WARNING: RISKS OF HEPATOTOXICITY Hepatotoxicity has occurred with the use of VEOZAH in the postmarketing setting ( 5.1 ). • Perform hepatic laboratory tests prior to initiation of treatment to evaluate for hepatic function and injury. Do not start VEOZAH if either aminotransferase is ≥ 2 x the upper limit of normal (ULN) or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. • Perform follow-up hepatic laboratory testing monthly for the first 3 months, at 6 months, and 9 months of treatment ( 2.1 , 5.1 ). • Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain) ( 2.1 , 5.1 ). • Discontinue VEOZAH if transaminase elevations are > 5 x ULN, or if transaminase elevations are > 3 x ULN and the total bilirubin level is > 2 x ULN. • If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution ( 5.1 ). WARNING: RISKS OF HEPATOTOXICITY See full prescribing information for complete boxed warning. Hepatotoxicity has occurred with the use of VEOZAH in the postmarketing setting ( 5.1 ). • Perform hepatic laboratory tests prior to initiation of treatment to evaluate for hepatic function and injury. Do not start VEOZAH if either aminotransferase is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. • Perform follow-up hepatic laboratory testing monthly for the first 3 months, at 6 months, and 9 months of treatment ( 2.1 , 5.1 ). • Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain) ( 2.1 , 5.1 ). • Discontinue VEOZAH if transaminase elevations are > 5 x ULN, or if transaminase elevations are > 3 x ULN and the total bilirubin level is > 2 x ULN. • If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution ( 5.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Cases of hepatotoxicity and jaundice have been reported in the postmarketing setting. Perform hepatic laboratory tests prior to initiation of VEOZAH to evaluate for hepatic function and injury. Perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain). ( 5.1 ) 5.1 Hepatotoxicity In three clinical trials, elevations in serum transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] levels > 3 x the upper limit of normal (ULN) occurred in 2.3% [exposure adjusted incidence rate (EAIR) of 2.7 per 100 person-years] of women receiving VEOZAH and 0.9% (EAIR of 1.5 per 100 person-years) of women receiving placebo. No elevations in serum total bilirubin (> 2 x ULN) occurred. Women with ALT or AST elevations were generally asymptomatic. Transaminase levels returned to pretreatment levels (or close to these) without sequelae with dose continuation, and upon dose interruption, or discontinuation. Women with cirrhosis were not studied [see Adverse Reactions ( 6.1 )] . In the postmarketing setting, cases of drug-induced liver injury with elevations of ALT, AST, alkaline phosphatase (ALP), and total bilirubin occurred within 40 days of starting VEOZAH. Patients reported a general sense of feeling unwell and symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine. The patients’ signs and symptoms gradually resolved after discontinuation of VEOZAH [see Adverse Reactions ( 6.2 )]. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury [including serum ALT, serum AST, serum ALP, and serum bilirubin (total and direct)] prior to VEOZAH initiation. Do not start VEOZAH if ALT or AST is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. Perform follow-up hepatic laboratory tests monthly for the first 3 months, at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZAH immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury: • new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain. Discontinue VEOZAH if: • transaminase elevations are > 5 x ULN. • transaminase elevations are > 3 x ULN and total bilirubin is > 2 x ULN. If transaminase elevations > 3 x ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution. Exclude alternative causes of hepatic laboratory test elevations.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatic Transaminase Elevation and Hepatotoxicity [see Warnings and Precautions ( 5.1 )] . The most common adverse reactions with VEOZAH [at least 2% in VEOZAH 45 mg and greater than placebo] are: abdominal pain, diarrhea, insomnia, back pain, hot flush, and hepatic transaminase elevation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 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 clinical practice. The safety of VEOZAH was evaluated in three 52-week clinical trials [see Clinical Studies ( 14 )] . Across the three clinical trials, a total of 1100 women received VEOZAH. Trials 1 and 2 were placebo-controlled for the first 12 weeks, followed by re-randomization of women previously receiving placebo to VEOZAH (women on VEOZAH remained on VEOZAH) for an additional 40 weeks of uncontrolled treatment. Trial 3 was a randomized, placebo-controlled, double-blind safety study evaluating the safety of VEOZAH for 52 weeks. The adverse reactions reported in at least 2% in VEOZAH 45 mg and greater than placebo in Trial 3 are presented in Table 1 . Table 1: Adverse Reactions Reported in at Least 2% in VEOZAH 45 mg and Greater Than Placebo in a Placebo‑Controlled, Double-Blind 52-Week Trial (Trial 3) Adverse Reaction VEOZAH 45 mg (n=609) Total Person-Years=504.2 n (%, EAIR EAIR = Number of individuals experiencing an adverse event divided by exposure time (total person-years) x 100. ) Placebo (n=610) Total Person-Years=475.0 n (%, EAIR ) Abdominal pain Abdominal pain (including Abdominal pain, Abdominal pain lower, Abdominal pain upper). 26 (4.3%, 5.2) 13 (2.1%, 2.7) Diarrhea 24 (3.9%, 4.8) 16 (2.6%, 3.4) Insomnia 24 (3.9%, 4.8) 11 (1.8%, 2.3) Back pain 18 (3.0%, 3.6) 13 (2.1%, 2.7) Hot flush 15 (2.5%, 3.0) 10 (1.6%, 2.1) Hepatic transaminase elevation Hepatic transaminase elevations (including Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase abnormal, Aspartate aminotransferase increased). 14 (2.3%, 2.8) 5 (0.8%, 1.1) In the pooled laboratory data of Trials 1, 2, and 3, elevated hepatic transaminases (> 3 x ULN) occurred in 25 women (2.3%, 2.7 EAIR) exposed to VEOZAH 45 mg (n=1100, 912.1 total person-years) as compared to 8 women (0.9%, 1.5 EAIR) exposed to placebo (n=952, 549.1 total person-years). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VEOZAH. Because these 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. Hepatic : Cases of serious drug-induced hepatotoxicity occurred within 40 days of starting VEOZAH. Patients experienced elevated transaminases (up to 50 x ULN at peak elevation), elevated alkaline phosphatase (up to 4 x ULN at peak elevation), and bilirubin (up to 5 x ULN at peak elevation) coupled with symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine. After discontinuation of VEOZAH, these abnormalities gradually resolved.