Enclomiphene Citrate Regulatory Status: US, EU, Canada, and UK

United States: no FDA approval

Repros Therapeutics submitted a new drug application for enclomiphene (Androxal) for secondary hypogonadism in fertile men. In 2015 the company announced a complete response letter from FDA. As FDA later summarized it, the agency said the design of the phase 3 studies was not adequate to demonstrate clinical benefit and raised concerns about study entry criteria, titration and the bioanalytical method used to validate testosterone measurement [1]. No approval has followed.

FDA's broader view of this drug class appears in its 2018 guidance on secondary hypogonadism: it is unclear whether raising testosterone in these men produces clinical benefit, trials should show meaningful improvement in at least one symptom or sign, and changes in semen parameters alone are not enough to establish efficacy [1].

What 'not approved' means for compounding in the US

There is no FDA-approved enclomiphene product. FDA is still evaluating enclomiphene citrate for use in compounding [1][3]. Its list of bulk drug substances used in compounding, updated 14 May 2026, places enclomiphene citrate in Category 1, 'Bulk Drug Substances Under Evaluation'. FDA says it does not intend to take action against a compounder that uses a Category 1 substance if the conditions in its guidance are met. That is an enforcement-discretion policy, not an approval, and not a finding that the product is safe or effective [3]. Enclomiphene has no USP monograph and is not on FDA's final list of bulk substances that can be used in compounding [3].

At the 8 June 2022 meeting of FDA's Pharmacy Compounding Advisory Committee, FDA proposed that enclomiphene citrate not be added to that allowed list. The committee voted 4 in favor, 8 against, with 0 abstentions. Members who voted no cited the lack of clinical efficacy evidence; one said more studies were needed, and a member who voted yes noted that clomiphene citrate has a USP monograph [4].

Compounded drugs are not FDA-approved, and FDA does not review them for safety, effectiveness or quality before they reach patients [7].

Enclomiphene is not the same drug as Clomid

The two are related but are not the same drug. Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (trans) and zuclomiphene (cis); by FDA's account, the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [1].

Clomiphene itself is FDA-approved, as Clomid and generics, for ovulatory dysfunction in women who want to become pregnant. Its label has no male indication and states that there are no adequate or well-controlled studies demonstrating effectiveness in male infertility, and that testicular tumors and gynecomastia have been reported in men taking clomiphene, with cause and effect not known [6]. Male use of clomiphene is therefore off-label. Enclomiphene is not approved by FDA or EMA [1][2].

European Union: authorization refused in 2018

In Europe the drug was formally reviewed. Renable Pharma Limited applied for a marketing authorization for EnCyzix (enclomifene) for hypogonadotropic hypogonadism in overweight men with a body-mass index of at least 25. On 25 January 2018 the EMA's Committee for Medicinal Products for Human Use adopted a negative opinion recommending refusal of the authorization [2].

Two reasons were given. The studies showed higher testosterone but did not examine whether symptoms improved — bone strength, weight gain, impotence, libido — and there was a risk of venous thromboembolism. The assessment rested on four main studies in 588 patients [2]. No EU authorization has followed.

Canada and the UK

The status of enclomiphene with Health Canada and the UK Medicines and Healthcare products Regulatory Agency is not covered on this page. Enclomiphene is not approved by FDA or by EMA [1][2], and a 2026 position statement from the British Society of Sexual Medicine says the same, adding that its manufacturer discontinued development in 2021 [10].

What regulators flagged as safety concerns

The safety concerns FDA listed in 2022, drawn from published trials, FDA adverse event reports and EMA's review, were cardiac and thromboembolic events (including pulmonary embolism and deep vein thrombosis in a safety study), raised estradiol, raised PSA, raised hematocrit, and the absence of long-term safety data. EMA noted a slightly higher rate of cardiac and thromboembolic events than with testosterone. Cataracts appeared in nonclinical studies and were not conclusively linked to people, and EMA wanted ocular monitoring [1].

Some warnings on the clomiphene label belong to the mixture, not to enclomiphene alone: visual symptoms such as blurring, scotomata and flashes, which are usually reversible but may rarely persist, and contraindications in liver disease, uncontrolled thyroid or adrenal dysfunction, pituitary tumor and pregnancy [6].

What the phase 3 trials measured

The phase 3 program measured testosterone, LH, FSH and sperm counts. In ZA-301, a randomized, double-blind, placebo-controlled trial in 151 overweight men aged 18 to 60 with acquired hypogonadotropic hypogonadism, 78.8 percent of men on enclomiphene (95% CI 70.3 to 85.3, n=113) reached an average 24-hour testosterone in the normal range of 300 to 1040 ng/dL [5]. ZA-302 used the same design in 181 men, and 81.3 percent on enclomiphene reached the normal range (95% CI 73.9 to 87.0, n=134) [8]. In the 16-week ZA-304 and ZA-305 trials against AndroGel 1.62 percent, testosterone rose in all treatment groups, and sperm concentration remained in the normal range with enclomiphene [9].

A 2026 British Society of Sexual Medicine position statement records that enclomiphene is not approved by FDA or EMA, that its manufacturer discontinued development in 2021, and advises use only by experienced clinicians in specialist or research settings because long-term efficacy and safety data are lacking [10].

Is any dose approved?

No. There is no FDA-approved dose for enclomiphene [1]. The doses that appear in the research are 6.25, 12.5 and 25 mg once daily for six weeks in the phase 2 dose-finding trial [11], and 12.5 mg once daily in phase 3, up-titrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL [5].