ABOUT FEMARELLE® (DT56a)
MENOPAUSE SYMPTOMS & FEMARELLE®
BONE HEALTH SUPPORT:
*Health Canada has not approved Femarelle for vaginal atrophy. Using Femarelle for vaginal atrophy would be considered off-label use.
*Femarelle is not recommended for use in breast cancer patients.
Clinical Study: Menopausal Symptoms
Efficacy and safety of Standard versus Low Dose of Femarelle for the Treatment of Menopausal Symptoms. Yoles I et al. J. of Clin Exper Obstet Gynecol 2004
The effects of Femarelle® were assessed on a wide variety of menopause-related symptoms. In a clinical trial, healthy post-menopausal women (n=80) were randomly allocated to receive either the standard dose (SD, 644 mg/day) of Femarelle® or a low dose (LD, 344 mg/day) of DT56a.
A detailed medical history was taken from each participant upon enrollment, and this was followed by a physical examination, pelvic ultrasound, and recording of sex hormone and lipid profiles. Each patient completed a detailed questionnaire comprising a Kupperman index plus six additional parameters. The hormonal blood profile, endometrial thickness, and breast tissue in all patients were monitored. These procedures were repeated every 3 months during the 12 months of the study.
Results: Both groups achieved a significant reduction in menopausal symptoms (Figure 3), which was sustained throughout the 12 months of treatment. There were no changes in mean levels of thyroid-stimulating hormone or in the sex hormones estradiol (E2) or follicle-stimulating hormone, nor were any changes perceived in mean endometrial thickness (Figure 4).
Conclusion: Femarelle® significantly alleviated menopausal symptoms in about 75% of the patients without affecting endometrial thickness or hormonal blood profiles. The lack of change in hormonal levels showed that the body does not recognize Femarelle® as estrogen, despite the fact that it affects estrogen receptors in designated sites. 4
Clinical Study: Femarelle vs. HT & Control
Efficacy and safety of DT56a (Femarelle) compared to hormone therapy in Greek postmenopausal women. Labos G., Trakakis E. et al. J. Endocrinol. Invest. 2013
Hormone therapy has been the treatment of choice for the alleviation of menopausal symptoms for many years; concerns, however, about its concomitant long term health risks have limited its use. The purpose of this study was to evaluate the efficacy and safety of Femarelle®, compared to hormone therapy (Activelle®, Novo-Nordisk- 17ß-estradiol 1mg plus norethisterone acetate 0.5mg), in symptomatic postmenopausal women.
89 postmenopausal women were studied prospectively. Women with climacteric symptoms were randomly assigned to receive either Femarelle® (n=27) or Activelle® (n=26). Symptomatic women not wishing to receive any treatment served as controls (n=36). Menopausal symptoms as assessed through the Kupperman index, serum lipids and lipoproteins, calcium, as well as bone mineral density, endometrial thickness, and mammography were assessed at baseline and at 12 months.
Results: Women receiving Femarelle® exhibited a significant decrease in the mean Kupperman score (paired t-test p-value 0.001). As far as Kupperman subscale scores are concerned, women in both treatment arms showed a significant reduction in hot flushes / night sweats. Lumbar spine bone mineral density T- score was significantly lower in women receiving no treatment, as opposed to the two treatment arms which showed no significant change. No differences in femoral bone density, endometrial thickness or mammography classification were detected in any of the treatment arms. Likewise, serum lipids or lipoproteins did not differ between the three groups.
Conclusion: This study demonstrates an efficacy of Femarelle® in relieving menopausal symptoms in direct comparison to HT (Activelle®). Femarelle® decreased menopausal symptoms significantly and in the same degree as HT. Women receiving Femarelle® or HT did not exhibit any change in bone mineral density, as compared to women not receiving treatment who exhibited a decrease in lumbar spine BMD. No change either in endometrial thickness or mammography classification was recorded after 12 months of treatment. Femarelle® may serve as an alternative to hormone replacement therapy for the relief of climacteric symptoms in postmenopausal women.19
Pre-Clinical Mechanism of Action: Brain Region Responsiveness to Femarelle®
Brain region responsiveness to DT56a (Femarelle) administration on allopregnanolone and opiod content in ovariectomized rats. Genazzani A.R. et al. Menopause 2009
It has been well established that certain neurotransmitters have a positive effect on various vasomotor symptoms. Allopregnanolone reduces anxiety and has the ability to create calm and beta-Endorphins act as an analgesic in the body, numbing or dulling pain. Beta-Endorphins also increase relaxation and promote overall well-being. Levels of Allopregnanolone and beta-Endorphins decrease in ovariectomized (OVX) rats, and in postmenopausal women. Estrogen therapy is well known for its beneficial effect on brain related vasomotor symptoms, such as hot flushes, sleep disturbances and mood changes. Estrogen has also been found to enhance allopregnanolone and improves beta-Endorphin activity in the brain. Based on this previous research, Femarelle® was examined to determine if it would have similar effects on these neurotransmitters as did estrogen.
