WO2008005333A2

WO2008005333A2 - Use of extended cycle and continuous estrogen contraceptive regimens in the treatment of osteopenia and related conditions in adolescent females

Info

Publication number: WO2008005333A2
Application number: PCT/US2007/015129
Authority: WO
Inventors: Kathleen Reape
Original assignee: Duramed Pharmaceuticals, Inc.
Priority date: 2006-06-30
Filing date: 2007-06-29
Publication date: 2008-01-10
Also published as: WO2008005333A3

Abstract

The present invention provides extended cycle contraceptive regimens in which a female is administered a combined dosage form of estrogen and progestin. The disclosed extended cycle contraceptive regimens can be administered to a female as a method of treating or preventing osteopenia and/or related conditions due to low estrogen levels in adolescent females.

Description

USE OF EXTENDED CYCLE AND CONTINUOUS ESTROGEN

CONTRACEPTIVE REGIMENS IN THE TREATMENT OF OSTEOPENIA AND

RELATED CONDITIONS IN ADOLESCENT FEMALES

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] The present invention provides extended cycle contraceptive regimens in which a female is administered a combined dosage form of estrogen and progestin. The disclosed extended cycle contraceptive regimens can be administered to a female as a method of treating or preventing osteopenia and/or related conditions due to low estrogen levels in adolescent females.

Related Art

[0002] Adolescent women with hypothalamic dysfunction resulting in amenorrhea due to weight loss, stress, or intense exercise (including high-level athletes) are at increased risk for bone loss (Miller, K.K. and Klibanski, A., J. Clin. Endocrinol. Metab. £4:1775-1783 (1999)). The effects of acquired estrogen deficiency in this population are of great concern, as an estimated 25-40% of peak bone mass is accumulated during the adolescent years in normal females, reflecting increases in both bone size and volume (Heaney, R.P. et al., Osteoporosis International 77:985-1009 (2000)). Although increases in bone mass can continue to occur until about the age of 30, about 90% of total bone mass is achieved by the age of 20 (Eliakim, A. and Beyth, Y., J. Pediatric Adolescent Gynecol. 16:201-206 (2003)). During the time of most rapid acquisition of bone mass, increases of between 2% and 10% per year can occur (Cromer, B.A. et al., J. Adolescent Health 35:434-441 (2004)). The amount of bone laid down between the ages of 13 to 15 in normal girls is comparable to the amount lost in the last four decades of life (Bailey, D. A. et al., J. Bone Mineral Res. 75:S202 (2000)). Normal increases in bone during adolescence are not linear over time and there is a fair degree of individual variability (Sabatier, J.P. et al., Osteoporosis International 5:141-48 (1996)).

[0003] Sabatier et al. {Osteoporosis International 5:141-48 (1996)), in a cross-sectional population study of 574 normal females, aged 10-24, reported a non-linear increase in bone mineral density (BMD) occurring during the adolescent years. Spinal BMD increased dramatically between ages 10-14 or the first year after menarche. Subsequently, between the ages of 14 and 17, moderate increases in spine BMD were reported. After age 17, or the fourth year after menarche, a plateau was reached where there were no further significant increases in BMD. Values at this time did not differ from those seen in older menstruating women (27-47 years) (Sabatier, J.P. et al., Osteoporosis International 6: 141-48 (1996)). Not only is chronologic age important in assessments of bone mass during adolescence, but gynecologic age (time since menarche) is equally important, because of the known effects of estrogen on bone and the wide individual variation in the age at onset of first menses.

[0004] Estrogen deficiency in adolescent females is associated with decreased accumulation of bone mass and bone loss, or osteopenia. Evidence includes a positive correlation between low BMD and increasing duration of estrogen deficiency (e.g., amenorrhea, which is often associated with estrogen deficiency) and a negative correlation with estradiol levels (Miller, K.K., and Klibanski, A., J. CHn. Endocrinol. Metab. 84: 1775-1783 (1999)). The longer the duration of amenorrhea, or the lower the serum estradiol levels, the greater the degree of bone loss. Oligomenorrhea or amenorrhea is often associated with estrogen deficiency due to functional gonadotropin releasing hormone (GnRH) deficiency, resulting in ovarian dysfunction. One-third of females who have amenorrhea for at least six months have a vertebral bone density of 2 standard deviations or more below the mean, and 3-66% of female athletes are affected by amenorrhea (Miller, K.K., and Klibanski, A., J. Clin. Endocrinol. Metab. 84: 1775- 1783 (1999)). Menstrual dysfunction (oligomenorrhea or amenorrhea) is also seen in female athletes with normal body weights, such as swimmers and cyclists (Warren, M.P, J. Clin. Endocrinol. Metab. £4:1892-1896 (1999)).

[0005] Untreated osteopenia during adolescence is of particular concern because it may carry both short and long-term health risks. The long-term risks are not known, but estrogen deficiency during this time period can impair the attainment of peak bone mineral density and increase the risk of fracture and osteoporosis later in life. In the short-term, adolescents with bone mass deficiency are at increased risk for stress fractures. Athletes with menstrual irregularities not only have a higher incidence of stress fractures, but also multiple ones (Warren, M.P. and Goodman, L.R., J. Endocrinol. Invest. 26:873-878 (2003)). A case-control study of 19 female athletes with stress fractures found that these women were more likely to have lower bone density, lower dietary calcium intake, current menstrual irregularity, and less oral contraceptive use (Myburgh, K.H. et al, Annals Intern. Med. 173:754-759 (1990)). In a 12-month prospective study of 53 Australian female track and field athletes (mean age 20.4), female athletes who developed stress fractures were found to have significantly less total-body bone mineral content, a later age of menarche and fewer menses per year since menarche when compared to their counterparts without stress fractures (Bennell, K.L., et al, Amer. J. Sports Med. 24:810-818 (1996)). By the time fractures are experienced, patients may already be osteopenic. Early treatment may help prevent osteopenia.

