Estradiol Vaginal Inserts

IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped, vaginal inserts for manual placement into the vagina. Inserts contain 4 mcg or 10 mcg of estradiol, an estrogen. Each insert is imprinted in white ink on one side with “04” or “10” corresponding to the insert’s dosage strength. IMVEXXY vaginal inserts are used intravaginally. When the insert comes in contact with the vaginal mucosa, estradiol is released into the vagina.

Estradiol is chemically described as estra-1,3,5 (10)-triene-3,17β-diol. The chemical formula is C18H24O2 with a molecular weight of 272.38.

The structural formula is:

IMVEXXY (estradiol vaginal inserts) contain the following inactive ingredients: Medium chain triglycerides, polyethylene glycol stearates, ethylene glycol palmitostearate, gelatin, hydrolyzed gelatin, sorbitol-sorbitan solution, purified water, glycerin, FD&C Red #40, ethanol, ethyl acetate, propylene glycol, titanium dioxide, polyvinyl acetate phthalate, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide, and lecithin. FDA approved acceptance criteria for assay, organic impurities, and dissolution tolerances differ from the USP test.

Mechanism Of Action

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. 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.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacodynamics

Currently there are no pharmacodynamics data known for IMVEXXY.

Pharmacokinetics

Estrogen drug products are well absorbed through the skin, mucous membranes, and the gastrointestinal tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

In a multicenter, double-blind placebo-controlled study of 574 postmenopausal women randomized to placebo, or 4 and 10 mcg of IMVEXXY, a subset of 54 women participated in a pharmacokinetics substudy. Women received 1 vaginal insert daily for the first 2 weeks, followed by 1 insert twice weekly for the following 10 weeks.

Mean (±SD) serum estradiol and estrone following 14 days of once daily administration of IMVEXXY are shown in Figure 1. Administration of the 4 mcg and 10 mcg IMVEXXY vaginal inserts and placebo once daily for 14 days resulted in a mean estradiol Cavg (0-24) of 3.6, 4.6, and 4.3 pg/mL, respectively, Table 2.

Figure 1: Mean (±SD) Serum Concentration of Estradiol and Estrone on Day 14 Following Daily Administration of IMVEXXY 4 mcg, IMVEXXY 10 mcg, and Placebo

Table 2: Arithmetic Mean (SD) of Estradiol and Estrone Pharmacokinetic Parameters Following 14 Daily Doses – Unadjusted for Baseline

At Day 84, estradiol concentrations compared to Baseline concentrations were: 4.3 vs 3.9 pg/mL for 4 mcg; 4.8 vs 5.0 pg/mL for 10 mcg; and 4.4 vs 4.5 pg/mL for placebo.

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to SHBG and albumin.

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Use In Specific Populations

No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

Clinical Studies

Effects On Moderate To Severe Dyspareunia

The effectiveness and safety of IMVEXXY on moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause were examined in one placebo-controlled clinical trial.

This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial enrolled 574 generally healthy postmenopausal women between 40 to 75 years of age (mean 59 years of age) who at baseline assessment had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and also identified, at baseline, moderate to severe dyspareunia as the most bothersome symptom to her. Greater than 90% of women also reported moderate to severe vaginal dryness at baseline. Treatment groups included 4 mcg IMVEXXY (n=191), 10 mcg IMVEXXY (n=191), and placebo (n=192). All women were assessed for improvement in the mean change from Baseline to Week 12 for the co-primary efficacy variables of: most bothersome moderate to severe symptom of dyspareunia, percentage of vaginal superficial and percentage of vaginal parabasal cells on a vaginal smear, and vaginal pH.

IMVEXXY 4 mcg and 10 mcg inserts were statistically superior to placebo in reducing the severity of moderate to severe dyspareunia at Week 12. See Table 3. A statistically significant increase in the percentage of superficial cells and a corresponding statistically significant decrease in the percentage of parabasal cells on a vaginal smear was also demonstrated for IMVEXXY 4 and 10 mcg inserts (p<0.0001). The mean reduction in vaginal pH between Baseline and Week 12 was also statistically significant for IMVEXXY 4 and 10 mcg inserts (p<0.0001).

