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Enclomiphene Citrate Dosing in Renal Impairment

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At a glance

  • FDA status / Not approved; no FDA-approved dose [1][2]
  • EMA status / EnCyzix marketing authorisation refused in 2018 [4]
  • Renal dosing / No labelled renal dose; no approved label [1]
  • Doses studied / 6.25, 12.5 and 25 mg once daily in a 6-week phase 2 trial [2]
  • Phase 3 dosing / 12.5 mg daily, uptitrated to 25 mg at week 6 if testosterone stayed below 300 ng/dL [3]
  • Half-life / About 10 hours [1]
  • Main excretion / Feces [1]
  • ESRD and low testosterone / 44% of 260 men had testosterone below 10 nmol/L [5]

Is there a renal dose for enclomiphene?

Enclomiphene is not FDA-approved, and no FDA-approved dose exists [1][2]. The European Medicines Agency's CHMP recommended refusing marketing authorisation for EnCyzix (enclomifene) in 2018 [4]. FDA's compounding list places enclomiphene citrate in Category 1, 'Bulk Drug Substances Under Evaluation' [6]. With no approved enclomiphene label, there is no labelled renal dose to quote. A missing renal dose is not the same as no adjustment being needed.

What doses were actually studied?

In a 6-week phase 2 dose-finding study, men with secondary hypogonadism received enclomiphene 6.25, 12.5 or 25 mg once daily [2]. The phase 3 protocols used 12.5 mg once daily, with up-titration to 25 mg daily at week 6 if morning testosterone stayed below 300 ng/dL [3].

How enclomiphene is handled by the body

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen receptors in the pituitary, which raises LH and FSH and drives the testes to make testosterone [1]. After an oral dose, peak levels occur about 2 to 3 hours later, the half-life is about 10 hours, the main metabolite is 4-hydroxy enclomiphene, and excretion is mainly in feces [1]. The main route is fecal, but that does not show what happens when kidney function falls.

Enclomiphene is proposed for secondary hypogonadism, where the testes are under-stimulated rather than failing; it would not be expected to work in primary hypogonadism [1].

Low testosterone in kidney disease

Low testosterone is common in advanced kidney disease. In one study of 260 men with end-stage renal disease, 44% had testosterone below 10 nmol/L [5]. In 239 men with CKD stages 1 to 5, total and free testosterone fell as kidney function fell [7].

Safety concerns regulators listed

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA and raised hematocrit, and noted no long-term safety data [1]. EMA's committee cited a risk of venous thromboembolism and said the studies showed higher testosterone but did not look at whether symptoms improved [4].

The Clomid label covers clomiphene citrate, a different product from enclomiphene. It lists visual symptoms in 1.5% of patients in clinical studies and contraindicates the drug in liver disease [8]. These are clomiphene figures, not enclomiphene rates.

Dialysis

The Clomid label says it is not known whether clomiphene citrate is dialyzable; the label covers the mixture, not enclomiphene [8].

Frequently asked questions

Does enclomiphene need a dose adjustment in kidney disease?
No renal dose exists. Enclomiphene has no approved label, so there is no labelled kidney-specific adjustment [1]. The trials used 6.25 to 25 mg daily in men with secondary hypogonadism [2][3].
What doses of enclomiphene were used in trials?
A 6-week phase 2 study used 6.25, 12.5 and 25 mg once daily [2]. Phase 3 protocols used 12.5 mg daily, uptitrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [3].
Is enclomiphene FDA-approved?
No. FDA has not approved any product containing enclomiphene, and EMA's committee recommended refusing marketing authorisation for EnCyzix in 2018 [1][4].
Does kidney disease lower testosterone?
Yes. In 260 men with end-stage renal disease, 44% had testosterone below 10 nmol/L [5]. In 239 men with CKD stages 1 to 5, total and free testosterone fell as kidney function fell [7].

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. Official web page. Official web page
  5. Carrero JJ, Qureshi AR, Nakashima A, Arver S, Parini P, Lindholm B, et al. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transplant. 2011;26(1):184-90. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease
  6. U.S. Food and Drug Administration. U.S. Food and Drug Administration
  7. Yilmaz MI, Sonmez A, Qureshi AR, Saglam M, Stenvinkel P, Yaman H, et al. Endogenous testosterone, endothelial dysfunction, and cardiovascular events in men with nondialysis chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(7):1617-25. Endogenous testosterone, endothelial dysfunction, and cardiovascular events in men with nondialysis chronic kidney disease
  8. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
Evidence overview for Enclomiphene Citrate Dosing in Renal Impairment