FDA Citizen Petition

To whom it may concern,

The undersigned submits this petition under the Federal Food, Drug and Cosmetic Act or the Public Health Service Act or any other statutory provision for which authority has been delegated to the Commissioner of Food and Drugs to request the Commissioner of Food and Drugs to take a form of administrative action.

Section A: Action Requested

I am requesting additional Pharmacokinetic Parameters for estradiol be added to Table 2 in Section 12.3, Pharmacokinetics, of the Full Prescribing Information insert for all doses of Premarin. I am requesting the following:

Mean± SD Pharmacokinetic Parameters following daily administration (7 Days) of PREMARIN Tablets 0.30 mg, 0.45 mg, 0.625 mg, 0.90 mg, 1.25 mg in Postmenopausal Women of unconjugated and conjugated estradiol be added to Table 2 in Section 12.3, Pharmacokinetics.

Currently there are no pharmacokinetic data for unconjugated estradiol and no pharmacokinetic data for conjugated estradiol in Table 2 of Section 12.3, Pharmacokinetics.

From:

Section 12.3, Pharmacokinetics

Table 2: Pharmacokinetic Parameters for PREMARIN

To:

Section 12.3, Pharmacokinetics

Table 2: Mean± SD Pharmacokinetic Parameters of Premarin following daily administration (7 Days) of PREMARIN Tablets 0.30 mg, 0.45 mg, 0.625 mg, 0.90 mg, 1.25 mg in Postmenopausal Women

PREMARIN Tablets 0.30 mg

Pharmacokinetic Parameters of Unconjugated or Free Estradiol, Free Estrone, Free Equilin following daily administration (7 Days) of PREMARIN Tablets 0.30 mg in Postmenopausal Women

Pharmacokinetic Parameters of Conjugated or Total Estradiol, Estrone, Equilin following daily administration (7 Days) of PREMARIN Tablets 0.30 mg in Postmenopausal Women

PREMARIN Tablets 0.45 mg

Pharmacokinetic Parameters of Unconjugated or Free Estradiol, Free Estrone, Free Equilin following daily administration (7 Days) of PREMARIN Tablets 0.45 mg in Postmenopausal Women

Pharmacokinetic Parameters of Conjugated or Total Estradiol, Estrone, Equilin following daily administration (7 Days) of PREMARIN Tablets 0.45 mg in Postmenopausal Women

PREMARIN Tablets 0.625 mg

Pharmacokinetic Parameters of Unconjugated or Free Estradiol, Free Estrone, Free Equilin following daily administration (7 Days) of PREMARIN Tablets 0.625 mg in Postmenopausal Women

Pharmacokinetic Parameters of Conjugated or Total Estradiol, Estrone, Equilin following daily administration (7 Days) of PREMARIN Tablets 0.625 mg in Postmenopausal Women

PREMARIN Tablets 0.90 mg

Pharmacokinetic Parameters of Unconjugated Free Estradiol, Free Estrone, Free Equilin following daily administration (7 Days) of PREMARIN Tablets 0.90 mg in Postmenopausal Women

Pharmacokinetic Parameters of Conjugated or Total Estradiol, Estrone, Equilin following daily administration (7 Days) of PREMARIN Tablets 0.90 mg in Postmenopausal Women

PREMARIN Tablets 1.25 mg

Pharmacokinetic Parameters of Unconjugated or Free Estradiol, Free Estrone, Free Equilin following daily administration (7 Days) of PREMARIN Tablets 1.25 mg in Postmenopausal Women

Pharmacokinetic Parameters of Conjugated or Total Estradiol, Estrone, Equilin following daily administration (7 Days) of PREMARIN Tablets 1.25 mg in Postmenopausal Women

Section B: Statement of Grounds

Premarin contains approximately 52.5 – 61.5% estrone sulfate which means it is a drug designed to produce estradiol.ⁱ Therefore, pharmacokinetic data about estradiol should be listed in the FDA approved Full Prescribing Information insert for all dosages, 0.30 mg, 0.45 mg, 0.625 mg, 0.90 mg and 1.25 mg.