Table 3: Efficacy of Dyspareunia Associated with Postmenopausal Vulvar and Vaginal Atrophy (Least Square Mean Change from Baseline to Week 12 in Severity of Woman’s Self-Identified Most Bothersome Moderate to Severe Symptom of Vulvar and Vaginal Atrophy)

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other causes. These substudies did not evaluate the effects of CE-alone or CE plus MPA on menopausal symptoms.

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 4.

Table 4: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHIa

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50-59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.461.11)].

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5.

These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 5: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Yearsa,b

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50-59 years of age, a non-significant trend toward reduced risk for overall mortality [HR 0.69 (95 percent CI, 0.44-1.07)].

Women’s Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominately healthy hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed types (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women [see WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

REFERENCES

9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006; 21:817-828.

10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006; 113:2425-2434.

IMVEXXY™
(im vex' ee)
(estradiol vaginal inserts)

Read this Patient Information before you start using IMVEXXY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is the most important information I should know about IMVEXXY (an estrogen hormone)?

• Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).
• Report any unusual vaginal bleeding right away while you are using IMVEXXY. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• Do not use estrogen-alone to prevent heart disease, heart attacks, strokes, or dementia (decline of brain function).
• Using estrogen-alone may increase your chances of getting strokes or blood clots.
• Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes or dementia.
• Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.
• Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older.
• You and your healthcare provider should talk regularly about whether you still need treatment with IMVEXXY.

What is IMVEXXY?

IMVEXXY is a prescription medicine that contains an estrogen hormone in a vaginal insert.

What is IMVEXXY used for?

IMVEXXY is used after menopause to treat moderate to severe painful intercourse, a symptom of changes in and around your vagina, due to menopause.

Who should not use IMVEXXY?

Do not start using IMVEXXY if you:

• have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb).
• currently have or have had certain cancers.
  Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus (womb). If you have or have had cancer, talk with your healthcare provider about whether you should use IMVEXXY.
• currently have or have had blood clots.
• had a stroke or heart attack.
• currently have or have had liver problems.
• have been diagnosed with a bleeding disorder.
• are allergic to IMVEXXY or any of its ingredients. See the list of ingredients in IMVEXXY at the end of this leaflet.
• think you may be pregnant. IMVEXXY is not for pregnant women.

Before you use IMVEXXY, tell your healthcare provider about all of your medical conditions, including if you:

• have any unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding or spotting to find out the cause.
• have certain medical conditions. Your healthcare provider may need to check you more carefully if you have certain medical conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• are going to have surgery or will be on bed rest. You may need to stop using IMVEXXY.
• are breast feeding. The hormone in IMVEXXY can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

IMVEXXY may affect the way other medicines work, and other medicines may affect how IMVEXXY works.

How should I use IMVEXXY?

For detailed instructions, see the step-by-step instructions for using IMVEXXY at the end of this Patient Information.

• Use IMVEXXY exactly as your healthcare provider tells you to use it.
• IMVEXXY is a vaginal insert that you place in your vagina.
• IMVEXXY is only for use in the vagina. Do not take IMVEXXY by mouth (orally).
• Estrogens should be used at the lowest dose possible for your treatment and for only as long as needed.
• Put 1 IMVEXXY insert inside your vagina, 1 time a day at about the same time for the first two weeks.
• Then put 1 IMVEXXY insert into your vagina two times a week, every three to four days (for example, Monday and Thursday), for as long as you use IMVEXXY.
• You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with IMVEXXY.

What are the possible side effects of IMVEXXY?

See, “What is the most important information I should know about IMVEXXY (an estrogen hormone)?”

