Enclomiphene Citrate in Men 65+: School, Work, and Daily Activity Considerations

Were men 65 and older included in the trials?

The phase 3 efficacy trials enrolled men aged 18 to 60 with low morning testosterone (about 300 ng/dL or less) [1][2][3]. A separate six-month open-label safety study (NCT01534208) enrolled men aged 18 to 65. A phase 2 pharmacokinetic study enrolled 48 men [7], and an earlier phase 2b study enrolled 12 [8]. The British Society of Sexual Medicine describes the evidence base as small, short-term studies and says long-term efficacy and safety data are lacking [9].

School and work

The phase 3 programs measured total testosterone, LH, FSH and sperm concentration [3]. EMA's refusal notice for EnCyzix said the studies showed higher testosterone but did not examine whether symptoms improved [6]. FDA's 2018 guidance on secondary hypogonadism, as FDA described it in 2022, says it is unclear whether raising testosterone in this population produces clinical benefit and that semen-parameter changes alone are not enough [4].

Reported adverse events included headache, hot flushes, nausea and muscle spasm. In ZA-302, headache occurred in 7 of 112 men on 12.5 mg versus 1 of 47 on placebo, and nausea in 4 of 112 versus 3 of 47 [2]. Aggression was listed among the reasons men stopped treatment [2]. These trials did not measure effects on work or school performance.

Driving

Enclomiphene has no FDA-approved label [4]. The clomiphene citrate label covers the mixture, not enclomiphene alone. The label says blurring, spots or flashes may occur, that these symptoms may make driving a car or operating machinery more hazardous than usual, particularly under variable lighting, and that visual symptoms increase in incidence with increasing total dose or therapy duration [5].

In the enclomiphene data, blurred vision was one of the reasons men stopped treatment [2]. EMA wanted ocular monitoring; cataracts appeared in nonclinical studies but were not conclusively linked in people [4].

Exercise and daily activity

No trial measured exercise capacity or fitness outcomes. The safety signals FDA listed are hematocrit and PSA rises and cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study [4]. FDA's safety summary reports that EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone [4]. EMA also cited a risk of venous thromboembolism [6].

Availability

Enclomiphene is not FDA-approved; FDA's 2022 advisory committee materials state that no approved drug contains it [4]. EMA's CHMP refused marketing authorisation for EnCyzix in January 2018 [6]. FDA lists enclomiphene citrate in Category 1, bulk substances under evaluation, which is enforcement discretion and not an approval [10]; the 2022 advisory committee voted 4 yes and 8 no on adding it to the allowed list [11]. WADA's 2026 Prohibited List names clomifene in S4 and is not limited to named substances; athletes should treat enclomiphene as prohibited and check with their anti-doping organisation [12].