[0006] There appears to be a critical window in time during adolescence when adequate estrogen is essential for the attainment of peak bone mass, so estrogen deficiency during this time places the patient at risk. Additionally, it is not known whether failure to accumulate bone during this critical time period is completely reversible. In a small study by Drinkwater et al. {J.A.M.A. 255:380-382 (1986)), a 6.2% increase in vertebral bone density during a mean follow-up of 14.4 months was documented in 7 athletes with a history of amenorrhea who experienced spontaneous resumption of menses, in contrast to two athletes who remained amenorrheic and continued to demonstrate decreases in bone density. However, bone density did not return to normal and an extended follow-up of a larger group of patients would be necessary to determine whether normal bone density for age is eventually achieved.

(0007) Post-menopausal osteoporosis is a different disease with different implications for morbidity and mortality. Low bone mass or osteopenia, or osteoporosis in the postmenopausal population, by definition can have no impact on child-bearing. In addition, activity levels in these two patient populations are dramatically different, as is expected longevity. It is also important to note that there are several alternative therapies available for the prevention and treatment of post-menopausal osteoporosis, which is not the case in the adolescent population. Also, because of the rapid increases in BMD occurring during adolescence, failure to achieve peak bone mass in a female under the age of 18 may have a more profound effect on overall bone health, than the same degree of bone loss occurring in an older reproductive-aged woman (Cromer, B. A. et al., 9. Adolescent Health 35:434-441 (2004)). [0008] The management issues related to post-menopausal osteopenia and osteoporosis are different than the issues associated with osteopenic adolescents. In the postmenopausal population, bone loss is an expected part of the aging process and treatment goals are aimed at decreasing the risk of fracture and restoring or maintaining bone. In contrast, in adolescents, bone accumulation is normal; in fact, large increases in bone are expected. Any failure to increase bone in an adolescent is abnormal, and the goal of treatment in this population is to normalize bone accumulation in order to achieve normal peak bone mass, creating a "reserve" which will help compensate for losses in bone associated with pregnancy and lactation as well as normal aging. If bone accrual is suboptimal during adolescence, and peak bone mass is not achieved, the result is an insufficient "reserve" of bone mass and patients are at increased risk for both stress fractures and osteoporosis later in life; the potential even exists for early-onset (premenopausal) osteoporosis. Other products prescribed for the treatment and prevention of osteoporosis in the postmenopausal population, such as the bisphosphonates, are usually not recommended for use in adolescents due to concerns about long-term safety and the potential for deleterious effects on the fetal skeleton when pregnancy occurs.

[0009] The therapeutic options for management of osteopenia in adolescents with oligomenorrhea or amenorrhea are limited. Weight gain, decreased exercise, and improved diet are usually the first line of therapy. For some patients, however, such therapeutic behavior modification can be problematic. For example, in some circumstances, modification of training programs to reduce exercise may not be an acceptable option for some patients. Also, because oligomenorrhea and amenorrhea can occur in normal weight females, behavior modification alone may not be effective in preventing bone loss in such patients (Warren, M.P, J. Clin. Endocrinol. Metab. £4:1892- 1896 (1999)). Even with changes in behavioral factors, amenorrhea may persist for several months. Given the fact that the window to correct osteopenia is limited, reversal of the failure to accumulate bone in a timely fashion is critical.

[0010] There exists a need for methods of treating and preventing osteopenia and conditions due to low estrogen levels in adolescent females that are both safe and effective. BRIEF SUMMARY OF THE INVENTION

[0011] The present invention is directed to a method of treating osteopenia in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

[0012] The present invention is also directed to a method of reducing loss of bone mineral density in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

[0013] The present invention is also directed to a method of increasing bone mass or bone mineral density in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

[0014] The present invention is also directed to a method of treating hypoestrogenism in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

[0015] The present invention is further directed to each of the methods provided above, wherein the estrogen administered with the progestin is administered to the adolescent female in a daily dosage equivalent to about 10 μg (micrograms) to about 30 μg of ethinyl estradiol, and the progestin is administered to the adolescent female in a daily dosage equivalent to about 0.05 mg (milligrams) to about 0.15 mg of levonorgestrel, respectively.

[0016] The present invention is further directed to each of the methods provided above, wherein the estrogen and progestin are administered for a period of 49 to 112 consecutive days, for a period of 56 to 112 consecutive days, for a period of 77 to 112 consecutive days, for a period of 77 to 91 consecutive days, for a period of at least 84 consecutive days, for a period of about one year, for a period of more than one year but less than two years, for a period of two years, for a period of more than two years, or continuously.

