Enclomiphene Citrate Side Effects: Withdrawal and Discontinuation Syndrome

Does enclomiphene cause a withdrawal syndrome?

Enclomiphene is an oral selective estrogen receptor modulator. It blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH and the testes make more testosterone [1]. FDA's 2022 safety concerns for enclomiphene were cardiac and thromboembolic events and changes in estradiol, PSA and hematocrit, and EMA's refusal cited venous thromboembolism risk; withdrawal is not among them [1][2]. The clomiphene label states that tolerance, abuse or dependence with clomiphene citrate has not been reported [5], but that label covers the two-isomer clomiphene mixture, not enclomiphene alone.

What happens to testosterone after stopping?

In a phase 2b trial, 12 men with secondary hypogonadism who had previously used topical testosterone were randomized, open-label, to oral enclomiphene or testosterone gel. Total testosterone rose on both treatments over six months, and one month after treatment ended it decreased to pretreatment values [3]. The trial enrolled only 12 men.

Two larger phase 3 studies compared enclomiphene with testosterone gel for 16 weeks [7]. Enclomiphene is absorbed quickly, with peak levels 2 to 3 hours after a dose and a half-life of about 10 hours; it is excreted mainly in feces [1].

Side effects while taking enclomiphene

In phase 3 and EMA data, the most frequent reactions were headache, hot flushes, nausea and muscle spasm [4]. In the 12-week ZA-302 study, headache was reported by 7 of 112 men on 12.5 mg and 1 of 47 on placebo; nausea by 4 of 112 and 3 of 47 [4]. Reasons given for stopping treatment included blurred vision, muscle spasm, headache and aggression [4].

Regulators also flagged cardiac and thromboembolic events, including pulmonary embolism and deep vein thrombosis in a safety study, raised estradiol, raised PSA and raised hematocrit, and noted that no long-term safety data exist [1]. EMA's refusal of the EnCyzix application in January 2018 cited a risk of venous thromboembolism and the absence of data on whether symptoms improved [2].

Do visual symptoms continue after stopping?

The clomiphene citrate label warns that blurring, spots or flashes usually reverse, but that prolonged visual disturbance has been reported, some of it occurring after the drug was discontinued, and that the disturbances may be irreversible, especially with higher doses or longer treatment [5]. The label says patients with any visual symptoms should stop treatment and have a complete ophthalmological evaluation carried out promptly [5]. That warning applies to clomiphene, not to enclomiphene alone; the clomiphene label also lists cataract among post-marketing visual disorders [5].

Is a taper needed?

Enclomiphene has no FDA-approved product, so there is no label instruction on dosing or stopping [1]. The 12-week trials used daily enclomiphene doses of 12.5 mg or 25 mg [8][4]. The British Society of Sexual Medicine position statement notes that long-term efficacy and safety data are lacking and describes use by experienced clinicians in specialist or research settings as the appropriate context [9].

Compounded versions have not been reviewed by FDA for safety, effectiveness or quality [6].