Enclomiphene Citrate Liver Function Impact: What the Clinical Evidence Shows

Does enclomiphene have a label that covers liver function?

No. No FDA-approved drug contains enclomiphene as an active ingredient, per FDA's own advisory-committee presentation from 8 June 2022, and EMA's committee refused marketing authorisation for EnCyzix (enclomifene) in January 2018 [2][4]. With no FDA-approved product there is no FDA-approved prescribing information: no hepatic contraindication, no monitoring schedule, no drug interactions section.

What the enclomiphene trials measured

One published comparison is the 2016 BJU International report of two parallel randomised, double-blind, double-dummy, placebo-controlled 16-week phase 3 studies, ZA-304 and ZA-305, in overweight men aged 18 to 60 with secondary hypogonadism and morning testosterone of 300 ng/dL or less [1]. Total testosterone rose in all treatment groups, LH and FSH rose with enclomiphene and fell with testosterone gel, and sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on the gel [1]. Earlier phase 2 studies reported hormone and semen endpoints [6][7][8].

What the clomiphene label says about the liver

The Clomid label contraindicates clomiphene citrate in patients with liver disease or a history of liver dysfunction, and its postmarketing section lists increased transaminases and hepatitis [3]. Clomiphene is a mixture: the USP monograph gives enclomiphene content of 50 to 70 percent, and the two are related but not the same drug [2]. The label covers ovulation induction in women; it has no male indication and states that adequate studies in male infertility are lacking [3]. It is not enclomiphene's label.

What regulators flagged

FDA's 2022 presentation listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA, raised hematocrit, and no long-term safety data [2]. Liver injury was not among the concerns FDA listed in that presentation [2]. EMA based its refusal on four main studies in 588 patients, where testosterone rose but symptom improvement was not examined, plus a venous thromboembolism risk [4].

How enclomiphene is handled

Peak levels come 2 to 3 hours after a dose, half-life is about 10 hours, the main metabolite is 4-hydroxy enclomiphene, and excretion is mainly in feces [2]. The clomiphene label notes that zuclomiphene has a longer half-life than enclomiphene and stayed detectable for longer than a month in single-dose studies [3]. Long-term safety data are lacking, as FDA noted in 2022 and as the 2026 British Society of Sexual Medicine position statement repeats, advising use only by experienced clinicians in specialist or research settings [2][5].