[0017] In some embodiments, the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by a hormone free period for 2 to 8 consecutive days, wherein neither estrogen nor progestin are administered to the adolescent female during the hormone free period. The hormone-free period can be achieved by administering a hormone-free placebo. [0018] In some embodiments, the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides extended cycle and estrogen-bridged estrogen/progestin regimens that are useful in the treatment of low bone mass (osteopenia) and other conditions related to hypoestrogenism in adolescent females. Hodgen, U.S. Pat. No. 5,898,032, relates to the administration of extended cycle estrogen/progestin regimens to provide contraceptive benefits. Pasquale, U.S. Pat. No. Re. 35,724, relates to administering estrogen and progestin to provide contraceptive benefits. Ben-Maimon et al., WO 2004/098517, relates to the administration of extended cycle estrogen/progestin regimens to provide non-contraceptive benefits. Bell et al., U.S. Appl. Publ. No. 2003/0139381 Al, and Bell et al, U.S. Appl. Publ. No. 2005/0143359 Al, relate to the administration of estrogen-bridged estrogen/progestin regimens to provide contraceptive benefits and non-contraceptive benefits, respectively. These patents and published applications are each fully incorporated by reference herein in their entirety.

Extended Cycle and Estrogen-Bridged Regimens

[0020] In the methods of the present invention, an adolescent female is administered an extended cycle regimen or an estrogen-bridged regimen. The term "extended cycle regimen" refers to a regimen in which estrogen and progestin (or progestogen) are administered to a subject for a period of 42 or more consecutive days, greater than 42 consecutive days, or at least 42 consecutive days.

[0021] In some embodiments, the period of administration of estrogen and progestin is 42 to 358 consecutive days, 42 to 182 consecutive days, 42 to 119 consecutive days, 56 to 112 consecutive days, or 77 to 91 consecutive days. In some embodiments, the estrogen and progestin are administered for a period of 42 to 47 consecutive days, 48 to 54 consecutive days, 55 to 61 consecutive days, 62 to 68 consecutive days, 69 to 75 consecutive days, 76 to 82 consecutive days, 83 to 89 consecutive days, 111 to 117 consecutive days, 174 to 180 consecutive days, 265 to 271 consecutive days, or 356 to 362 consecutive days.

[0022] In some embodiments, the period of administration of estrogen and progestin is at least 84 consecutive days. In other embodiments, the period of administration can be about one year, more than one year but less than two years, two years, or more than two years. In other embodiments, the period of administration is continuous.

[0023] In the extended cycle regimen, the period of administration of estrogen and progestin is optionally followed by a period of 2 to 8 consecutive days during which neither estrogen nor progestin is administered (the hormone-free period). In some embodiments of the invention, the hormone-free period is 2 to 7 consecutive days, 3 to 7 consecutive days, or 3 to 5 consecutive days. In other embodiments, the hormone-free period is 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, or 7 consecutive days.

[0024] In some embodiments, the hormone-free period comprises administering a hormone-free placebo pill or tablet during that period. In some embodiments, the hormone-free placebo administered comprises calcium.

[0025] For example, on a schedule of 84 consecutive days of administration of estrogen and progestin followed by a hormone- free period of 7 consecutive days, there are only four treatments and menstrual cycles per year. As another example, on a schedule of 175 consecutive days of administration of estrogen and progestin followed by a hormone-free period of 7 consecutive days, there are only two treatments and menstrual cycles per year.

[0026] The present invention is also directed to methods where the adolescent female is administered an estrogen-bridged regimen (bridged regimen). The terms "estrogen- bridged regimen" and "bridged regimen" refer to a regimen in which estrogen and progestin (or progestogen) are administered to a subject for a period of 42 or more consecutive days, greater than 42 consecutive days, or at least 42 consecutive days, followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days ("unopposed estrogen period").

[0027] In other embodiments of the bridged regimen, estrogen and progestin are administered for a period of 42 or more consecutive days ("extended cycle bridged regimen"). Thus, in some embodiments, the estrogen and progestin are administered for a period of 42 to 47 consecutive days, 48 to 54 consecutive days, 55 to 61 consecutive days, 62 to 68 consecutive days, 69 to 75 consecutive days, 76 to 82 consecutive days, 83 to 89 consecutive days, 111 to 117 consecutive days, 174 to 180 consecutive days, 265 to 271 consecutive days, or 356 to 362 consecutive days.

[0028] In some embodiments, the estrogen and progestin are administered for a 60 to 110 consecutive days, 81 to 110 consecutive days, or 81 to 89 consecutive days. In other embodiments, the estrogen and progestin are administered for a period of at least 81 consecutive days, or at least 84 consecutive days. In other embodiments, the period of administration of estrogen and progestin can be about one year, more than one year but less than two years, two years, or more than two years.

[0029] In some embodiments, estrogen and progestin are administered for a period of 42 to 356 consecutive days, 42 to 182 consecutive days, 42 to 119 consecutive days, 56 to 112 consecutive days, or 77 to 91 consecutive days. In other embodiments, the estrogen and progestin are administered for a period of at least 77 consecutive days, or at least 84 consecutive days. In some embodiments, the period of administration of estrogen and progestin can be about one year, more than one year but less than two years, two years, or more than two years.

[0030] In the bridged regimen, the period of administration of estrogen and progestin is followed by administration of estrogen for a period of 2 to 8 days during which progestin is not administered ("unopposed estrogen period"). In some embodiments, the unopposed estrogen period is 2 to 8 consecutive days, 3 to 8 consecutive days, 2 to 7 consecutive days, or 3 to 7 consecutive days. In another embodiment, the unopposed estrogen period is 7 consecutive days. In yet other embodiments, the unopposed estrogen period is 2 to 5 consecutive days, 3 to 5 consecutive days, or 2 to 3 consecutive days. In some embodiments, the unopposed estrogen period is 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, or 7 consecutive days.

