What are the most common side effects of fezolinetant?

Published

Prescribing Information including BOXED WARNING

In pooled data from the Phase 3 SKYLIGHT trial program, the most frequently reported adverse reactions (≥ 2% and greater than placebo) with fezolinetant 45 mg included headache (8.2%), upper respiratory tract infection (URTI; 7.7%), COVID-19 (6.1%), arthralgia (3.2%), diarrhea (3.2%), back pain (3.1%), insomnia (3.0%), urinary tract infection (UTI; 2.9%), and alanine aminotransferase (ALT) increase (2.8%).

The safety of fezolinetant was evaluated across three Phase 3 trials, SKYLIGHT 1, 2 and 4, involving 2852 women for up to 52 weeks.^1–3
In the 52-week safety trial, SKYLIGHT 4, the most frequently reported adverse reactions (≥ 2% and greater than placebo) with fezolinetant 45 mg included abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), hot flush (2.5%), and hepatic transaminase elevation (2.3%)⁴

Table 1. Most frequently (≥ 1% in either group) reported treatment-emergent adverse events (TEAEs) in the safety analysis set^a; pooled data from SKYLIGHT 1, 2, and 4⁵

Preferred Term, n (%)	Placebo^b (n = 952)	Fezolinetant 45 mg Total^c (n = 1100)
Headache	73 (7.7)	90 (8.2)
URTI	78 (8.2)	85 (7.7)
COVID-19	39 (4.1)	67 (6.1)
Arthralgia	25 (2.6)	35 (3.2)
Diarrhea	23 (2.4)	35 (3.2)
Back pain	16 (1.7)	34 (3.1)
Insomnia	15 (1.6)	33 (3.0)
UTI	22 (2.3)	32 (2.9)
ALT increased	9 (0.9)	31 (2.8)
Nasopharyngitis	24 (2.5)	27 (2.5)
Nausea	19 (2.0)	27 (2.5)
Hypertension	22 (2.3)	26 (2.4)
Fatigue	21 (2.2)	26 (2.4)
Hot flush	12 (1.3)	24 (2.2)
Blood creatine phosphokinase increased	3 (0.3)	23 (2.1)
Blood alkaline phosphatase increased	21 (2.2)	16 (1.5)
Gamma-glutamyl transferase increased	12 (1.3)	16 (1.5)
Abdominal pain	6 (0.6)	20 (1.8)
Aspartate aminotransferase increased	2 (0.2)	17 (1.5)
Weight increased	10 (1.1)	8 (0.7)

^aAll randomized participants who took at least one dose of study intervention.

^bPlacebo includes 175 participants from SKYLIGHT 1 and 167 participants from SKYLIGHT 2 who received placebo for 12 weeks, and 610 participants who received placebo for 52 weeks in SKYLIGHT 4.

^cFezolinetant 45 mg Total includes 151 participants who received fezolinetant 45 mg for 40 weeks (re randomized after Week 12 from placebo to fezolinetant 45 mg for the active treatment extension period in SKYLIGHT 1 and 2), and 949 participants who received fezolinetant 45 mg for 52 weeks in SKYLIGHT 1, 2 and 4.

In the pooled 52-week analysis, TEAEs occurred in 55.3% of participants in the placebo group and 62.9% in the fezolinetant 45 mg group.⁵ However, when controlled for exposure, the exposure-adjusted incidence ratio for overall TEAEs was 95.8 per 100 participant-years in the placebo group and 75.9 per 100 participant-years in the fezolinetant 45 mg group. The majority of TEAEs in all treatment groups were mild or moderate in severity and were generally similar between treatment groups.
There was a slightly higher proportion of participants with TEAEs and serious TEAEs in the fezolinetant 45 mg total group than in the placebo group; however, the majority of TEAEs were not drug-related and the proportion of participants with drug-related TEAEs was similar across treatment groups.⁵ The incidences of drug-related serious TEAEs and drug-related TEAEs leading to withdrawal were low.
Overall, fezolinetant demonstrated a favorable safety and tolerability profile over 52 weeks.⁵

Table 2. Overview of TEAEs in the safety analysis set^a; pooled data from SKYLIGHT 1, 2, and 4⁵

n (%) [rate^b]	Placebo^c (n = 952)	Fezolinetant 45 mg Total^d (n = 1100)
TEAE (overall)	526 (55.3) [95.8]	692 (62.9) [75.9]
Serious TEAE	15^e (1.6) [2.7]	45^f (4.1) [4.9]
TEAE leading to withdrawal of treatment	37 (3.9) [6.7]	47 (4.3) [5.2]
Drug-related TEAE	140 (14.7) [25.5]	171 (15.5) [18.7]
Drug-related serious TEAE	1^g (0.1) [0.2]	4^h (0.4) [0.4]
Drug-related, leading to withdrawal of treatment TEAE	24 (2.5) [4.4]	31 (2.8) [3.4]
Death (unrelated to treatment)	0	1 (0.1) [0.1]

^aAll randomized participants who took at least one dose of study intervention.

^bExposure-adjusted incidence rate per 100 participant-years.

^cPlacebo includes 175 participants from SKYLIGHT 1 and 167 participants from SKYLIGHT 2 who received placebo for 12 weeks, and 610 participants who received placebo for 52 weeks in SKYLIGHT 4.

^dFezolinetant 45 mg Total includes 151 participants who received fezolinetant 45 mg for 40 weeks (rerandomized after Week 12 from placebo to fezolinetant 45 mg for the active treatment extension period in SKYLIGHT 1 and 2), and 949 participants who received fezolinetant 45 mg for 52 weeks in SKYLIGHT 1, 2 and 4.

^eEach occurring in only one participant.

^fEach occurring in one participant except for abdominal pain (n = 2), chest pain (n = 3), COVID-19 (n = 2), colon cancer (n = 2), and endometrial adenocarcinoma (n = 2).

^gGamma-glutamyltransferase and transaminases increased.

^hHepatotoxicity (n = 1), ALT increased (n = 1), liver function test abnormal (n = 1), and endometrial adenocarcinoma (n = 1).

Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocr Metab. 2023;108(8):1981-1997. https://dx.doi.org/10.1210/clinem/dgad058.
Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401(10382):1091-1102. https://dx.doi.org/10.1016/s0140-6736(23)00085-5.
Neal-Perry G, Cano A, Lederman S, et al. Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial. Obstet Gynecol. 2023;141(4):737-747. https://dx.doi.org/10.1097/aog.0000000000005114.
VEOZAH [package insert]. Northbrook, IL, USA: Astellas Pharma, Inc. Available at: https://www.astellas.com/us/system/files/veozah_uspi.pdf.
Kagan R, Cano A, Nappi RE, et al. Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies. Adv Ther. 2024. https://dx.doi.org/10.1007/s12325-024-03073-8.