Fezolinetant

VEOZAH ® is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. VEOZAH is a neurokinin 3 (NK3) receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. ( 1 )

Tablets: 45 mg, round, light red, film-coated tablets, debossed with the Astellas logo and ‘645’ on the same side. Tablets: 45 mg ( 3 )

VEOZAH is contraindicated in women with any of the following conditions:

• Known cirrhosis [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )] .
• Severe renal impairment or end-stage renal disease [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .
• Concomitant use with CYP1A2 inhibitors [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] .
• Known cirrhosis ( 4 , 5.1 )
• Severe renal impairment or end-stage renal disease ( 4 , 8.6 )
• Concomitant use with CYP1A2 inhibitors ( 4 , 7.1 )

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.

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.

7.1 Effect of Other Drugs on VEOZAH CYP1A2 Inhibitors VEOZAH is a substrate of CYP1A2. Concomitant use of VEOZAH with drugs that are weak, moderate, or strong CYP1A2 inhibitors, increase the plasma C max and AUC of VEOZAH [see Clinical Pharmacology ( 12.3 )] . VEOZAH is contraindicated in individuals using CYP1A2 inhibitors.

8.1 Pregnancy Risk Summary There are no data on VEOZAH use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed. In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats. Additionally, in the male offspring delayed male reproductive maturation was observed, characterized by incomplete preputial separation, which affected male fertility at doses above the human therapeutic dose in rats [see Data ] . In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16‑fold the human AUC 24 at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats [see Nonclinical Toxicology ( 13.1 )] . In the pre- and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36‑fold the human AUC 24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F 1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC 24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC 24 at the human therapeutic dose). The F 1 male showed delayed male reproductive maturation, characterized as incomplete balanopreputial separation at time of mating, at doses of greater than or equal to 30 mg/kg/day (36-fold the human AUC 24 at the human therapeutic dose), which affected male fertility [see Nonclinical Toxicology ( 13.1 )] .

8.2 Lactation Risk Summary There are no data on the presence of fezolinetant in human milk, the effects on the breastfed child, or the effects on milk production. It is not known if fezolinetant is present in human milk. Data Animal Data Following administration of radiolabeled fezolinetant to lactating rats, the radioactivity concentration in milk was higher than that in the plasma at all time points, indicating that fezolinetant-derived components transferred to the tissues in infant rats via breast milk.

8.4 Pediatric Use The efficacy and safety of VEOZAH in individuals less than 18 years of age have not been established.

8.5 Geriatric Use There have not been sufficient numbers of geriatric women involved in clinical trials utilizing VEOZAH to determine whether those over 65 years of age differ from younger women in their response to VEOZAH.

8.6 Renal Impairment VEOZAH is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m 2 ) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m 2 ) [see Clinical Pharmacology ( 12.3 )] . No dose adjustment of VEOZAH is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m 2 ) or moderate (eGFR 30 to less than 60 mL/min/1.73 m 2 ) renal impairment.

8.7 Hepatic Impairment Child-Pugh Class A or B hepatic impairment increased the exposure of VEOZAH [see Clinical Pharmacology ( 12.3 )] . VEOZAH has not been studied in individuals with Child-Pugh Class C hepatic impairment. VEOZAH is contraindicated in individuals with cirrhosis [see Clinical Pharmacology ( 12.3 )] .

VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than binding affinity to NK1 or NK2 receptors.