[0031] In some embodiments, the period of administration of estrogen and progestin is followed by a hormone free period of 2-5 consecutive days (e.g., by administering placebo pills), followed by administration of estrogen without progestin for 3-5 consecutive days. For example, 2 consecutive hormone free days can be followed by 5 consecutive days of estrogen without progestin.

[0032] For example, on a schedule of 84 consecutive days of administration of estrogen and progestin, followed by 7 consecutive days of administration of estrogen, there are only four treatments and menstrual cycles per year. As another example, on a schedule of 175 consecutive days of administration of estrogen and progestin, followed by 7 consecutive days of administration of estrogen, there are only two treatments and menstrual cycles per year. In yet another example, on a schedule of 25 consecutive days of administration of estrogen and progestin, followed by 3 consecutive days of administration of estrogen, there are thirteen treatments and menstrual cycles per year.

[0033] The bridged regimen or the hormone free period is optionally administered with an antidepressant. In some aspects of the invention, the antidepressant is administered in combination with estrogen during the unopposed estrogen interval of the bridged regimen. In other aspects of the invention, the antidepressant is administered continuously throughout the regimen, or, in yet other aspects of the invention, the antidepressant is administered intermittently. For example, in one aspect of the invention, the antidepressant is administered intermittently during the late luteal phase, which is typically one to two weeks before menses. In yet other aspects of the invention, the antidepressant is administered one time during a menstrual cycle, or once weekly.

[0034] In the extended cycle regimen or the bridged regimen, the estrogen and progestin can be administered monophasically, biphasically, triphasically, or multiphasically. As used herein, "monophasic" refers to the continuous use of one particular dose of estrogen and progestin during the period of administration of estrogen and progestin. "Biphasic" refers to administration of a first continuous dose of estrogen and progestin during a first portion of the period of administration of the estrogen and progestin, with administration of a second continuous dose of estrogen and progestin during the second portion of the period of administration of the estrogen and progestin. "Triphasic" refers to administration of first, second, and third continuous doses of estrogen and progestin during the first, second, and third portions, respectively, of the period of administration of the estrogen and progestin. "Multiphasic" refers to administration of four or more continuous doses of estrogen and progestin during the first, second, third, and fourth or more portions, respectively, of the period of administration of the estrogen and progestin.

[0035] The extended cycle regimen and the bridged regimen can include administration to an adolescent female beginning at Day 1 of a menstrual cycle that is defined as beginning at the first day of menstrual flow. In alternative embodiments, the extended cycle regimen and bridged regimen can also include administration to the female beginning at Day 1 of a menstrual cycle that is defined as beginning at the day after the ending of the menstrual flow. In alternative embodiments, the extended cycle regimen or bridged regimen also can include administration to the female beginning at Day 1 of a menstrual cycle that is defined as beginning at any day within the menstrual cycle.

Methods of Treatment

[0036] The extended cycle regimen and bridged regimen disclosed herein are useful in the treatment or prevention of osteopenia and conditions related to hypoestrogenism, i.e., low serum estrogen levels, in adolescent females. The extended cycle regimen and bridged regimen can be administered to adolescent females, e.g., females 12-18 years of age, who have not yet achieved peak bone density, but who, due to various conditions such as anorexia, amenorrhea, or oligomenorrhea, are at risk of loss of bone density or at risk of not achieving a normal physiologic bone density for age and developmental maturity.

[0037] The extended cycle regimen and the bridged regimen can also be used as a method of female contraception. Thus, the extended cycle regimen and the bridged regimen can be used as a method of providing contraception to an adolescent female for the treatment of a condition or disorder disclosed herein, e.g., for the treatment of a condition or disorder in the adolescent female related to low estrogen levels, such as osteopenia. The extended cycle regimen and the bridged regimen can also be used as a method of providing contraception and of treating a condition or disorder disclosed herein in the adolescent female.

[0038] Typically, adolescent females at risk of developing osteopenia, or those who have already developed osteopenia, have low serum estradiol levels (hypoestrogenism) and often exhibit secondary oligomenorrhea or amenorrhea.

[0039] The terms "secondary oligomenorrhea" and "oligomenorrhea" refer to infrequent or light menstruation in a female after menarche (i.e., in a female whose periods were regularly established before developing problems with infrequent flow). In females with oligomenorrhea, menstrual periods typically occur at intervals of greater than 35 days, with only four to nine periods per year.

[0040] The terms "secondary amenorrhea" and "amenorrhea" as used herein refer to the absence of menstrual periods in a female after menarche (i.e., in a female whose periods were regularly established before menstruation fails to occur). [0041] The term "osteopenia" refers to reduction in bone volume and/or density to below normal levels. For example, osteopenia, as used herein, refers to a bone density between about 0.5 standard deviation and about 2.5 standard deviations below the average bone density for normal adolescent females. Osteopenia can also include weight-adjusted bone density that is somewhat low and has been defined as a weight-adjusted bone density between about 0.5 standard deviation and about 2.5 standard deviations below the average weight-adjusted bone density for normal adolescent females.

[0042] The term "adolescent" or "adolescent female" refers to a human female who is close to adulthood, but is not yet considered to be adult, e.g., a human female between the ages of about 12 and about 20, in particular, between the ages of 12 and 18.

