2.1 Recommended Dosage

Take a single 45 mg VEOZAH tablet orally once daily with or without food.

Take VEOZAH with liquids and swallow whole. Do not cut, crush, or chew tablets.

Administer VEOZAH orally at about the same time each day. If a dose of VEOZAH is missed or not taken at the usual time, administer the missed dose as soon as possible, unless there is less than 12 hours before the next scheduled dose. Return to the regular schedule the following day.

Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury [including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and serum bilirubin (total and direct)] before initiating treatment with VEOZAH. 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.

While using VEOZAH, 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 [see Warnings and Precautions (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.

6.1 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.

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 Cmax 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 AUC24 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 AUC24 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 AUC24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC24 at the human therapeutic dose). The F1 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 AUC24 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 m2) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m2) [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 m2) or moderate (eGFR 30 to less than 60 mL/min/1.73 m2) 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)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. Transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant.

Cardiac Electrophysiology

At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

In healthy women, fezolinetant Cmax and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage).

Steady-state plasma concentrations of fezolinetant were reached after two once daily doses, with minimal fezolinetant accumulation.

Absorption

The median (range) time to reach fezolinetant Cmax is 1.5 (1 to 4) hours in healthy women.

Effect of Food

No clinically significant differences in fezolinetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal containing approximately 1000 calories (500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein).

Distribution

The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L. The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9.

Elimination

The effective half-life (t1/2) of fezolinetant is 9.6 hours in women with vasomotor symptoms. The apparent clearance at steady-state of fezolinetant is 10.8 L/h.

Metabolism

Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

Excretion

Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged).

Specific Populations

There were no substantive differences in the pharmacokinetics of VEOZAH based on race and body weight (93 to 278 pounds).

Women with Renal Impairment

Following single-dose administration of 30 mg fezolinetant, there was no effect on VEOZAH exposure (Cmax and AUC) in women with mild (eGFR 60 to less than 90 mL/min/1.73 m2) to severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment. The AUC of ES259564 (a major metabolite of fezolinetant) in women with moderate (eGFR 30 to less than 60 mL/min/1.73 m2) and severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment increased by approximately 75% and 380%, respectively. VEOZAH has not been studied in individuals with end-stage renal disease (eGFR less than 15 mL/min/1.73 m2).

Women with Hepatic Impairment

Following single-dose administration of 30 mg fezolinetant in women with mild Child-Pugh Class A cirrhosis, the mean Cmax increased by 23% and AUCinf increased by 56%, relative to women with normal hepatic function. In women with moderate Child-Pugh Class B cirrhosis, the mean Cmax of fezolinetant decreased by 15% and AUCinf increased by 96%. The Cmax of ES259564 decreased in both mild and moderate cirrhosis while AUCinf and AUClast increased less than 15%. VEOZAH has not been studied in individuals with severe Child-Pugh Class C cirrhosis.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP1A2 Inhibitors: Fezolinetant Cmax increased by 80% and AUC increased by 840% following concomitant use with fluvoxamine (strong CYP1A2 inhibitor).

Moderate CYP1A2 Inhibitors: Fezolinetant Cmax increased by 40% and AUC increased by 360% following concomitant use with mexiletine (moderate CYP1A2 inhibitor) 400 mg every 8 hours.

Weak CYP1A2 Inhibitors: Fezolinetant Cmax increased by 30% and AUC increased by 100% following concomitant use with cimetidine (weak CYP1A2 inhibitor) 300 mg every 6 hours.

No clinically significant differences in fezolinetant exposure were observed in smokers (moderate CYP1A2 inducer).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Fezolinetant and ES259564 are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fezolinetant and ES259564 are not inducers of CYP1A2, CYP2B6, and CYP3A4.

Transporter Systems

Fezolinetant is not a substrate nor an inhibitor of P-glycoprotein (P-gp). ES259564 is a substrate of P-gp, but not an inhibitor of P-gp.

