- ACRONYMS AND DEFINITIONS
- CrCl - Creatinine clearance
- RCT - Randomized controlled trial
- ULN - Upper limit of normal
- MECHANISM OF ACTION
- Estrogen inhibits neurokinin 3 receptors (NK3) in the thermoregulatory center of the hypothalamus, and declining levels during menopause trigger heat dissipation processes, including cutaneous vasodilation felt as upper body warmth, sweating, and chills (hot flash).
- Fezolinetant is a neurokinin 3 receptor antagonist that blocks neurokinin B binding on the kisspeptin/neurokinin B/dynorphin neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has high affinity for the NK3 receptor, which is more than 450-fold higher than binding affinity to NK1 or NK2 receptors. [1,2]
- FDA-APPROVED INDICATIONS
- Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause
- EFFICACY
- Overview
- The effects of fezolinetant on menopausal vasomotor symptoms in a 12-week study are described in the table below
| Fezolinetant 45 mg (N=174) |
Placebo (N=175) |
|
|---|---|---|
| Mean Frequency of Moderate to Severe Vasomotor Symptoms over 24 Hours | ||
| Baseline | 10.4 | 10.5 |
| Change from baseline at 4 weeks |
-5.4 | -3.3 |
| Change from baseline at 12 weeks |
-6.4 | -3.9 |
| Mean Severity of Moderate to Severe Vasomotor Symptoms over 24 Hours | ||
| Baseline | 2.4 | 2.4 |
| Change from baseline at 4 weeks |
-0.5 | -0.3 |
| Change from baseline at 12 weeks |
-0.6 | -0.4 |
- SIDE EFFECTS
| Side effects reported in a 52-week trial | ||
|---|---|---|
| Side effect | Fezolinetant 45 mg (N=609) |
Placebo (N=610) |
| Abdominal pain | 4.3% | 2.1% |
| Diarrhea | 3.9% | 2.6% |
| Insomnia | 3.9% | 1.8% |
| Back pain | 3.0% | 2.1% |
| Hot flush | 2.5% | 1.6% |
| Hepatic transaminase elevation | 2.3% | 0.8% |
- Liver enzyme elevations
- In studies, ALT and/or AST elevations greater than 3 X ULN occurred in 2.3% of fezolinetant-treated women and 0.9% of placebo-treated women. Elevations returned to pretreatment levels with continued therapy, dose interruptions, or discontinuation.
- Check LFTs before therapy and do not start fezolinetant if ALT or AST is more than 2 X ULN or if bilirubin is elevated. Check LFTs at 3, 6, and 9 months of therapy and for symptoms of liver disease (e.g. jaundice, nausea, vomiting).
- CONTRAINDICATIONS
- Known cirrhosis
- CrCl < 30 ml/min
- Concomitant use with CYP1A2 inhibitors
- PRECAUTIONS
- Kidney disease
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: DO NOT USE. Contraindicated.
- Liver disease
- Child-Pugh A, B, or C cirrhosis: DO NOT USE. Exposure is increased.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Fezolinetant (Veozah®)
- CYP1A2 inhibitors - DO NOT COMBINE. Fezolinetant is a CYP1A2 sensitive substrate, and CYP1A2 inhibitors (weak, moderate, and strong) increase its exposure.
- Metabolism and clearance
- DOSING
- Dosage form
- 45 mg tablet
- Dosing
- Dosing: 45 mg once daily
- Take at approximately the same time each day
- Do not crush, cut, or chew tablets
- May take without regard to food
- Missed doses: if a dose 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.
- Check LFTs before initiating therapy. See liver enzyme elevations.
- LONG-TERM SAFETY
- Fezolinetant was FDA-approved in 2023. No long-term safety data is available.
- BIBLIOGRAPHY
- 1 - Veozah PI
- 2 - PMID 36734148 - Efficacy and Safety of Fezolinetant in Moderate-to-Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT, J Clin Endocrinol Metab (2023)