[0043] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the condition, disorder or disease progression; amelioration of the condition, disorder or disease state, remission (whether partial or total) the condition, disorder or disease, whether detectable or undetectable; or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response, without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0044] The term "continuous" or "consecutive," as used herein in reference to

"administration," means that the frequency of administration is at least once daily. Note, however, that the frequency of administration can be greater than once daily and still be "continuous" or "consecutive," e.g., twice or even three times daily, as long as the dosage levels as specified herein are not exceeded.

[0045] The terms "dosage" and "dosage level," mean the total amount of estrogen or progestin administered per day. Thus, for example, "continuous administration" of a progestin to a woman at a "dosage level" of 30 μg means that the woman receives a total of 30 μg of progestin on a daily basis, whether the progestin is administered as a single 30 μg dose or, e.g., three separate 10 μg doses. A conventional means of continuously administering an estrogen or progestin is as a single daily oral dose at the prescribed dosage level.

[0046] Secondary oligomenorrhea or amenorrhea in adolescent females is a common and important clinical problem. Adolescent females who enter adulthood with decreased bone mass may be predisposed to significant morbidity as they proceed into adulthood, through pregnancy and lactation, and through menopause. Oligomenorrhea and amenorrhea are associated with estrogen deficiency and osteopenia. Minimizing impairment of bone accrual is important since adolescence is a time of rapid bone deposition and failure to attain peak bone mineral density during the adolescent years may increase the risk of stress fractures and osteoporosis in later life.

[0047] The extended cycle and bridged regimens of the present invention can be beneficial in the management of osteopenia in adolescent females because both the extended cycle and bridged regimens provide periods of estrogen exposure that would be longer than the periods of estrogen exposure provided by conventional 28-day estrogen/progestin regimens during the same course of treatment. The bridged regimen, for example, provides continuous estrogen exposure during administration due to the absence of a hormone-free period. By inducing regular cycles in oligomenorrheic or amenorrheic adolescent females, the extended cycle and bridged regimens of the invention can also have additional beneficial effects, such as reducing other adverse effects related to estrogen deficiency, e.g., such as endometrial abnormalities and lipid changes.

[0048] The extended cycle and bridged regimens of the present invention can be used in treating or preventing low bone mass or low bone mineral density in an adolescent female. Thus, the present invention is directed to a method of treating or preventing low bone mass or low bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0049] The present invention is also directed to a method of providing contraception and treating or preventing low bone mass or low bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein. [0050] The extended cycle regimen and the bridged regimen can also be used in preventing or reducing loss of bone mineral density in an adolescent female. Thus, the present invention is directed to a method of preventing or reducing loss of bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[00511 The present invention is also directed to a method of providing contraception and preventing or reducing loss of bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0052] The extended cycle regimen and the bridged regimen can also be used in reducing the risk of bone loss or the risk of osteopenia in an adolescent female. Thus, the present invention is directed to a method of reducing the risk of bone loss or the risk of osteopenia in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0053] The present invention is also directed to a method of providing contraception and reducing the risk of bone loss or the risk of osteopenia in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0054] The extended cycle regimen and the bridged regimen can also be used in increasing bone mass or increasing bone mineral density in an adolescent female. Thus, the present invention is directed to a method of increasing bone mass or increasing bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0055] The present invention is also directed to a method of providing contraception and increasing bone mass or increasing bone mineral density in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0056] The extended cycle regimen and the bridged regimen can also be used in restoring normal increase in bone mass in an adolescent female in order to achieve normal peak bone mass in the female. Thus, the present invention is directed to a method of restoring normal increase in bone mass in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein. (0057] The present invention is also directed to a method of providing contraception and restoring normal increase in bone mass in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0058] Further, the extended cycle regimen and the bridged regimen can be used in treating hypoestrogenism, or low plasma estrogen levels, in an adolescent female. Thus, the present invention is directed to a method of treating hypoestrogenism in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein. The present invention is directed to a method of treating low plasma estrogen levels in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0059] The present invention is also directed to a method of providing contraception and treating hypoestrogenism in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein. The present invention is also directed to a method of providing contraception and treating low plasma estrogen levels in an adolescent female in need thereof by administering to the female the extended cycle regimen, or the bridged regimen, disclosed herein.

[0060] The extended cycle regimen and the bridged regimen can also be used in treating conditions and disorders in an adolescent female related to low plasma estrogen levels, including, but not limited to, conditions such as irregular withdrawal bleeding and the menstrual disorders amenorrhea and oligomenorrhea.

Dosages and Formulations

[0061] Various dosage amounts can be used in the extended cycle regimen and bridged regimen of the present invention. When administered in a dosage form containing progestin, the daily dosage of the estrogen is equivalent to about 10 μg to about 30 μg of ethinyl estradiol. In some embodiments, the daily dosage of estrogen is equivalent to about 15 μg to about 25 μg of ethinyl estradiol or about 25 μg to about 30 μg of ethinyl estradiol. The daily dosage of estrogen can also be equivalent to about 20 μg to about 30 μg of ethinyl estradiol. In some aspects of the invention, the daily dosage of estrogen that is administered with the progestin in the extended cycle regimen and in the bridged regimen is equivalent to about 10 μg, about IS μg, about 20 μg, about 25 μg, or about 30 μg of ethinyl estradiol.

[0062] The daily dosage of the progestin administered in a dosage form with estrogen can be equivalent to about 0.05 mg to about 0.15 mg of levonorgestrel. In some embodiments, the daily dosage of progestin is equivalent to about 0.05 mg to about 0.10 mg of levonorgestrel. In other embodiments, the daily dosage of progestin is equivalent to about 0.1 mg to about 0.15 mg of levonorgestrel. Accordingly, the daily dosage of progestin can be equivalent to about 0.05 mg, about 0.10 mg, or about 0.15 mg of levonorgestrel .