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects could include:

• heart attack
• stroke
• blood clots
• cancer of the ovary
• breast cancer
• cancer of the lining of the uterus (womb)
• dementia
• gallbladder disease
• high blood calcium (hypercalcemia)
• changes in vision
• high blood pressure
• high triglyceride (fat) levels in your blood
• liver problems
• low blood calcium (hypocalcemia)
• worsening of angioedema (swelling of face and tongue)
• low thyroid levels in your blood
• changes in certain laboratory test results
• fluid retention
• enlargement of benign tumors of the uterus (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden, new, severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness, and fatigue

The most common side effects of IMVEXXY include:

• headache
• breast tenderness or pain
• nausea and vomiting

These are not all of the possible side effects of IMVEXXY. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to TherapeuticsMD® at 1-888-228-0150.

What can I do to lower my chances of a serious side effect with IMVEXXY?

• Talk with your healthcare provider regularly about whether you should continue using IMVEXXY.
• If you have a uterus (womb), talk with your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for women with a uterus to reduce the chance of getting cancer of the uterus.
• See your healthcare provider right away if you get vaginal bleeding while using IMVEXXY.
• Have a pelvic exam, breast exam, and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have a higher chance of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.

General information about the safe and effective use of IMVEXXY.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMVEXXY for a condition for which it was not prescribed. Do not give IMVEXXY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMVEXXY that is written for health professionals.

What are the ingredients in IMVEXXY?

Active ingredient: IMVEXXY (estradiol vaginal inserts) are small, light pink, tear-shaped inserts that contain estradiol.

Inactive ingredients: Each insert also contains medium chain triglycerides, polyethylene glycol stearates, ethylene glycol palmitostearate, gelatin, hydrolyzed gelatin, sorbitol-sorbitan solution, water, glycerin, FD&C Red #40, ethanol, ethyl acetate, propylene glycol, titanium dioxide, polyvinyl acetate phthalate, isopropyl alcohol, polyethylene glycol, ammonium hydroxide, and lecithin. IMVEXXY is supplied in blister cartons of 18 or 8 vaginal inserts.?

Instructions For Use

IMVEXXY™
(im vex' ee)
(estradiol vaginal inserts)

Read this Instructions for Use before you start using IMVEXXY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

How should I use IMVEXXY?

• IMVEXXY is an insert only for use in the vagina. Do not take by mouth.
• Put 1 IMVEXXY insert inside your vagina, 1 time a day at about the same time for the first two weeks, then put 1 IMVEXXY insert into your vagina two times a week, every three to four days (for example, Monday and Thursday), for as long as you use IMVEXXY.
• Write down the days you will put in your IMVEXXY insert.
• Wash and dry your hands before handling the IMVEXXY insert.

Step 1: Push 1 IMVEXXY insert through the foil of the blister package.

Figure A

Step 2: Hold the IMVEXXY insert with the larger end between your fingers.

Figure B

Step 3: Select the best position for vaginal insertion that is most comfortable for you to put in the IMVEXXY insert. See Figure C for suggested insertion in the lying down position or Figure D for suggested insertion in the standing position. With the smaller end up, put the insert about two inches into your vagina using your finger.

Figure C

Figure D

If you have any questions, please ask your healthcare provider or pharmacist.

How should I store IMVEXXY?

• Store IMVEXXY at room temperature between 68°F to 77°F (20°C to 25°C).
• IMVEXXY packaging is not child-resistant.

Keep IMVEXXY and all medicines out of the reach of children.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular Disorders [see WARNINGS AND PRECAUTIONS].
• Malignant Neoplasms [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of IMVEXXY 4 mcg and 10 mcg was assessed in a single, double-blind, parallel-group, placebo-controlled trial (N=382). The duration of treatment in this trial was 12 weeks (dosing occurred every day for 14 days and then twice weekly thereafter for maintenance).

Adverse reactions with an incidence of ≥3 percent in any IMVEXXY group and numerically greater than those reported in the placebo group are listed in Table 1.

Table 1: Treatment-Emergent Adverse Reactions Reported at a Frequency of ≥3% and Numerically More Common in Women Receiving IMVEXXY

Read the entire FDA prescribing information for Imvexxy (Estradiol Vaginal Inserts)

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