Enclomiphene Citrate Geriatric (65+) Dosing: What Older Men Need to Know

Is there a dose for men over 65?

Trial data in older men are thin. ZA-304 and ZA-305, the two parallel phase 3 studies, enrolled overweight men aged 18 to 60 with secondary hypogonadism, morning testosterone of 300 ng/dL or less and low or normal LH [1]. Enclomiphene blocks estrogen receptors in the pituitary, raising LH and FSH release, which tells the testes to make more testosterone; it would not be expected to work in primary hypogonadism, where the testes have failed [4].

What doses were studied

A randomised, single-blind, two-centre phase 2 trial of 48 men compared enclomiphene 6.25, 12.5 and 25 mg once daily with transdermal testosterone gel for 6 weeks; testosterone and LH rose with enclomiphene [2].

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].

A separate 6-month open-label phase 3 safety study in the same programme enrolled 499 men aged 18 to 65 with secondary hypogonadism, taking 12.5 or 25 mg daily [11].

The two phase 3 comparison studies, ZA-304 and ZA-305, were randomised, double-blind, double-dummy and placebo-controlled, comparing two enclomiphene doses with testosterone gel 1.62 percent over 16 weeks. In these studies testosterone rose in all treatment groups, while LH and FSH rose with enclomiphene and fell with testosterone gel; sperm concentration stayed in the normal range on enclomiphene while spermatogenesis fell markedly on the gel [1].

What regulators flagged

In 2022 FDA listed concerns drawn from published trials, adverse event reports and the European review: 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 [4]. EMA's 2018 refusal of EnCyzix rested on four main studies in 588 patients: testosterone rose, but the studies did not examine whether symptoms improved, and there was a risk of venous thromboembolism [5]. EMA also noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [4].

Is enclomiphene approved?

No. FDA's advisory-committee material states that no FDA-approved drugs contain enclomiphene as an active ingredient [4], and EMA refused marketing authorisation in 2018 [5]. FDA lists enclomiphene citrate as a bulk drug substance under evaluation for compounding, an enforcement-discretion position and not a finding that the product is safe or effective [6]. In June 2022 the advisory committee voted 4 yes and 8 no on adding it to the allowed list [7].

Side effects reported

Headache, hot flushes, nausea and muscle spasm were the most frequent side effects, and reasons for stopping included blurred vision, muscle spasm, headache and aggression [8]. In ZA-302, headache was reported by 7 of 112 men on 12.5 mg against 1 of 47 on placebo, and nausea by 4 of 112 against 3 of 47 [8]. Visual symptoms such as blurring, scotomata and flashes appear in the Clomid label for clomiphene citrate, the two-isomer mixture; that label does not cover enclomiphene alone [9].