[0063] When administered in a dosage form that does not contain progestin, the daily dosage of estrogen can be equivalent to about 10 μg to about 30 μg of ethinyl estradiol. In some embodiments, the daily dosage amount of estrogen is equivalent to about 10 μg to about 25 μg of ethinyl estradiol, about 10 μg to about 20 μg of ethinyl estradiol, or about 25 μg to about 30 μg of ethinyl estradiol. Thus, in some embodiments, the dosage of estrogen when administered without progestin can be equivalent to about 15 μg, 20 μg, 25 μg, or 30 μg of ethinyl estradiol.

[0064] In some embodiments, (a) the estrogen that is administered with the progestin for the period of about 56 to about 112 consecutive days is administered in a daily dosage equivalent to about 10 μg to about 30 μg of ethinyl estradiol; (b) the progestin that is administered with the estrogen for the period of about 56 to about 112 consecutive days is administered in a daily dosage equivalent to about 0.05 mg to about 0.15 mg of levonorgestrel; and (c) the estrogen that is administered without the progestin for the period of 2 to 8 consecutive days is administered in a daily dosage equivalent to about 10 μg to about 30 μg of ethinyl estradiol. In some embodiments, the estrogen in (a) is administered in a daily dosage equivalent to about 30 μg of ethinyl estradiol and the estrogen in (c) is administered in a daily dosage equivalent to about 10-30 μg of ethinyl estradiol. In some embodiments, the estrogen in (c) is administered in a daily dosage equivalent to about 10 μg of ethinyl estradiol. In some embodiments, the estrogen in (c) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol. In some embodiments, the estrogen in (c) is administered in a daily dosage equivalent to about 30 μg of ethinyl estradiol. In some embodiments, the estrogen in (a) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol and the estrogen in (c) is administered in a daily dosage equivalent to about 10-20 μg of ethinyl estradiol. In some embodiments, the estrogen in (c) is administered in a daily dosage equivalent to about 10 μg of ethinyl estradiol. In some embodiments, the estrogen in (c) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol.

[0065] In some aspects of the present invention, the estrogen and progestin of the extended cycle and bridged regimens can be ethinyl estradiol and levonorgestrel, respectively, although other suitable estrogens and progestins can be employed. The weight ratio of estrogen and progestin can be about 1:0.2 to about 1:300. In some aspects of the invention, the weight ratio of estrogen and progestin is about 1:1 to about 1:50. In other aspects of the invention, the weight ratio of estrogen and progestin is about 1 :1 to about 1 :10. For example, the daily amount of ethinyl estradiol is about 10 μg to about 30 μg and the daily amount of levonorgestrel is about 0.05 mg to about 0.15 mg.

[0066] The values given above are for ethinyl estradiol and levonorgestrel, and if a different estrogen or progestin is employed, an adjustment in the amount based on the relative potency or activity can be made. Correlations in potency among the various estrogens and among the various progestins are known. See, for example, EP 0 253 607, which is hereby incorporated in its entirety by reference. For example, in a contraceptive regimen, 30 μg of ethinyl estradiol is roughly equivalent to about 60 μg of mestranol or about 2,000 μg of 17β-estradiol. Similarly, 0.050 mg of levonorgestrel is roughly equivalent to about 0.175 mg of norethindrone acetate, about 0.050 mg of desogestrel, about 0.050 mg 3-ketodesogestrel, about 0.035 mg of gestodene, or about 0.100 mg of norgestrel. It should be understood that when norgestrel is used in place of levonorgestrel, its concentration is twice that of levonorgestrel. Norgestrel (dl-norgestrel) is a racemic mixture of optically active isomers, while levonorgestrel is one of the optically active isomers present in norgestrel.Equivalent concentrations of estrogens and of progestins can be determined using either in vitro or in vivo assay methods. See, for example, Kuhl, H., Drugs 51(2):\%&-2\5 (1996); Philibert, D., et al, Gynecol. Endocrinol. /3:316-326 (1999); and Lundeen, S., et al., J. Steroid Biochem. Molec. Biol. 75:137-143 (2001), in which the relative potencies of various progestins are compared using both in vitro and in vivo test assays. See also, for example, Dickey, R. P., "Contraceptive Therapy," OBG Management Supplement (October 2000), pp. 2-6. Each of these documents is hereby incorporated by reference in its entirety.For example, various combinations of progestin and estrogen that have been used in oral contraceptives are shown in Table 1.

Table 1. Combinations of Progestin and Estrogen

^♦Equivalencies: 0.050 mg Mestranol = approximately 0.035 mg Ethinyl estradiol (EE); and 0.10 mg dl-Norgestrel = approximately 0.15 mg Norethindrone

[0067] Each block in Table 1 describes a specific combination of progestin and estrogen, e.g., norethynodrel and mestranol, and within each block older combinations are listed first, with successively newer combinations following.

[0068] Suitable progestins for use in the present invention include, but are not limited to, natural and synthetic compounds having progestational activity, such as, for example, progesterone, chlormadinone acetate, norethindrone, cyproterone acetate, norethindrone acetate, desogestrel, levonorgestrel, drospirenone, trimegestone, norgestrel, norgestimate, norelgestromin, etonogestrel, gestodene, and other natural and/or synthetic gestagens. Prodrugs of suitable progestins can also be used in the extended cycle regimen and bridged regimen of the present invention.

