Dosing & Uses
Dosage Forms & Strengths
tablet
- 45mg
Menopausal Vasomotor Symptoms
Indicated for treatment of moderate-to-severe vasomotor symptoms (VMS) caused by menopause
45 mg PO qDay
Dosage Modifications
Renal impairment
- Mild or moderate (eGFR 30-89 mL/min/1.73 m2): No dose adjustment required
- Severe (eGFR 15-29 mL/min/1.73 m2 or end-stage renal disease [ESRD]): Contraindicated
Hepatic impairment
- Mild or moderate (Child-Pugh A or B): Increased systemic exposure observed; no recommendations listed in prescribing information
- Severe (Child-Pugh C): Not studied
- Cirrhosis: Contraindicated
Dosing Considerations
Monitoring
-
Before initiating
- Perform baseline bloodwork for hepatic function and injury (including ALT, AST, and serum bilirubin [total and direct])
- May initiate fezolinetant if baseline hepatic transaminases <2x ULN and total bilirubin is normal
- Do not start fezolinetant if ALT or AST ≥2x ULN or if total bilirubin elevated (eg, ≥2x ULN)
-
During treatment
- Perform follow-up bloodwork at 3, 6, and 9 months after initiating and when symptoms (eg, nausea, vomiting, jaundice) suggest liver injury
Not indicated
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (26)
- caffeine
caffeine will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- cannabidiol
cannabidiol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- cimetidine
cimetidine will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- ciprofloxacin
ciprofloxacin will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- conjugated estrogens
conjugated estrogens will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- disulfiram
disulfiram will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- estradiol
estradiol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- estrogens conjugated synthetic
estrogens conjugated synthetic will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- ethinylestradiol
ethinylestradiol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- fexinidazole
fexinidazole will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- fluvoxamine
fluvoxamine will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- givosiran
givosiran will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- interferon alfa 2b
interferon alfa 2b will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- leniolisib
leniolisib will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- mestranol
mestranol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- methoxsalen
methoxsalen will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- mexiletine
mexiletine will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- peginterferon alfa 2a
peginterferon alfa 2a will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- peginterferon alfa 2b
peginterferon alfa 2b will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- propafenone
propafenone will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- propranolol
propranolol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- rucaparib
rucaparib will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- stiripentol
stiripentol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- verapamil
verapamil will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- viloxazine
viloxazine will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- zileuton
zileuton will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
1-10%
Abdominal pain (4.3%)
Diarrhea (3.9%)
Insomnia (3.9%)
Back pain (3%)
Hot flush (2.5%)
Elevated hepatic transaminase (2.3%)
Warnings
Contraindications
Known cirrhosis
Severe renal impairment or ESRD
Coadministration with CYP1A2 inhibitors
Cautions
Hepatic transaminase elevation
- ALT and AST >3x ULN observed during clinical trials
- 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
- Obtain baseline bloodwork before initiating and at 3, 6, and 9 months, or if symptoms suggestive of liver injury (eg, nausea, vomiting, jaundice) occur after starting fezolinetant
- May initiate fezolinetant if baseline hepatic transaminases <2x ULN and total bilirubin is normal
- Do not start fezolinetant if ALT or AST ≥2x ULN or if total bilirubin elevated (eg, ≥2x ULN)
Drug interaction overview
- CYP1A2 substrate
-
CYP1A2 inhibitors
- Contraindicated
- Peak plasma concentration and AUC of fezolinetant are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
Pregnancy & Lactation
Pregnancy
There are no data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Animal studies
- In a 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 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
Lactation
Data are not available on presence in human milk, effects on breastfed children, or effects on milk production
Unknown if present in human milk
Animal studies
- Following administration of radiolabeled fezolinetant to lactating rats, concentration in milk was higher than that in plasma at all time points
- This indicated that fezolinetant-derived components transferred to tissues in infant rats via breast milk
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Nonhormonal selective neurokinin 3 (NK3) receptor antagonist
Blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin/dynorphin (KNDy) neuron to modulate neuronal activity in the hypothalamus, and thereby reduces frequency and severity of vasomotor symptoms
Absorption
Peak plasma time: 1.5 hr
Steady-state was reached after 2 once daily doses, with minimal fezolinetant accumulation
Distribution
Protein bound: 51%
Vd: 189 L
Blood-to-plasma ratio: 0.9
Metabolism
Primarily metabolized by CYP1A2 and to lesser extent by CYP2C9 and CYP2C19
Major metabolite is ES259564 (~20-fold less potent than parent compound)
Elimination
Half-life: 9.6hr
Clearance: 10.8 L/hr
Excretion: Urine 76.9% (1.1% unchanged); feces 14.7% (0.1% unchanged)
Administration
Oral Administration
May take with or without food
Administer at approximately the same time each day
Swallow tablet whole with liquids; do not cut, crush, or chew
Missed dose
- If dose is missed or not taken at usual time, administer as soon as possible, unless <12 hr before next scheduled dose
- Return to regular schedule the next day
Storage
Store at 20-25ºC (68-77ºF) with excursions permitted from 15-30ºC (59-86ºF)
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