Five groups of ovariectomized (OVX) rats received one of the following treatments for 14 days: DT56a (Femarelle®) at a dose of 6 mg/kg/day, 12 mg/kg/day, 60 mg/kg/day, 120 mg/kg/day (the equivalent to the recommended human dosage); E2 at a dose of 0.05 mg/kg/day; 2 control groups, one consisting of young rats, and the second one, OVX rats. Allopregnanolone concentration was assessed in the frontal and parietal lobes, hippocampus, hypothalamus, anterior pituitary and serum. The beta-endorphin content was evaluated in the frontal and parietal lobes, hippocampus, hypothalamus, neurointermediate lobe, anterior pituitary and plasma.
Results: Femarelle® increased Allopregnanolone levels (compared to placebo) in all tested areas of the brain of OVX rats showing a classical dose-range curve, with the optimal effect at the dose of 120mg/kg/day. (Figure 5- Anterior Pituitary) In some brain areas, levels of Allopregnanolone attained were comparable to those of ovariectomized rats treated with E2. Femarelle® was also found to increase beta-Endorphin levels in selected areas of the brains of OVX rats. (Figure 6- Hippocampus) These areas included the hypothalamus, hippocampus, anterior pituitary and the neurointermediate lobe. Treatment with Femarelle® raised beta-Endorphin levels in these areas within the range of those rats treated with E2.
Conclusion: This study demonstrated that Femarelle® positively affects brain neurosteroidogenesis and the opiatergic system: Femarelle® exerts an estrogen-like effect on selective areas related to mood, cognition and homeostasis control, presenting a specific pattern of interaction with the brain function. These findings may, in part, explain the clinical effect of Femarelle® on menopausal symptoms.5
Post-Marketing Study: Menopausal Symptoms
A POst Marketing Menopausal Symptoms International Survey (POMMSIS) was launched in 5 countries: India, Norway, Lithuania, Spain and Sweden. These countries represent 3 races: Indian, North-European and Mediterranean-European.
2,022 women participated in this survey, the mean age of menopause was 51 (SD=4.97). The survey monitored selected menopausal symptoms—hot flushes, quality of sleep, quality of life, night sweats, headaches and joint and muscle pains before and following 4 weeks of treatment with Femarelle®. A detailed questionnaire regarding the main menopausal symptoms was filled at entry of the study and following 4 weeks of treatment. A daily hot flushes diary looking at the number and intensity of hot flushes was filled for 5 weeks, one week without treatment as baseline followed by 4 weeks of treatment.
Results: In this survey hot flushes and night sweats were the prominent symptoms in all 5 countries. Cultural differences could be seen when looking at smoking habits, weight and even how hot flushes were perceived in different countries. European women were significantly heavier than Indian women and smoking was in higher prevalence in Europe. The perception of hot flushes was different in warmer climates, such as Spain and India than in colder climates, such as Lithuania and Norway. And the percentage of natural vs. surgical induced menopause was also seen to differ between India and Europe.
Femarelle® was found to significantly relieve menopausal symptoms within the first two weeks of treatment and this trend continued following 4 weeks of treatment in all countries surveyed. (Figure 7- hot flushes before and after 4 weeks of treatment) A statistically significant reduction was found at each week of treatment.
Conclusion: Menopausal bothersome symptoms were found to be a cross cultural phenomenon although symptoms may vary in different countries. Treatment with Femarelle® resulted in a significant improvement in all symptoms within the month of treatment. Interestingly, the beneficial effect of Femarelle® was perceived as beneficial even beyond the improvement of the specific symptoms.20