Enclomiphene Citrate Drug-Drug Interactions: A Complete Clinical Profile

Why there is no interaction list

FDA's June 2022 advisory committee materials state that no FDA-approved drug contains enclomiphene as an active ingredient [1], and EMA's committee recommended refusing marketing authorisation for EnCyzix (enclomifene) in January 2018 [2]. In 2022 FDA proposed that enclomiphene citrate not be added to the list of bulk substances allowed in compounding, and its advisory committee voted 4 in favour and 8 against [6]. FDA lists it among bulk substances under evaluation, which is enforcement discretion, not approval [7].

Metabolism: what is measured

Enclomiphene peaks 2 to 3 hours after a dose with a half-life of about 10 hours; its main metabolite is 4-hydroxy enclomiphene and excretion is mainly in feces [1].

Testosterone and drugs acting on the same axis

Two parallel randomized, double-blind, double-dummy, placebo-controlled phase 3 trials (ZA-304 and ZA-305) compared enclomiphene with AndroGel 1.62% in overweight men aged 18 to 60 with morning testosterone of 300 ng/dL or lower, over 16 weeks. Total testosterone rose in every treatment group; LH and FSH rose with enclomiphene and fell with testosterone gel, sperm concentration stayed in the normal range on enclomiphene, and spermatogenesis fell markedly on the gel [3]. These trials gave each treatment to a separate group, so they do not test the two together.

hCG and fertility combinations

A 2025 meta-analysis of randomized trials pooled clomiphene and enclomiphene and compared SERM treatment with hCG. Total testosterone levels were significantly higher with SERM therapy and with SERM plus hCG than with hCG alone (158, 153 and 134 ng/dL respectively; P<0.002 for both comparisons) [4]. Because it pooled the two SERMs, the analysis does not establish an enclomiphene-specific interaction with hCG.

The Clomid label covers a different drug

Clomiphene citrate is a mixture of enclomiphene and zuclomiphene; per FDA, the USP monograph gives an enclomiphene content of clomiphene of 50 to 70 percent [1]. The Clomid label covers ovulation induction in women and has no male indication; it states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility, and that testicular tumors and gynecomastia have been reported in males using clomiphene, with cause and effect unknown [5]. Its contraindications include liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy, and it warns about visual symptoms such as blurring, spots or flashes [5]. Those warnings are written for the mixture, not for enclomiphene alone.