[0069] The expression "prodrug" denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug and is transformed into the active drug by an enzymatic or chemical process. Ethynodiol diacetate, which is converted in vivo to norethindrone, is an example of a progestin prodrug that can be used in the present invention. Additional examples of progestin prodrugs include, but are not limited to, norgestimate (which is converted in vivo to 17-deacetyl norgestimate, also known as norelgestromin), desogestrel (which is converted in vivo to 3-keto desogestrel, also known as etonogestrel), and norethindrone acetate (which is converted in vivo to norethindrone).

[0070] Suitable estrogens in the present invention include, but are not limited to, natural and synthetic compounds having estrogenic activity, such as, for example, estradiol (17β- estradiol), 17α-estradiol, estriol, estrone, and their esters, such as the acetate, sulfate, valerate or benzoate esters of these compounds, including, for example, estradiol 17β- cypionate, estradiol 17-propionate, estradiol 3-benzoate, and piperazine estrone sulfate; ethinyl estradiol; conjugated estrogens (natural and synthetic); mestranol; agonistic anti- estrogens; and selective estrogen receptor modulators. Prodrugs of suitable estrogens can also be used in the extended cycle regimen and bridged regimen of the present invention. Examples of estrogen prodrugs that can be used in the present invention include, but are not limited to, estradiol acetate (which is converted in vivo to 17β-estradiol) and mestranol (which is converted in vivo to ethinyl estradiol).

[0071] The estrogen and progestin are administered in the conventional manner by any route where they are active. For example, administration can be by, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by hormone implants. Thus, modes of administration for the estrogen and progestin (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams. [0072] Pharmaceutical formulations containing the estrogen and/or progestin and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder comprising an effective amount of the estrogen and/or progestin as taught in this invention. It is also known in the art that the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, "Modern Pharmaceutics," Banker & Rhodes, Marcel Dekker, Inc. (1979); and "Goodman & Giϊman's The Pharmaceutical Basis of Therapeutics " MacMillan Publishing Co., New York, 6th ed. (1980) can be consulted.

[0073] Most estrogens and progestins are orally active and this route of administration can be used in the invention. Accordingly, administration forms can include, but are not limited to, tablets, dragees, capsules and pills, which contain the estrogen and the progestin and one or more suitable pharmaceutically acceptable carriers.

[0074] For oral administration, the estrogen and/or progestin can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0075] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0076] Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the estrogen and/or progestin in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the estrogen and/or progestin can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0077] For buccal administration, the estrogen and/or progestin compositions can take the form of, e.g., tablets or lozenges formulated in a conventional manner.

[0078] For administration by inhalation, the estrogen and/or progestin are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0079] The estrogen and/or progestin can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. The estrogen and/or progestin can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0080] The estrogen and/or progestin can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0081] In addition to the formulations described previously, the estrogen and/or progestin can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the estrogen and/or progestin can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0082] For transdermal administration, the estrogen and progestin can be applied by any transdermal, therapeutic system that is consequently supplied to the organism, such as, for example, as a transdermal patch, transdermal cream or plaster. For example, the estrogen and/or progestin can be formulated as a transdermal patch. The preparation and use of transdermal patches are well known to those of skill in the art and are available in different designs, including matrix-type or reservoir-type designs. In addition to the estrogen and/or progestin, transdermal patches can contain additional components such as penetration-enhancing agents and/or additional excipients that are conventionally employed, such as, e.g., carriers, gelling agents, suspending agents, dispersing agents, preservatives, stabilizers, wetting agents, emulsifying agents, and the like.

[0083] For vaginal administration, the estrogen and/or progestin can be formulated as vaginal gels, creams, tampons, suppositories, vaginal rings, intrauterine devices and the like. The preparation of each of these formulations is well known to those of skill in the art.

[0084] The estrogen and progestin can also be administered according to the methods of the present invention in combination with other pharmaceutically active agents or compounds, including, for example, glucocorticoids such as vitamin D or vitamin D analogues; and/or minerals such as, for example, calcium. For example, the estrogen and/or progestin can be administered with vitamin D and/or calcium in an extended cycle regimen as a method of maintaining or preventing loss of bone density. The form of vitamin D and of calcium used in the present invention would be well known to those of skill in the art, as would the amount. For example, calcium can be administered in the form of calcium carbonate, at a daily dosage level of about 500 mg.

[0085] Examples of other pharmaceutically active agents that can be administered with estrogen and progestin according to the methods of the present invention include, but are not limited to, one or more of the B complex vitamins, such as vitamin B3 (niacin (i.e., nicotinic acid and/or nicotinamide)), vitamin B9 (folic acid or folate), vitamin B6 and/or vitamin B12; iron (e.g., ferrous iron, such as, e.g., ferrous sulfate, ferrous fumarate, ferrous gluconate, or an iron glycine amino acid chelate); bisphosphonates (e.g., alendronate); teriparatide (e.g., FORTEO™); and SERMs (selective estrogen receptor modulators, e.g., raloxifene.

