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Fezolinetant

FDA Drug Information • Also known as: Veozah

Brand Names
Veozah
Drug Class
Neurokinin 3 Receptor Antagonist [EPC]
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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 ).

    • Description

    11 DESCRIPTION VEOZAH (fezolinetant) is a small-molecule NK3 receptor antagonist. The chemical name of fezolinetant is (4-Fluorophenyl)[(8 R )-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3- a ]pyrazin-7(8 H )-yl]methanone having a molecular formula of C 16 H 15 FN 6 OS and a molecular weight of 358.39. The structural formula of fezolinetant is: Fezolinetant is a white powder. It is very slightly soluble in water (0.29 mg/mL). Each VEOZAH (fezolinetant) tablet for oral use contains 45 mg of fezolinetant and the following inactive ingredients: ferric oxide, hydroxypropyl cellulose, hypromellose, low-substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide. structural formula of fezolinetant

    What Is Fezolinetant Used For?

    1 INDICATIONS AND USAGE 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 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION One 45 mg tablet orally once daily with or without food. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury before beginning VEOZAH. 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 or when signs or symptoms suggest liver injury. ( 2.1 ) 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 )].

    Side Effects (Adverse Reactions)

    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.

    • Drug Interactions

    7 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 C max and AUC of VEOZAH [see Clinical Pharmacology ( 12.3 )] . VEOZAH is contraindicated in individuals using CYP1A2 inhibitors.

    Contraindications

    4 CONTRAINDICATIONS 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 )

    • Pregnancy and Breastfeeding

    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)....

    Overdosage

    10 OVERDOSAGE Treatment of overdose consists of discontinuation of VEOZAH therapy with institution of appropriate symptomatic care.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 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, (NDC 0469-2660-30)
  • Bottles of 90 tablets with child resistant closure, (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].

    • About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.