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Enclomiphene Citrate: Restarting After Acute Illness

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At a glance

  • Approval / Not FDA-approved; no label with interruption or missed-dose instructions [1]
  • Half-life / About 10 hours; peak 2 to 3 hours after a dose [1]
  • Doses studied / 6.25, 12.5 and 25 mg once daily [2]
  • Phase 3 dosing / 12.5 mg daily, up to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [3]
  • After stopping / Testosterone fell back to pre-treatment values one month later in a 12-man phase 2b study [9]
  • Endpoints measured / Testosterone, LH, FSH and sperm counts, not symptoms [1]
  • FDA-flagged concerns / Clot and cardiac events, raised estradiol, PSA and hematocrit; no long-term data [1]
  • Regulatory status / Category 1 bulk substance under evaluation; 2022 committee vote 4 yes, 8 no [4][5]

Is there a restart protocol?

No. With no approved product there is no label section on missed doses or interruptions [1].

What is documented is timing: peak levels arrive 2 to 3 hours after a dose, the half-life is about 10 hours, and excretion is mainly fecal [1]. In a phase 2b study of 12 men previously on topical testosterone, testosterone fell back to pre-treatment values one month after stopping enclomiphene [9].

What the trials measured

The phase 3 programme measured hormones, not symptoms. In ZA-301, 151 overweight men aged 18 to 60 with morning testosterone below 300 ng/dL took 12.5 mg, 25 mg or placebo for 12 weeks; 78.8% of the pooled enclomiphene group reached an average 24-hour testosterone of 300 to 1,040 ng/dL [3]. ZA-302, the same design in 181 men, reported 81.3% [6].

ZA-304 and ZA-305 compared enclomiphene with AndroGel 1.62% for 16 weeks. Testosterone rose in every group; LH and FSH rose on enclomiphene and fell on the gel; sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on the gel [7].

What regulators listed as risks

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, along with raised estradiol, raised PSA, raised hematocrit and no long-term safety data [1]. EMA refused marketing authorisation in 2018: the four main studies in 588 patients showed higher testosterone without examining symptom improvement, and it cited venous thromboembolism risk [8].

The most frequent side effects were headache, hot flushes, nausea and muscle spasm [6].

Dosing and product status

The phase 3 programme tied one dose change to a measurement: 12.5 mg daily, raised to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [3]. Doses studied are 6.25, 12.5 and 25 mg once daily [2].

Enclomiphene has no FDA-approved product [1]. FDA lists enclomiphene citrate as a bulk substance under evaluation, which is not an approval [4]; in June 2022 FDA proposed not adding it to the allowed list and the advisory committee voted 4 yes, 8 no [5]. HealthRX.com offers enclomiphene by prescription.

Frequently asked questions

Which labs did the trials use to judge response?
Morning and 24-hour total testosterone, LH, FSH and sperm counts [3][7]. Symptom or quality-of-life improvement was not measured; EMA cited that gap along with a risk of venous thromboembolism when it recommended refusing authorisation in 2018 [8].
Can I restart at my usual dose?
No FDA-approved dose exists, so no label sets a restart dose [1]. The phase 3 protocols started at 12.5 mg once daily and increased it to 25 mg at week 6 when morning testosterone remained below 300 ng/dL [3].
Does enclomiphene raise the risk of blood clots?
FDA's 2022 review listed thromboembolic events including pulmonary embolism and deep vein thrombosis in a safety study, and noted there are no long-term safety data [1]. EMA cited venous thromboembolism risk when it refused authorisation [8].
Is enclomiphene approved for low testosterone?
No. FDA's 2022 advisory-committee materials state that no FDA-approved drugs contain enclomiphene as the active ingredient, and Repros announced a complete response letter from FDA in 2015 [1]. EMA refused authorisation in 2018 [8].

References

  1. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  2. Wiehle R, Cunningham GR, Pitteloud N, Wike J, Hsu K, Fontenot GK, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU Int. 2013;112(8):1188-200. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics
  3. Official web page. Official web page
  4. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  5. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  6. Official web page. Official web page
  7. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-85. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement
  8. Official web page. Official web page
  9. Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628-35. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel
Evidence overview for Enclomiphene Citrate: Restarting After Acute Illness