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 section 5.2, Venous Thromboembolism (VTE), of the Full Prescribing Information for Duavee tablets be updated to include pertinent and vital information about the risk of blood clots when taking SERM Bazedoxifene and Premarin together.

From:

Section 5.2

Venous Thromboembolism (VTE)

In the WHI estrogen-alone substudy, the risk of VTE [DVT and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years.

If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.

To:

Section 5.2

Venous thromboembolism (VTE)

In clinical trials of up to 2 years duration in postmenopausal women with CE/BZA, cases of VTE have been reported. Should a VTE event occur or be suspected, CE/BZA should be discontinued immediately.

SERMs (including bazedoxifene) and oestrogens individually increase the risk of VTE (see section 4.8). Hormone therapy is associated with a 1.3-3 fold risk of developing VTE. The occurrence of such an event is more likely in the first year of HRT than later.

Patients with known thrombophilic states have an increased risk of VTE and hormone therapy may add to this risk. CE/BZA is contraindicated in these patients.

Generally recognized risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilization, obesity (BMI > 30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need be considered to prevent VTE following surgery. If prolonged immobilization is to follow elective surgery temporarily stopping CE/BZA 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilized. In addition, women taking CE/BZA should be advised to move about periodically during travel involving prolonged immobilization.

In women with no personal history of VTE but with a first-degree relative with a history of thrombosis at young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening). If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g., antithrombin, protein S, or protein C deficiencies or a combination of defects) hormone therapy is contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit risk of use of hormone therapy.

If VTE develops after initiating therapy, or is suspected, CE/BZA should be discontinued immediately. Women should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).

Section B: Statement of Grounds

The European Medicine Agency or EMA recognizes the increased risk of venous thrombosis when using a combination of SERM Bazedoxifene with Premarin. The EMA includes information about this risk in the Venous thromboembolism (VTE) section of its Full Prescribing Information for European distribution of Duavive (Duavee is called Duavive in Europe).ⁱⁱ

In the Venous thromboembolism (VTE) section of the Full Prescribing Information for Duavee in the United States, the FDA omits disclosing the risk of venous thrombosis when using a combination of SERM Bazedoxifene with Premarin.

Duavee and Duavive are the exact same drug with the exact same ingredients.

Duavive and Duavee both contain Premarin, which carries a risk of venous thrombosis on its own.

Duavive and Duavee both contain SERM Bazedoxifene, which carries a risk of venous thrombosis on its own.

Pfizer explained to the FDA that Duavee’s ingredients, Premarin and SERM Bazedoxifene, when used together have been observed to reduce the risk of venous thrombosis. Pfizer cited the 5 SMART clinical trials as proof.

In the 5th SMART trial, Effects of conjugated estrogens/bazedoxifene on lipid and coagulation, page 647, Pfizer postulated reasons for the low rate of VTE. Pfizer stated that Bazedoxifene could be a Selective Estrogen Receptor Degrader or SERD with no proof. Pfizer also said that the short length of each of the 5 SMART trials, ranging from 3 to 24 months, might be too short to see VTE. Pfizer said the younger age of the participants, mean age 54, might be why there was a lower incidence of VTE. Pfizer also said that the 5 SMART trials were observational studies that were not designed with the statistical power to detect differences in VTE parameters.

All of these reasons are theories why the 5 SMART trials observed a reduced, rather than an increased rate, of VTE when using two pro-coagulant drugs together.

The FDA approved Duavee as a combination of a SERM and Premarin and not a SERD and Premarin. If the FDA believes the observations made in the 5 SMART trials support evidence that Bazedoxifene is a SERD and not a SERM, then the FDA is required to remove the FDA approval of Duavee.

Without proof, Pfizer convinced the FDA that the combination of two pro-coagulant drugs reduced the risk of thrombosis and this reduced risk was published in the Full Prescribing Information. Notably, Pfizer chose a less rigorous modified intention to treat protocol (mITT), in each of the 5 SMART clinical trials, which can dilute the harm of Duavee.

The EMA rejected Pfizer’s reasoning that SERM Bazedoxifene is actually a SERD and would reduce the risk of blood clots based only on observational data which used a mITT protocol and not the more rigorous Intention to Treat protocol (ITT). The EMA rejected Pfizer’s conclusion that the use of two pro-coagulants together, SERM Bazedoxifene and Premarin, could actually reduce the risk of blood clots without rigorous proof.

Women in Europe have access to the information of the increased risk of venous thrombosis when using Duavive. Women in the United States deserve the same access to the information of the increased risk of venous thrombosis when using Duavee.

I am requesting the FDA give women in the United States who take Duavee access to the same pertinent and vital information about the risk of VTE that women in Europe who take Duavive have access to because Duavee and Duavive are the same drug.

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 Duavee Full Prescribing Information
ⁱⁱ ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS Duavive

FDA Response

FDA response to Citizen Petition

Demand NIH stop unethical research with Premarin – a menopause drug