Fezolinetant

Indications

Fezolinetant is used for: Menopausal Vasomotor Symptoms

Adult Dose

Adult Tablet Menopausal Vasomotor Symptoms Indicated for the treatment of moderate-to-severe vasomotor symptoms (VMS) caused by menopause 45 mg PO daily

Child Dose

Renal Dose

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

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

Contra Indications

Known cirrhosis Severe renal impairment or ESRD Coadministration with CYP1A2 inhibitors

Precautions

Hepatotoxicity Elevated transaminases reported in clinical trials; most patients were asymptomatic Patients with cirrhosis were not studied Cases of serious drug-induced liver injury (i.e., increased AST/ALT [≤50x ULN], alkaline phosphatase [≤4x ULN], and bilirubin [≤5x ULN] at peak elevation) occurring within 40 days of starting therapy reported in postmarketing surveillance; signs and symptoms resolved after therapy discontinuation Exclude alternative causes of abnormal LFTs Monitoring Parameters Before initiating Obtain liver function tests (LFTs), including ALT/AST, alkaline phosphatase, and total and direct bilirubin Do not begin therapy if ALT/AST >2x ULN or TB >2x ULN During treatment Monitor LFTs monthly for the first 3 months, at 6 months, and 9 months after starting therapy Perform more frequent LFT monitoring (until resolution) if ALT/AST >3x ULN develops

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

Interactions

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 Contraindicated (27) caffeine cannabidiol cimetidine ciprofloxacin conjugated estrogens diazoxide choline disulfiram enasidenib estradiol estrogens conjugated synthetic ethinylestradiol fexinidazole fluvoxamine givosiran interferon alfa 2b mestranol methoxsalen mexiletine peginterferon alfa 2a peginterferon alfa 2b propafenone propranolol rucaparib stiripentol verapamil viloxazine zileuton

Adverse Effects

Side effects of Fezolinetant : 1-10% Abdominal pain (4.3%) Diarrhea (3.9%) Insomnia (3.9%) Back pain (3%) Hot flush (2.5%) AST/ALT >3x ULN (2.3%)

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