Currently, in the Full Prescribing Information there is only pharmacokinetic data for estrone and equilin. Estradiol is a stronger estrogen hormone than both estrone and equilin, thereby making it important to list the pharmacokinetic data for estrone, equilin and estradiol.

The potency and importance of estradiol is acknowledged in the current Full Prescribing Information insert. In Section 12.1, Clinical Pharmacokinetics Mechanism of Action, the following is said:

Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.ⁱⁱ

Additionally, in the current Full Prescribing Information insert, in section 5.18, Laboratory Tests, laboratory testing is encouraged for the treatment of hypogonadism.

5.18 Laboratory Tests

Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy.

Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure.ⁱⁱⁱ

As stated in Medline Plus, National Library of Congress, every woman who is menopausal has, by definition, hypogonadism.^iv To be able to guide dosage, a doctor needs to know what the steady state level of estradiol is for all dosages of Premarin tablets (0.30 mg, 0.45 mg, 0.625 mg, 0.90 mg, 1.25 mg).

Currently, the FDA does not require pharmacokinetic data be available for drugs that produce estradiol. However, per the Nonbinding Recommendations Draft – Not for Implementation Draft Guidance on Estradiol October 2024

For the estradiol (unconjugated) and estrone (unconjugated), the following data should be submitted: individual and mean concentrations, individual and mean pharmacokinetic parameters, and geometric means and ratios of means for AUC and Cmax.

that data should be included.

Each dose of Premarin produces a specific amount of estradiol. The amount of estradiol produced determines its therapeutic effectiveness. As stated in the current Full Prescribing Information insert, a doctor would find the pharmacokinetic information useful when ordering lab tests to ensure estradiol levels aren’t too low or too high and are consistent with therapeutic goals.

Even though it isn’t mandatory, I am requesting the FDA request the manufacturer to list pharmacokinetic data for estradiol for all dosages of Premarin tablets (0.30 mg, 0.45 mg, 0.625 mg, 0.90 mg, 1.25 mg) to give women the information they need to meet their therapeutic goals.

Of note, per FDA guidance on the pharmacokinetics of estradiol from vaginal cream, and even though it isn’t mandatory, Pfizer has voluntarily provided steady state pharmacokinetic data in the Full Prescribing Information insert for Premarin vaginal cream.

Since Pfizer has voluntarily provided this information for Premarin vaginal cream, Pfizer can voluntarily provide steady state pharmacokinetic data for estradiol for each dosage of Premarin tablets.

Pfizer can give women who take Premarin tablets the same opportunity to know the steady state level of estradiol for the dosage of Premarin tablets prescribed to them. Therefore, this data should be available in the prescribing information for Premarin tablets.

Even though the FDA doesn’t mandate it, I am requesting the FDA request Pfizer to list steady state pharmacokinetic data on estradiol for Premarin tablets as Pfizer has done with Premarin vaginal cream. The FDA can facilitate updating the pharmacokinetic tables to include individual and mean concentrations, individual and mean pharmacokinetic parameters, and geometric means and ratios of means for AUC and Cmax.

Women have a right to know what their estradiol level is when taking different doses of Premarin tablets.

Section C: Environmental Impact

According to section § 25.30 General subsection (a) and § 25.31 Human drugs and biologics subsection (a) there is no requirement to provide an environmental impact.

Section D: Economic Impact

not applicable at this time

Section E: Certification

The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.

(Signature) Beth Rosenshein
(Name of petitioner) Beth Rosenshein
(Mailing address) Diamond Research Foundation, 300 Center Dr #248, Superior CO, 80027
(Telephone number) 425-417-9091

ⁱ MeSH Browser National Library of Medicine Estrogens, Conjugated (USP) MeSH Descriptor Data 2025

^iv Medline Plus Library of Congress definition of hypogonadism — Hypogonadism: MedlinePlus Medical Encyclopedia