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B: 0.625/25 O E: G: H: 8 US 20090005351A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0005351A1 Pickar et al. (43) Pub. Date: Jan. 1, 2009 (54) HORMONE REPLACEMENT THERAPY (60) Provisional application No. 60/268,607, filed on Feb. 14, 2001, provisional application No. 60/190,630, (75) Inventors: James H. Pickar, Springfield, PA filed on Mar. 20, 2000. (US); Michael S. Dey, Narberth, PA (US) Publication Classification Correspondence Address: (51) Int. Cl WYETH/FINNEGAN HENDERSON, LLP A 6LXwe 3/57 (2006.01) 901 NEW YORKAVENUE, NW A6IP3/00 (2006.01) WASHINGTON, DC 20001-4413 (US) (73) Assignee: Wyeth (52) U.S. Cl. ........................................................ S14/17O (21) Appl. No.: 11/979,633 (57) ABSTRACT (22) Filed: Nov. 6, 2007 This invention relates to methods and pharmaceutical com Related U.S. Application Data positions for providing hormone replacement therapy in peri .S. App menopausal, menopausal, and postmenopausal women (63) Continuation of application No. 09/808,878, filed on through the continuous administration of combinations of Mar. 15, 2001, now abandoned. conjugated estrogens and medroxyprogesterone acetate. MEAN NUMBER OF HOT FUSHES PER DAY 12 Group B: 0.625/25 O E: G: H: 8 6 4. 2 Patent Application Publication Jan. 1, 2009 Sheet 1 of 3 US 2009/0005351A1 MEAN NUMBER OF HOT FUSHES PER DAY 12 Group B: 0.625/25 10 E: 0.45/15 e 8 2 5 6 3. is 4 2 O 1 2 3 4 5 6 7 8 9 10 11 12 Week FIG.1 Patent Application Publication Jan. 1, 2009 Sheet 2 of 3 US 2009/0005351A1 MEAN SEVERTY OF HOT FLASHES Group A-A-Ao-O-O B:E: 0.45/1.5E. H. G: 0.5/15 4--- H: Plocebo Patent Application Publication Jan. 1, 2009 Sheet 3 of 3 US 2009/0005351A1 PERCENTAGE OF PATENIS WITH AMENORRHEA 25/2.5 5/15 Hu G: 0.3/1.5 ---- H: Plocebo 1 2 3 4 5 6 7 8 9 10 11 12 13 Cycle FIG.3 US 2009/0005351 A1 Jan. 1, 2009 HORMONE REPLACEMENT THERAPY manifested as hot flushes. Other menopausal disturbances may include depression, insomnia, and nervousness. The long-term physiologic effects of postmenopausal estrogen 0001. This application claims the benefit of U.S. Provi deprivation may result in significant morbidity and mortality sional Application No. 60/268,607, filed Feb. 14, 2001, and due to increase in the risk factors for cardiovascular disease U.S. Provisional Application No. 60/190,630, filed Mar. 20, and osteoporosis. Menopausal changes in blood lipid levels, a 2OOO. major component of the pathogenesis of coronary heart dis ease (CHD), may be precursors to increased incidence of BACKGROUND ischemic heart disease, atherosclerosis, and other cardiovas cular disease. A rapid decrease in bone mass of both cortical 0002 This invention relates to methods and pharmaceuti (spine) and trabecular (hip) bone can be seen immediately cal compositions for providing hormone replacement therapy after the menopause, with a total bone mass loss of 1% to 5% in perimenopausal, menopausal, and postmenopausal women per year, continuing for 10 to 15 years. through the continuous administration of combinations of 0005 Estrogen replacement therapy (ERT) is beneficial conjugated estrogens and medroxyprogesterone acetate. for symptomatic relief of hot flushes and genital atrophy and 0003 Menopause is generally defined as the last natural for prevention of postmenopausal osteoporosis. ERT has menstrual period and is characterized by the cessation of been recognized as an advantageous treatment for relief of ovarian function, leading to the Substantial diminution of vasomotor symptoms. There is no acceptable alternative to circulating estrogen in the bloodstream. Menopause is usu estrogen treatment for the atrophic changes in the vagina; ally identified, in retrospect, after 12 months of amenorrhea. estrogen therapy increases the vaginal mucosa and decreases It is not a sudden event, but is often preceded by a time of vaginal dryness. Long term ERT is the key to preventing irregular menstrual cycles prior to eventual cessation of osteoporosis because it decreases bone loss, reduces spine menses. Following the cessation of menstruation, the decline and hip fracture, and prevents loss of height. In addition, ERT in endogenous estrogen concentrations is typically rapid. has been shown to be effective in increasing high density There is a decrease in serum estrogens from circulating levels lipoprotein-cholesterol (HDL-C) and in reducing low density ranging from 40-250 pg/mL of estradiol and 40-170 pg/mL of lipoprotein cholesterol (LDL-C), affording possible protec estrone during ovulatory cycles to less than 15 pg/mL of tion against CHD. ERT also can provide antioxidant protec estradiol and 30 pg/mL of estrone in postmenopausal women. tion against free radical mediated disorders or disease states. 