Does TRICARE Cover Enclomiphene Citrate?

What is known about enclomiphene's regulatory status

Enclomiphene is an oral selective estrogen receptor modulator that blocks estrogen receptors in the pituitary, so the pituitary releases more LH and FSH, which tells the testes to make more testosterone [1].

FDA's advisory-committee presentation of June 8, 2022 states that no FDA-approved drugs contain enclomiphene as an active ingredient [1]. The sponsor, Repros Therapeutics, submitted a new drug application for enclomiphene (Androxal) for secondary hypogonadism in fertile men. In 2015 it announced a complete response letter from FDA, which, as summarized by FDA, said the design of the phase 3 studies was not adequate to demonstrate clinical benefit and raised concerns about study entry criteria, titration and bioanalytical method validation. No FDA approval has followed [1].

In Europe, EMA's committee adopted a negative opinion on 25 January 2018 recommending refusal of a marketing authorisation for EnCyzix (enclomifene) [3].

What FDA's compounding decisions say

Enclomiphene has no FDA-approved product or USP monograph and is not on FDA's final list of bulk substances that can be used in compounding. FDA currently lists enclomiphene citrate as under evaluation [4]. FDA says it does not intend to take action against a compounder using a Category 1 substance if the conditions in its guidance are met; that is an enforcement-discretion policy, not an approval [4].

At the June 8, 2022 meeting of FDA's Pharmacy Compounding Advisory Committee, FDA proposed that enclomiphene citrate not be added to the list of permitted bulk substances. The committee voted 4 yes, 8 no, and members who voted no cited a lack of clinical efficacy evidence [5].

Is clomiphene citrate a different case?

Clomiphene citrate (Clomid and generics, oral tablets) is FDA-approved, but only for ovulatory dysfunction in women desiring pregnancy. Its label has no male indication and states there are no adequate or well-controlled studies demonstrating effectiveness in male infertility; use in men with low testosterone is off-label [6].

Clomiphene is a mixture of two isomers, enclomiphene and zuclomiphene. Per FDA, the USP monograph gives enclomiphene content of clomiphene as 50 to 70 percent [1].