Enclomiphene Citrate Side Effects: Delayed-Onset Adverse Events Explained

Is there a known delayed side-effect pattern?

Enclomiphene has no approved product: FDA's 2022 presentation states that no FDA-approved drugs contain enclomiphene as an active ingredient [1], and EMA's committee recommended refusing marketing authorization for EnCyzix in January 2018 [8].

The evidence comes from short studies: a 6-week dose-finding trial [3], two 12-week phase 3 trials [4][5], two 16-week phase 3 trials [6] and a 6-month study in 12 men [7]. FDA's 2022 presentation lists no long-term safety data among its concerns [1].

What side effects were reported during treatment?

Across phase 3 and EMA data, the most frequent were headache, hot flushes, nausea and muscle spasm [5][8]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo, and nausea by 4 of 112 and 3 of 47 [5]. Reasons for stopping included blurred vision, muscle spasm, headache and aggression [5].

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][5]. These were measured after 12 weeks of treatment [4][5].

What does the clomiphene label say about vision?

The Clomid label covers clomiphene citrate, the two-isomer mixture that contains enclomiphene; enclomiphene itself has no approved product [1][9]. The label warns that blurring, spots or flashes (scintillating scotomata) may occur, that these symptoms increase in incidence with higher total dose or longer duration, are usually reversible, but prolonged visual disturbance has been reported, some of it appearing after clomiphene was stopped, and the disturbances may be irreversible, especially with higher dose or longer therapy [9]. The label says they may make driving or machinery use hazardous [9]. It says patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation promptly [9].

In the enclomiphene trials, blurred vision was a reason for stopping [5]. FDA's 2022 review noted cataracts in nonclinical studies, and EMA wanted ocular monitoring [1].

What heart, clot and blood-count concerns did regulators raise?

FDA's 2022 presentation listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA and raised hematocrit [1]. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone, and cited a risk of venous thromboembolism [1][8].

What about mood and gynecomastia?

Aggression was one reason for stopping in the enclomiphene trials [5]. The Clomid label lists anxiety, irritability, mood changes and psychosis among postmarketing psychiatric reactions, and says frequency cannot be reliably estimated from voluntary reports [9]. That section belongs to clomiphene, not enclomiphene.

The label also states that testicular tumors and gynecomastia have been reported in males using clomiphene, with cause and effect not known [9]. That statement is about clomiphene, not enclomiphene.

What did regulators flag to watch?

Enclomiphene has no approved product and no label [1]. The parameters regulators flagged were hematocrit, PSA, estradiol, and cardiac and thromboembolic events [1]. The eye instruction belongs to the clomiphene label [9]. The British Society of Sexual Medicine position statement advises use only by experienced clinicians in specialist or research settings [2].