Enclomiphene Citrate Side Effects: Rare but Serious Adverse Events

Does enclomiphene have a label that lists serious side effects?

Not in the United States. FDA's own advisory committee materials state that no FDA-approved drugs contain enclomiphene as an active ingredient [1]. In Europe, the CHMP adopted a negative opinion on 25 January 2018 recommending refusal of marketing authorization for EnCyzix (enclomifene) [2].

Clomiphene citrate is FDA-approved, but it is a different product: a mixture of enclomiphene and zuclomiphene, licensed only for ovulatory dysfunction in women who want to become pregnant [4]. Its warnings describe the mixture and have not been proven to apply to enclomiphene alone [4].

What serious risks did regulators actually flag?

FDA's June 2022 advisory committee briefing document lists the safety concerns identified from published trials, FDA adverse event reports and EMA's review: cardiac and thromboembolic events (including pulmonary embolism and deep vein thrombosis in a safety study), raised estradiol, raised PSA and raised hematocrit [1].

Blood clots and cardiac events

EMA noted a slightly higher rate of cardiac and thromboembolic events with enclomiphene than with testosterone [1]. EMA's assessment covered four main studies in 588 patients [2].

The clomiphene label lists pulmonary embolism, thrombophlebitis and phlebitis among postmarketing cardiovascular reactions, alongside chest pain, palpitation, tachycardia, arrhythmia and hypertension [4]. The label also states that these reports are voluntary, come from a population of uncertain size, and cannot be used to estimate frequency or establish causation [4].

Vision changes

EMA wanted ocular monitoring because cataracts appeared in nonclinical studies, though they have not been conclusively linked to people [1]. In the enclomiphene trials, blurred vision was one of the recorded reasons men stopped treatment, together with muscle spasm, headache and aggression [3].

The clomiphene label gives the fullest description of the visual syndrome for the mixture: blurring, spots or flashes (scintillating scotomata), which increase in incidence with higher total dose or longer treatment [4]. The label says these are usually reversible, but that prolonged visual disturbance has been reported, sometimes after the drug was stopped, and that the disturbances may be irreversible, especially with increased dosage or duration [4]. In clomiphene's clinical studies, visual symptoms were recorded in 1.5% of patients [4]. The label states that patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly [4].

Raised hematocrit, estradiol and PSA

FDA's list includes raised hematocrit, raised estradiol and raised PSA [1]. The phase 3 program measured testosterone, LH, FSH and sperm counts rather than symptom or quality-of-life outcomes [1].

Mood and psychiatric events

Aggression appears in the enclomiphene record as a reason for stopping treatment, not as a measured rate [3]. The clomiphene label lists depression in fewer than 1% of patients in clinical trials, and in postmarketing reports anxiety, irritability, mood changes and psychosis [4].

Liver

The enclomiphene concerns FDA listed in 2022 were cardiac and thromboembolic events and changes in estradiol, PSA and hematocrit [1]. Hepatic warnings belong to the clomiphene label: clomiphene citrate is contraindicated in people with liver disease or a history of liver dysfunction, and postmarketing reports include raised transaminases and hepatitis [4]. Those are statements about the mixture.

Sperm counts

One finding from the enclomiphene program concerns sperm rather than hormones. In ZA-301, which randomized 151 men, sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo over 12 weeks [5]. In ZA-302, which randomized 181 men, the figures were 14.2% versus 4.3% [3].

How long and how large the studies were

ZA-301 randomized 151 men and ZA-302 randomized 181 [5][3]. Treatment lasted 12 weeks in those two studies [5][3] and 16 weeks in the two parallel studies against AndroGel 1.62% [6]. EMA's assessment covered four main studies and 588 patients in total [2]. A 2026 British Society of Sexual Medicine position statement describes the evidence as coming from small short-term studies and advises use only by experienced clinicians in specialist or research settings [7].