, Study 2) and from an expanded access program [see Clinical Studies (14) ] . Permanent discontinuation of KYGEVVI due to an adverse reaction occurred in 9% of patients (Trial 1, Study 1, and Study 2). The adverse reactions which resulted in permanent discontinuation of KYGEVVI in >2% of patients were diarrhea (3%) and elevated liver enzymes (3%). In the expanded access program, diarrhea resulted in permanent discontinuation in 2 patients. Dose reductions of KYGEVVI due to an adverse reaction occurred in 22% of patients (Trial 1, Study 1, and Study 2). Adverse reactions which required dose reduction in >2% of patients included diarrhea (21%) and abdominal pain (3%). Diarrhea resulted in hospitalization in 2 pediatric patients (Study 1 and expanded access program). Adverse Reactions from Trial 1 A total of 47 patients, between the ages of 0.7 and 74 years of age at enrollment, received KYGEVVI or pyrimidine nucleosides dosages up to 800 mg/kg/day [see Clinical Studies (14) ] . KYGEVVI is not approved for use in patients with an age of TK2d symptom onset > 12 years. The mean (SD) KYGEVVI or pyrimidine nucleosides exposure during Trial 1 was 6.6 (2) years. Table 3 summarizes the adverse reactions reported in ≥ 5% patients treated with KYGEVVI or pyrimidine nucleosides. Table 3: Adverse Reactions That Occurred in ≥5% Adult and Pediatric Patients with TK2d Treated with KYGEVVI or Pyrimidine Nucleosides (Trial 1) Adverse reactions Treated Patients (N=47) n (%) Diarrhea 34 (72) Abdominal pain (including abdominal pain upper) 11 (23) Vomiting 10 (21) Alanine aminotransferase increased (ALT) 10 (21) Aspartate aminotransferase increased (AST) 8 (17) Adverse reactions, vomiting and elevated liver transaminases, were observed in a higher percentage of pediatric patients than in adult patients. In Trial 1, vomiting occurred in 28% (9/32) of pediatric patients compared to 7% (1/15) of adult patients. Elevated liver transaminases occurred in 25% (8/32) for ALT and 22% (7/32) for AST of pediatric patients compared to 13% (2/15) for ALT and 7% (1/15) for AST of adult patients. Laboratory Adverse Reaction Elevated liver enzymes have been observed as a clinical manifestation of TK2d. In Trial 1 and Study 1, elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) occurred in 28% (14/50) and 22% (11/50) of patients respectively. In Trial 1, of all the patients who started treatment with elevated AST/ALT at baseline, 5% had last post-baseline ALT values that were higher severity than the baseline severity while continuing treatment [see Warnings and Precautions (5.1) ] .