Enclomiphene Citrate Side Effects: Severity Distribution by Patient Phenotype

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Is there a severity distribution by patient phenotype?

The adverse-event figures available are counts for each dose arm, for example 7 of 112 men on 12.5 mg, rather than breakdowns by body weight, age, baseline estradiol or another patient characteristic [1]. Both phase 3 trials enrolled overweight men aged 18 to 60 with morning testosterone under 300 ng/dL and normal sperm concentration, treated for 12 weeks [3][1]. EMA reviewed four main studies involving 588 patients when considering enclomiphene for overweight men with a BMI of at least 25 [5].

What the trials recorded

ZA-302 assigned 181 men to enclomiphene 12.5 mg (112 men), 25 mg (22 men) or placebo (47 men). Headache was reported by 7 of the 112 on 12.5 mg and 1 of the 47 on placebo; nausea by 4 of 112 and 3 of 47 [1]. Across the phase 3 program and the EMA review, the most frequent effects were headache, hot flushes, nausea and muscle spasm, and the reasons men stopped were blurred vision, muscle spasm, headache and aggression [1].

Enclomiphene compared with clomiphene

A retrospective comparison followed 66 men at one academic center who took clomiphene and later enclomiphene. Adverse effects were significantly less frequent on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44); estradiol changed by -5.92 pg/mL on enclomiphene versus +17.50 pg/mL on clomiphene (P=0.001), and median testosterone rose 166 ng/dL versus 98 ng/dL (P=0.20) [4]. It was retrospective and not randomized.

Serious events regulators flagged

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, plus raised estradiol, raised PSA and raised hematocrit, and noted the absence of long-term safety data [2]. EMA recorded a slightly higher rate of cardiac and thromboembolic events than with testosterone and refused authorization partly over venous thromboembolism risk; cataracts appeared in nonclinical studies and EMA wanted ocular monitoring [2][5].

Visual symptoms

Blurred vision was one of the recorded reasons men stopped enclomiphene in the phase 3 data [1]. The Clomid label, which covers clomiphene citrate (the two-isomer mixture) and not enclomiphene alone, says visual symptoms such as blurring, spots or flashes increase with dose and duration, are usually reversible but have been reported to persist, and it directs patients who develop any visual symptom to stop treatment and have a prompt ophthalmological evaluation [6].