Enclomiphene Citrate: Switching From and To Other Drugs in Class

Is there an established switching protocol?

No. FDA's June 8, 2022 advisory-committee presentation states that no FDA-approved drugs contain enclomiphene as an active ingredient [1]. No FDA-approved dose exists. In a phase 2 study, the doses tested were 6.25, 12.5 and 25 mg once daily [1][5].

Clomiphene citrate is FDA-approved only for ovulatory dysfunction in women who want to become pregnant. Its label carries no male indication and states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility [6]. Clomiphene use in men is off-label [6].

Clomiphene to enclomiphene

Clomiphene citrate is a mixture of enclomiphene and zuclomiphene. Per FDA, the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent, and zuclomiphene is the more estrogenic of the two [1][7]. The Clomid label notes that zuclomiphene has a longer half-life than enclomiphene and that detectable zuclomiphene levels persisted longer than a month in single-dose studies of normal volunteers [6].

The comparison in men is retrospective. Among 66 men who took clomiphene and later enclomiphene, median testosterone rose 166 ng/dL on enclomiphene versus 98 ng/dL on clomiphene (P=0.20), estradiol changed by -5.92 versus +17.50 pg/mL (P=0.001), and adverse effects were significantly less frequent on enclomiphene (odds ratio 0.18, 95% CI 0.07 to 0.44) [2]. The study reports hormone changes and adverse-effect rates after sequential clomiphene and enclomiphene use, not a dose conversion between them [2].

After testosterone

In two phase 3 trials, testosterone gel lowered LH and FSH while enclomiphene raised them [8]. In a randomized, open-label phase 2B study of 12 men with secondary hypogonadism previously treated with topical testosterone, total testosterone rose on both gel and enclomiphene after the gel was stopped and was similar between them at six months; only the enclomiphene group had increased LH and FSH. Sperm counts rose in 7 of 7 men on enclomiphene at 3 months, and gel did not raise counts above 20 million/mL in any of 5 men at 3 months. Testosterone fell back to pre-treatment values one month after treatment stopped [3].

Two parallel 16-week phase 3 trials compared enclomiphene with AndroGel 1.62% in separate groups: LH and FSH rose with enclomiphene and fell with gel, and sperm concentration stayed in the normal range on enclomiphene while spermatogenesis dropped markedly on gel [8]. Sperm was not always preserved. In ZA-301, sperm concentration fell by 50 percent or more in 14.2 percent of men on enclomiphene versus 2.6 percent on placebo [9].

What carries across any change

FDA's 2022 review listed cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA, raised hematocrit, and no long-term safety data [1]. In the phase 3 program the most frequent side effects were headache, hot flushes, nausea and muscle spasm; in ZA-302, headache was reported by 7 of 112 men on 12.5 mg versus 1 of 47 on placebo [10]. The phase 3 trials measured testosterone, LH, FSH and sperm counts, not symptom or quality-of-life improvement, and FDA's 2018 guidance on secondary hypogonadism said semen changes alone are not enough to establish efficacy [1].