BRIEF SUMMARY-

FEZOLINETANT- (May 2023)

Indication-  To treat severe hot flashes caused by menopause                                                                                                  

Dosage- One 45 mg tablet orally once daily with or without food.

ADR-  most common adverse  reactions, are.abdominal pain, diarrhea, insomnia, back pain, hot flush, and hepatic transaminase elevation.

CI- CONTRAINDICATION-

  Known cirrhosis,  Severe renal impairment or end-stage renal disease,  Concomitant use with CYP1A2 inhibitors

 WARNINGS-  Hepatic transaminase elevation: Elevations in serum transaminase concentrations greater than three times the upper limit of normal (ULN) occurred in the clinical trials.

Pat inform -Inform patients of possible serious adverse reactions of VEOZAH including hepatic transaminase elevation.

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Serial No 16

Name-        VEOZAH

Acive  Ingredient -  Fezolinetant

 Pharmacological clssificiation-      To treat severe hot flashes caused by menopause                                                                                                                                                                                                                                                                                                                  

    Date of Approval-         5/10/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                                     VEOZAH safely and effectively.

See full prescribing information for VEOZAH. VEOZAHTM (fezolinetant) tablets, for oral use

Initial U.S. Approval: 2023

 INDICATIONS AND USAGE -

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

 ADVERSE REACTIONS-

 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.

 CONTRAINDICATION-

 • Known cirrhosis

 • Severe renal impairment or end-stage renal disease

 • Concomitant use with CYP1A2 inhibitors

 WARNINGS AND PRECAUTIONS-

 Hepatic transaminase elevation: Elevations in serum transaminase concentrations greater than three times the upper limit of normal (ULN) occurred in the clinical trials.

Perform bloodwork prior to initiation of VEOZAH to evaluate for hepatic function and injury.

Do not start therapy if serum transaminase concentration is equal to or exceeds two times the ULN.

Perform follow-up evaluations of hepatic transaminase concentration at 3 months, 6 months, and 9 months after initiation of therapy. 

 DOSAGE AND ADMINISTRATION-

 Perform baseline bloodwork to evaluate for hepatic function and injury before beginning VEOZAH. While using VEOZAH, perform follow-up bloodwork at 3 months, 6 months, and 9 months after initiation of therapy and when symptoms suggest liver injury. One 45 mg tablet orally once daily with or without food.

 DOSAGE FORMS AND STRENGTHS -

 Tablets: 45 mg

 PATIENT COUNSELING INFORMATION-

Advise patients to read the FDA-approved patient labeling (Patient Information).

Evaluation of Liver Enzymes with VEOZAH-                                                           Inform patients that they will have to have a blood test to evaluate their liver before beginning VEOZAH and while using VEOZAH at 3 months, 6 months, and 9 months of use, and when clinically indicated to evaluate symptoms of liver abnormalities such as nausea, vomiting, or yellowing of the skin or eyes.

Serious Adverse Reactions with VEOZAH-                                                                Inform patients of possible serious adverse reactions of VEOZAH including hepatic transaminase elevation.].

Common Adverse Reactions with VEOZAH-                                                                  Inform patients of possible less serious but common adverse reactions of VEOZAH including abdominal pain, diarrhea, insomnia, back pain, and hot flush..

Drug Interactions -                                                                                                         Advise patients to report their use of any other prescription or nonprescription medications or dietary supplements..

Distributed by: Astellas Pharma US, Inc. Northbrook, IL 60062 VEOZAH is a trademark of Astellas US LLC. © 2023 Astellas Pharma US, Inc.

CLINICAL PHARMACOLOGY

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.

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.

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 highcalorie, 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.

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%.

DRUG INTERACTIONS 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. 3 Reference ID: 5173194 8 USE IN SPECIFIC POPULATIONS 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. 4 Reference ID: 5173194 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)]. 10 OVERDOSAGE Treatment of overdose consists of discontinuation of VEOZAH therapy with institution of appropriate symptomatic care.

11 DESCRIPTION VEOZAH (fezolinetant) is a small-molecule NK3 receptor antagonist. The chemical name of fezolinetant is (4-Fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone having a molecular formula of C16H15FN6OS and a molecular weight of 358.39. The structural