Innofem (Estradiol) - Summary

INNOFEM SUMMARY

WARNINGS

Innofem™ (Estradiol Tablets, USP) for oral administration contains 0.5, 1 or 2 mg of micronized estradiol per tablet.

Innofem™ (Estradiol Tablets, USP) is indicated in the:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause. There is no adequate evidence that estrogens are effective for nervous symptoms or depression which might occur during menopause and they should not be used to treat these conditions.
2. Treatment of vulval and vaginal atrophy.
3. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure.
4. Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease.
5. Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).
6. Prevention of osteoporosis.

Since estrogen administration is associated with risk, selection of patients should ideally be based on prospective identification of risk factors for developing osteoporosis. Unfortunately, there is no certain way to identify those women who will develop osteoporotic fractures. Most prospective studies of efficacy for this indication have been carried out in white menopausal women, without stratification by other risk factors, and tend to show a universally salutary effect on bone. Thus, patient selection must be individualized based on the balance of risks and benefits. A more favorable risk/benefit ratio exists in a hysterectomized woman because she has no risk of endometrial cancer (see BOXED WARNINGS).

Estrogen replacement therapy reduces bone resorption and retards or halts post menopausal bone loss. Case-control studies have shown an approximately 60 percent reduction in hip and wrist fractures in women whose estrogen replacement was begun within a few years of menopause. Studies also suggest that estrogen reduces the rate of vertebral fractures. Even when started as late as 6 years after menopause, estrogen prevents further loss of bone mass for as long as the treatment is continued. The results of a two-year, randomized, placebo-controlled, double-blind, dose-ranging study have shown that treatment with 0.5 mg estradiol daily for 23 days (of a 28 day cycle) prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.

At skeletal maturity there are sex and race differences in both the total amount of bone present and its density, in favor of men and blacks. Thus, women are at higher risk than men because they start with less bone mass and, for several years following natural or induced menopause, the rate of bone mass decline is accelerated. White and Asian women are at higher risk than black women.

Early menopause is one of the strongest predictors for the development of osteoporosis. In addition, other factors affecting the skeleton which are associated with osteoporosis include genetic factors (small build, family history), and endocrine factors (nulliparity, thyrotoxicosis, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia, Type 1 diabetes), lifestyle (cigarette smoking, alcohol abuse, sedentary exercise habits) and nutrition (below average body weight, dietary calcium intake).

The mainstays of prevention and management of osteoporosis are estrogen, an adequate lifetime calcium intake, and exercise. Postmenopausal women absorb dietary calcium less efficiently than premenopausal women and require an average of 1500 mg/day of elemental calcium to remain in neutral calcium balance. By comparison, premenopausal women require about 1000 mg/day and the average of calcium intake in the USA is 400-600 mg/day, therefore, when not contraindicated, calcium supplementation may be helpful.

Weight-bearing exercise and nutrition may be important adjuncts to the prevention and management of osteoporosis. Immobilization and prolonged bed rest produce rapid bone loss, while weight-bearing exercise has been shown both to reduce bone loss and to increase bone mass. The optimal type and amount of physical activity that would prevent osteoporosis have not been established, however in two studies an hour of walking and running exercise twice or three times weekly significantly increased lumbar spine bone mass.

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NEWS HIGHLIGHTS

Published Studies Related to Innofem (Estradiol)

The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. [2009.11.15]
Multiple sclerosis (MS) affects 1 in 1000 people in western countries, mainly women in their childbearing years. It is an autoimmune disease of the central nervous system, which results in a chronic focal inflammatory response with subsequent demyelination and axonal loss... Assuming the results of the trial to be positive, this new treatment could be considered in the relapsing-remitting phase of the disease in women afar from pregnancy and post-partum.

A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. [2009.09]
OBJECTIVE: To assess the efficacy of a combined oral contraceptive (COC) containing 3 mg drospirenone (drsp) plus 20 microg ethinylestradiol (EE) administered in 24 days of active treatment followed by a four-day hormone-free interval (24/4 regimen) compared with placebo for the treatment of moderate acne vulgaris... CONCLUSION: The 3 mg drsp/20 microg EE COC administered in a 24/4 regimen significantly reduced acne lesions.

Steady-state pharmacokinetics following application of a novel transdermal estradiol spray in healthy postmenopausal women. [2009.09]
This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24 participants/dose level) of a 1.7% estradiol metered-dose transdermal spray (1.53 mg/spray) once daily for 14 days...

Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. [2009.08.19]
CONTEXT: Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy. OBJECTIVE: To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer... CONCLUSIONS: In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00324259.

Evaluation of different add-back estradiol and progesterone treatments to gonadotropin-releasing hormone agonist treatment in patients with premenstrual dysphoric disorder. [2009.08]
OBJECTIVE: The aim of this study was to investigate which add-back hormone replacement therapy would be most beneficial in terms of mood effects for patients with premenstrual dysphoric disorder who are receiving gonadotropin-releasing hormone agonist therapy... CONCLUSION: Based on the findings of the present study, long-cycle add-back treatment to avoid frequent progestagen use appears to be most beneficial for patients with premenstrual dysphoric disorder.

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Clinical Trials Related to Innofem (Estradiol)

Effect of Angeliq on Blood Pressure (BP) in Postmenopausal Hypertensive Women [Completed]
The objective of the study is to evaluate the effects of Angeliq on BP over a period of 8 weeks in postmenopausal women who may benefit from hormone replacement therapy (HRT) for the relief of vasomotor symptoms and who have hypertension.