Both fezolinetant and ES259564 are not a substrate of BCRP, OATP1B1, and OATP1B3. In addition, ES259564 is not a substrate of OAT1, OAT3, OCT2, MATE1, and MATE2-K.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC24 at the human therapeutic dose of 45 mg, respectively.

Mutagenesis

Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.

Impairment of Fertility

Fezolinetant had no effect on female fertility or early embryonic development up to 100 mg/kg/day in rats (143-fold the human AUC24 at the human therapeutic dose). In the pre- and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC24 at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC24 at the human therapeutic dose) [see Use in Specific Populations (8.1)].

13.2 Animal Toxicology and/or Pharmacology

Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC24 at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC24 at the human therapeutic dose) showed reduced ovarian activity.

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women

The efficacy of VEOZAH for the treatment of moderate to severe vasomotor symptoms due to menopause was evaluated in the first 12-week, randomized, placebo-controlled, double-blind portion of each of two phase 3 clinical trials. In each of these two trials, after the first 12 weeks, women on placebo were then re-randomized to VEOZAH for a 40-week extension to evaluate safety for up to 52 weeks total exposure.

In Trials 1 (NCT04003155) and 2 (NCT04003142), 1022 women (522 in Trial 1 and 500 in Trial 2) who had a minimum average of 7 moderate to severe vasomotor symptoms per day were randomized to one of two doses of fezolinetant (including the 45 mg dosage strength) or placebo. Randomization was stratified by smoking status.

The mean age of the postmenopausal women was 54 years. Women self-identified as Caucasian (81%), African American (17%), Asian (1%), and Hispanic/Latina ethnicity (24%). The study population included menopausal women with one or more of the following: prior hysterectomy (32.1%), prior oophorectomy (21.6%), or prior hormone therapy use (19.9%). Those who were on prior hormone therapy underwent a wash-out period prior to trial participation.

The co-primary efficacy endpoints for both trials were the mean change from baseline in moderate to severe vasomotor symptoms frequency and severity to Weeks 4 and 12. Data from each trial demonstrated statistically significant and clinically meaningful (≥ 2 hot flashes over 24 hours) reduction from baseline in the frequency of moderate to severe vasomotor symptoms for VEOZAH 45 mg compared to placebo at Weeks 4 and 12. Data from each trial also demonstrated a statistically significant reduction from baseline in the severity of moderate to severe vasomotor symptoms (over 24 hours) at Weeks 4 and 12 for VEOZAH 45 mg compared to placebo.

Results of the co-primary endpoint for change from baseline to Weeks 4 and 12 in mean frequency of moderate to severe vasomotor symptoms over 24 hours from Trials 1 and 2 are shown in Table 2.

Results of the co-primary endpoint for change from baseline to Weeks 4 and 12 in mean severity of moderate to severe vasomotor symptoms over 24 hours from Trials 1 and 2 are shown in Table 3.

14.2 Effects on Endometrium in Postmenopausal Women

In the VEOZAH 45 mg dose group across Trials 1, 2, and 3, endometrial biopsy assessments identified one case of endometrial hyperplasia and one case of endometrial malignancy. The rate of these events in the VEOZAH 45 mg dose group was ≤ 1% with the upper bound of the one-sided 95% confidence limit being ≤ 4%.

Five cases of disordered proliferative endometrium were reported in women receiving VEOZAH 45 mg and four cases were reported in women receiving placebo across the three clinical trials. The EAIR was 1.4 per 100 person-years in VEOZAH 45 mg versus 2.0 per 100 person-years in the placebo group.

16.1 How Supplied

VEOZAH (fezolinetant) 45 mg tablets are supplied as round, light red, film-coated tablets, debossed with the Astellas logo and ‘645’ on the same side. VEOZAH tablets are available in the following package sizes:

•

Bottles of 30 tablets with child resistant closure and desiccant, (NDC 0469-2660-30)

•

Bottles of 90 tablets with child resistant closure and desiccant, (NDC 0469-2660-90)

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].