Enclomiphene Citrate Side Effects: Incidence Rates Across Clinical Trials

The counts that actually exist

Enclomiphene was studied in two identically designed 12-week phase 3 trials in overweight men aged 18 to 60 with secondary hypogonadism and morning testosterone under 300 ng/dL: ZA-301, with 151 men, and ZA-302, with 181 men (112 on 12.5 mg daily, 22 on 25 mg, 47 on placebo) [4][2]. The arm-by-arm adverse-event figures come from the ZA-302 posting. At 12 weeks, headache was reported by 7 of 112 men on 12.5 mg (6%) versus 1 of 47 on placebo (2%), and nausea by 4 of 112 (3.6%) versus 3 of 47 (6.4%) [2]. Sperm concentration fell by 50% or more in 14.2% of men on enclomiphene versus 2.6% on placebo in ZA-301, and 14.2% versus 4.3% in ZA-302 [4][2].

Those are small counts from a single 12-week comparison, and the wider program is not large either: EMA's assessment covered four main studies in 588 patients [5].

Headache, hot flushes, nausea and muscle spasm

Across the phase 3 and EMA review data, the most frequently reported side effects were headache, hot flushes, nausea and muscle spasm [2][5]. The reasons recorded for stopping treatment were blurred vision, muscle spasm, headache and aggression [2].

Visual symptoms

Blurred vision was one of the reasons men stopped treatment in the phase 3 and EMA data [2]. FDA's 2022 presentation notes that cataracts were seen in nonclinical studies, without a conclusive link in people, and that EMA wanted ocular monitoring [1].

The Clomid label covers clomiphene citrate, the two-isomer mixture, not enclomiphene alone [3]. That label warns that blurring, spots or flashes can occur during treatment, become more frequent with higher total dose or longer duration, and are usually reversible but may be irreversible. It tells patients with any visual symptoms to stop treatment and have a complete ophthalmological evaluation promptly [3]. That instruction was written for clomiphene; enclomiphene has no label of its own [1].

Heart, clot and blood-count signals

FDA's 2022 summary of the enclomiphene program lists the safety concerns as 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 [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [1].

Why clomiphene's published percentages do not transfer

The Clomid label carries an incidence table of events greater than 1% from 8,029 patients in clinical studies: ovarian enlargement 13.6 percent, vasomotor flushes 10.4 percent, nausea and vomiting 2.2 percent, breast discomfort 2.1 percent, visual symptoms 1.5 percent and headache 1.3 percent [3]. Those patients were women treated for ovulatory dysfunction, and the drug they took was clomiphene, a mixture of enclomiphene and zuclomiphene [1][3]. The USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [1].

The label also notes that zuclomiphene has a longer half-life than enclomiphene and that detectable zuclomiphene persisted for longer than a month in single-dose studies [3]. Applying a table generated by that mixture in women to enclomiphene alone in men is not a like-for-like comparison, and the label has no male indication: it states that there are no adequate or well-controlled studies demonstrating the effectiveness of clomiphene citrate in male infertility [3].

Enclomiphene compared with clomiphene in 66 men

A retrospective single-center study compared 66 men who took clomiphene and later enclomiphene. Adverse effects were significantly less frequent on enclomiphene, with an odds ratio of 0.18 (95% CI 0.07 to 0.44). Estradiol change was minus 5.92 pg/mL on enclomiphene versus plus 17.50 pg/mL on clomiphene (P=0.001), and the median testosterone rise was 166 versus 98 ng/dL (P=0.20) [7].

The design limits what it can show: nothing was randomized, and the study found fewer recorded adverse effects during enclomiphene use but cannot establish how common those effects would be in other patients [7].

What the trials did not measure

The phase 3 trials measured testosterone, LH, FSH and sperm counts, not symptom relief or quality of life, and both FDA and EMA flagged that gap [1][5]. EMA's refusal opinion states that the studies showed higher testosterone but did not examine whether symptoms such as bone strength, weight gain, impotence or libido improved, and it cites a risk of venous thromboembolism [5].

Spontaneous reports cannot give a rate

FDA's own dashboard page states that reports cannot be used to estimate the incidence of an event, that duplicate and incomplete reports are in the system, and that the existence of a report does not establish that the drug caused the event [8]. A count of reports filed for enclomiphene or clomiphene tells you that something was reported, not how often it happens.

See enclomiphene for the product page. Enclomiphene is not an FDA-approved product [1].