Evaluation of Adhesion Quality of a New Formulation of the Mylan Estradiol Transdermal System 0.025 mg/Day and Climara® Transdermal System 0.025 mg/Day [Completed]
The primary objective of this study was to compare the adhesive quality of a new formulation of the Mylan Estradiol Transdermal System with that of Climara® Transdermal System following a single system application in 80 healthy postmenopausal female volunteers. As a secondary objective, primary dermal irritation was assessed after removal of each transdermal system.

Treatment of Hot Flushes in Asian Women With Ultra-Low Dose Estradiol Patch [Completed]
150 postmenopausal Asian women with vasomotor symptoms, after fulfilling the inclusion and exclusion criteria will be enrolled in the study. The women will be randomly assigned to one of two treatment groups (Menostar® or placebo), after which they will be asked to use a patch once a week for 12 weeks.

Vasomotoric Symptoms Study of a 0.5 mg Estradiol and 2.5 mg Dydrogesterone Combination [Completed]

Neoadjuvant Estradiol or Androgen Deprivation in Clinically Localized Prostate Cancer [Completed]
Prostate cancer is the most commonly diagnosed cancer among males in the U. S. More than 220,000 men will be diagnosed with prostate cancer in the USA this year and more that 31,000 will die of this disease.

Androgen deprivation, the elimination of testosterone and its active metabolites, remains the single most effective intervention available for the treatment of advanced prostate carcinoma. Androgen deprivation induces an immune response to normal prostate and prostate cancer, which is usually short-lived. Estradiol induces activation of many arms of the immune system and may be a more effective and long lasting means of inducing immunity to prostate tissue.

This study will treat clinically localized prostate cancer patients with either estrogens, or standard androgen deprivation without estrogens, prior to prostatectomy in order more completely to describe immune regulation by estradiol in men. Control tissue from patients who have not been treated with androgen deprivation will be procured from the Northwest Special Projects in Oncology Research Excellence (SPORE) tissue core and used as comparisons against the cancers treated before prostatectomy. Tumors removed at prostatectomy, tissue samples and blood samples will be assessed for immune system changes.

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PATIENT REVIEWS / RATINGS / COMMENTS

Innofem review by 50 year old female patient
		Rating
Overall rating:
Effectiveness:		Considerably Effective
Side effects:		No Side Effects
		Treatment Info
Condition / reason:		Hormone replacement
Dosage & duration:		1 mg taken twice a day for the period of 1 year
Other conditions:		none
Other drugs taken:		vitamins
		Reported Results
Benefits:		continuation of hormone replacement after stopping birth control pills No hot flashes or night sweats.
Side effects:		Break-through bleeding or spotting, breast pain and changes in sexuality(decrease in libido). Fluid retention. Brown patcheson the forehead,temples.
Comments:		Oral dose taken in the morning and evening. Tried the estrogen patch, but did not like the sticky 'bandaid' on my skin.It would get sticky on the edges and be a magnet for clothes fibers.

Innofem review by 50 year old female patient
		Rating
Overall rating:
Effectiveness:		Highly Effective
Side effects:		No Side Effects
		Treatment Info
Condition / reason:		Menopause symptoms
Dosage & duration:		.025 (dosage frequency: daily (patch applied 1x week)) for the period of ongoing
Other conditions:		acid reflux
Other drugs taken:		Nexium
		Reported Results
Benefits:		Benefits: Patch applied 1x weekly assured consistent delivery of dosage. No skin irritation reported by patient but recommended that site used be rotated weekly. Patch can come off if not applied correctly to clean dry skin - no lotions or creams s/b present. May not be metabolized through liver as much as oral estrogen - advantage.
Side effects:		Slight irritation at application site of patch. If mfrs. directions followed and site rotated, this can be reduced or eliminated. No other notable side effects.
Comments:		Patch is applied 1x weekly. Treatment continued to alleviate hot flashes. Original dosage was higher and company has come out with smaller dosages. Patient can be slowly "weaned" to smaller dosages until no longer needed.

Innofem review by 54 year old female patient
		Rating
Overall rating:
Effectiveness:		Moderately Effective
Side effects:		No Side Effects
		Treatment Info
Condition / reason:		hot flashes, unable to sleep
Dosage & duration:		1 mg taken daily for the period of 1 year
Other conditions:		high blood pressure
Other drugs taken:		dyazide
		Reported Results
Benefits:		I did get relief from the hot flashes and this did contribute to a good nights sleep. I had a hystirectomy a year before I was put on the hormones. I say an increase in wrinkles in that first year. I can not say that I have seen a slowing in the aging process but I am sleeping better and that of course will bennefit the skin.
Side effects:		I have not experienced any side effects to my knowledge. I feel as if an increase in the dose would maybe last longer as I seem to be waking at least once a night with a hot flash. I take it in the morning so maybe by the time I hit the sheets it is out of my system. I do not miss a day and always take it at the same time each morning.
Comments:		As I stated I had a hystirectomy at 50 years old. I went over a year w/out any homone treatment and the hot flashes got so severe I was waking about 5 to 6 times a night. I was using over the counter sleep aids and did not like them. I got the doctor to prescribe the hormones and the benefits were almost immediate. I have been on the same dose for over a year now and feel I might benefit from an increased dose. I am 54 now and am looking not quite my age but the aging process is speeding up I feel.