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Enclomiphene Citrate Side Effects: Severity Distribution by Patient Phenotype

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At a glance

  • Approval status / Not approved by FDA or EMA [2]
  • Population studied / Overweight men 18 to 60 with secondary hypogonadism [3][1]
  • Most frequent effects / Headache, hot flushes, nausea, muscle spasm [1]
  • Headache in ZA-302 / 7 of 112 on 12.5 mg vs 1 of 47 on placebo [1]
  • Nausea in ZA-302 / 4 of 112 vs 3 of 47 [1]
  • Reasons for stopping / Blurred vision, muscle spasm, headache, aggression [1]
  • Versus clomiphene / Fewer adverse effects, odds ratio 0.18 in a 66-man retrospective study [4]
  • Long-term safety data / none; FDA also listed cardiac and clot events, estradiol, PSA and hematocrit [2]

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].

Frequently asked questions

Which side effects are most common with enclomiphene?
Headache, hot flushes, nausea and muscle spasm were most frequent, and blurred vision, muscle spasm, headache and aggression were the recorded reasons men stopped [1].
Do enclomiphene side effects differ by patient type?
The trial figures are counts for each dose arm, not breakdowns by patient characteristics. In ZA-302, headache was reported by 7 of 112 men taking 12.5 mg and 1 of 47 taking placebo, and nausea by 4 of 112 and 3 of 47; the men were overweight, aged 18 to 60, with secondary hypogonadism [1][3].
Does enclomiphene cause fewer side effects than clomiphene?
In a retrospective study of 66 men who took clomiphene and later enclomiphene, adverse effects were less frequent on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44). It was not randomized [4].
Is enclomiphene FDA approved?
No. FDA's advisory committee materials state that no FDA-approved drugs contain enclomiphene as an active ingredient, and EMA refused marketing authorization in 2018 [2][5]. In June 2022 the committee also voted 4 yes and 8 no on adding enclomiphene citrate to the bulk substances list for compounding [7].
Does enclomiphene cause visual problems?
Blurred vision was a recorded reason for stopping in the phase 3 data [1]. The Clomid label, which covers the clomiphene mixture rather than enclomiphene alone, says visual symptoms are usually reversible but may persist and directs patients with any visual symptom to stop treatment and have a prompt ophthalmological evaluation [6].

References

  1. Official web page. Official web page
  2. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  3. Official web page. Official web page
  4. Saffati G, Kassab J, Orozco Rendon D, Hinojosa-Gonzalez DE, Kronstedt S, Lipshultz LI, et al. Safety and efficacy of enclomiphene and clomiphene for hypogonadal men. Transl Androl Urol. 2024;13(9):1984-1990. Safety and efficacy of enclomiphene and clomiphene for hypogonadal men
  5. Official web page. Official web page
  6. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  7. U.S. Food and Drug Administration. U.S. Food and Drug Administration
Evidence overview for Enclomiphene Citrate Side Effects: Severity Distribution by Patient Phenotype