0004 As these estrogens decline during the time preced Estrogens have also been reported to confer neuroprotection, ing (perimenopause) and following the menopause (post and inhibit neurodegenerative disorders, such as Alzheimer's menopause), various physiological changes may result, disease (see U.S. Pat. No. 5,554,601, which is hereby incor including Vulvar and vaginal atrophy causing vaginal dry porated by reference). The following table contains a list of ness, pruritus and dyspareunia, and vasomotor instability estrogen preparations currently available. Estrogen replacement therapies available in the United States and/or Europe Generic Name Brand Name Strength Oral estrogens Conjugated equine estrogens (natural) Premarin 0.3, 0.625, 0.9, 1.25, 2.5 mg Conjugated estrogens (synthetic) Cenestin 0.625, 0.9 mg Esterified estrogens (75-80% estrone sulfate Estratab 0.3, 0.625, 1.25. 2.5 mg 6-15% equilin sulfate derived from plant sterols) Estropipate (Piperazine estrone sulfate) Ogen Ortho-Est 0.625, 1.25, 2.5 mg Micronized estradiol Estrace 0.5, 1.0.2.0 mg Raloxifene (selective estrogen receptor modulator) Evista 60 mg Esterified estrogens and methylestosterone Estratest 1.25 mg esterified estrogen and 2.5 mg methylestosterone Estratest HS 0.625 mg esterified estrogen and 1.25 mg methylestosterone Estradiol valerate Climaval 1 mg, 2 mg Estradiol Elleste Solo 1 mg, 2 mg Estradiol Estrofem 2ng Estradiol Estrofem Forte 4 mg Piperazine esterone sulfate Harmogen 1.5 mg Combination; Estrone Hormonin 1.4 mg Estradiol 0.6 mg Estriol 0.27 mg Estradiol valerate Progynova 1 mg, 2 mg Estradiol Zumenon 1 mg, 2 mg Transdermal estrogens Estradiol Alora (twice weekly) 0.025, 0.0375. 0.05, 0.075, Climara (weekly) 0.1 mg of estradiol released Estraderm (2x weekly) daily (dose options for various Fem. Patch (weekly) products) Vivelle (twice weekly) US 2009/0005351 A1 Jan. 1, 2009 -continued Estrogen replacement therapies available in the United States and/or Europe Generic Name Brand Name Strength Estradiol Dermestril 25, 50, 100 g Estradiol Estraderm 25, 50, 100 g Estradiol Evorel (Systen) 25, 50, 75, 100 g Estradiol Fematrix 40, 80 g Estradiol Menorest 25, 37.5, 50, 75 pig Estradiol Progynova TS 50, 100 g And TS Forte (Climara) Vaginal estrogens Conjugated equine estrogens Premarin vaginal 0.625 mgg Ce3 Dienestrol Ortho dienestrol cream 0.1 mg/g Estradiol Estring 7.5 Ig Estropipate Ogen vaginal cream 1.5 mg/g Micronized estradiol Estrace vaginal cream 1.0 mg/g 0006 To minimize the occurrence of estrogen-related side effects and to maximize the benefit-risk ratio, the lowest dose -continued effective in relief of symptoms and prevention of osteoporosis should be used. Although ERT reduces the relative risk (RR) Oral Combination HRT Products for ischemic heart disease (RR, 0.50) and osteoporosis (RR, Brand Name Estrogen Progestin Strengths 0.40), the relative risk of endometrial cancer for postmeno Trisequens Estradiol 2 or 4 mg. days 1-22 pausal women with a uterus may be increased. There are And Norethisterone 1 mg, days 23-28 extensive clinical data showing that the relative risk of Trisequens 1 mg, days 13-22 Forte endometrial cancer can be reduced by the addition of a Ortho-Prefest Estradiol 1.0 mg. days 1-6 progestin, either sequentially or continuously. The addition of Nogestimate 0.09 mg, days 4-6 a progestin to estrogen therapy prevents estrogen-induced Femhirt 1.5 Ethinyl estradiol 1.0 mg endometrial proliferation. Continuous combined hormone Norethindrone acetate 5 Jug replacement therapy (HRT), with appropriate doses of daily estrogen and progestin, has been shown to be effective in 0007 Since it is possible that progestins ameliorate of the relieving vaginal atrophy and vasomotor symptoms, prevent favorable estrogen effects on lipids and may potentially ing postmenopausal osteoporosis, and reducing the risk of impair of glucose tolerance, it is desirable, and an objective to endometrial cancer by prevention of endometrial hyperplasia. find the lowest dose estrogen plus progestin HRT product, The following table contains a list of some currently available which also minimizes or eliminates endometrial hyperplasia. oral combination HRT products. In addition, a major factor affecting a woman's decision to start and to continue taking HRT is vaginal bleeding, and many women would prefer a bleed-free product. Therefore, another objective is to provide the lowest effective dose which Oral Combination HRT Products provides an acceptable bleeding pattern. Doses as low as Brand Name Estrogen Progestin Strengths NETA 0.5 mg, NET 0.35 mg, MPA 2.5 mg, levonorgesterel 0.25 mg, and dydrogesterone 5 mg have been used previously Activelle Estradio 1 mg Norethisterone acetate (NETA) 0.5 mg in continuous uninterrupted HRT regimens. Climagest Estradiol valerate (Climaval) 1 or 2 mg Norethisterone (NET) 1 mg days 17-28 BRIEF DESCRIPTION OF THE DRAWINGS Cyclo Estradiol valerate 1 or 2 mg, days 1-21 Progynova Levonorgestrel 250 or 500 g, 0008 FIG. 1 shows the mean number of hot flushes per days 2-21 Elleste Duet Estradio 1 or 2 mg day in patients receiving PREMARIN plus MPA combina Norethisterone acetate 1 mg days 17-28 tions or placebo.
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