[0086] The estrogen and/or progestin can also be administered with an antidepressant, such as, for example, a selective serotonin reuptake inhibitor (SSRI), a tricyclic antidepressant or anxiolytic, or any antidepressant known to one of skill in the art. Suitable antidepressants include, but are not limited to, alprazolam (XANAX^®, Pharmacia and Upjohn, a division of Pfizer Inc., New York, NY), clomipramine (ANAFRANIL^®, Mallinckrodt Inc., St. Louis, MO), fluoxetine (PROZAC^®, Eli Lilly and Co., Indianapolis, IN), paroxetine (PAXIL^®, GlaxoSmithKline Corporation, Research Triangle Park, NC), sertraline (ZOLOFT^®, Pfizer Inc., New York, NY), nefazodone, and venlafaxine (EFFEXOR^®, Wyeth Pharmaceuticals Inc., Philadelphia, PA).

[0087] The additional pharmaceutically active agents can be administered using any suitable modes of administration, including, but not limited to, parenteral, oral, buccal, rectal, subcutaneous, intravenous, intramuscular, intranasal, transdermal modes of administration, and by inhalation. In some aspects of the invention, the additional active agent is administered using the same mode of administration as the estrogen and/or progestin. For example, the additional active agent and the estrogen and/or progestin are administered together using the same mode of administration, either in the same dosage form (e.g., transdermally, using the same vaginal ring) or, alternatively, in two different dosage forms (e.g., as two separate vaginal creams). In other aspects, the additional active agent is administered using a different mode of administration, e.g., the estrogen and/or progestin are administered transdermally, using a transdermal delivery device such as a vaginal ring, and the additional active agent, e.g., an antidepressant, is administered orally, in the form of a pill or tablet.

[0088] The dosage of the additional active agent can be determined readily by one of skill in the medical arts and will depend upon the condition or disorder to be treated, the physiological effect desired, and the mode of administration. For example, the amount of antidepressant administered with the estrogen, or with the estrogen and progestin, depending on the antidepressant used, is about 0.75 to about 2 mg/24 hours, about 10 to about 20 mg/24 hours, or about 50 to about 100 mg/24 hours. Thus, in some aspects of the invention, the estrogen and progestin are administered with about 5 mg to about 120 mg/24 hours of fluoxetine hydrochloride.

[0089] The extended cycle regimen and bridged regimen can be produced in the form of a kit or package containing one or more dosage units to be administered according to the methods of the present invention. The kit or package can contain one dosage unit, or more than one dosage unit (i.e., multiple dosage units). If multiple dosage units are present in the kit or package, the multiple dosage units can be optionally arranged for sequential administration.

[0090] For example, in some embodiments of the present invention, the kit contains about

42 or more tablets for oral administration, each tablet containing a combination of estrogen and progestin and intended for ingestion on successive days, followed by 2 to about 8 tablets ("hormone free placebo"), each tablet containing neither estrogen nor progestin and intended for ingestion on successive days. In each tablet that contains the combination of estrogen and progestin, estrogen is present in an amount equivalent to about 10 μg to about 25 μg of ethinyl estradiol, and progestin is present in an amount equivalent to about 50 μg to about 125 μg levonorgestrel. Administration is daily for at least 42 consecutive days using tablets containing both the estrogen and the progestin, followed by administration that is daily for 2 to 8 consecutive days using the hormone- free placebo tablets. For example, administration can be for 42-84 consecutive days, using tablets comprising 20 μg to 30 μg estrogen and 0.1 mg to 0.15 mg levonorgestrel, followed by administration of hormone-free placebo tablets for 2 to 8 consecutive days.

[0091] In another example, the extended cycle regimens of the present invention can be provided in kit form containing, e.g., for a 91 -day regimen, 84 tablets, each tablet containing estrogen and progestin, intended for ingestion on successive days, followed by 7 hormone-free placebo tablets, intended for ingestion on successive days.

[0092] The kits of the present invention can optionally contain instructions associated with the dosage units of the kits. Such instructions can be in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of the manufacture, use or sale for human administration to treat a condition or disorder. The instructions can be in any form which conveys information on the use of the dosage units in the kit according to the methods of the invention. For example, the instructions can be in the form of printed matter, or in the form of a pre-recorded media device.

[0093] "Printed matter" can be, for example, one of a book, booklet, brochure or leaflet.

The printed matter can describe the use of the dosage units of the kit according to the methods of the present invention. Possible formats include, but are not limited to, a bullet point list, a list of frequently asked questions (FAQ) or a chart. Additionally, the information to be imparted can be illustrated in non-textual terms using pictures, graphics or other symbols.

[0094] "Pre-recorded media device" can be, for example, a visual media device, such as a videotape cassette, a DVD (digital video disk), fϊlmstrip, 35 mm movie or any other visual media device. Alternately, pre-recorded media device can be an interactive software application, such as a CD-ROM (compact disk-read only memory) or floppy disk. Alternately, pre-recorded media device can be, for example, an audio media device, such as a record, audiocassette or audio compact disk. The information contained on the pre-recorded media device can describe the proper use of the dosage units in the kit for the treatment of one or more of the conditions or disorders as described herein, e.g., treatment of osteopenia in an adolescent female.

[0095] hi addition to instructions, the kit can optionally contain a planner. A "planner" can be, for example, a weekly, a monthly, a multi-monthly, a yearly, or a multi-yearly planner. The planner can be used as a diary to monitor dosage amounts, to keep track of dosages administered, or to prepare for future events wherein taking the dosages of the kit can be difficult. Alternately, the planner can be a calendar which will provide a means to monitor when a dosage has been taken and when it has not been taken. This type of planner will be particularly useful for patients having unusual schedules for administering medication to themselves. One skilled in the art will appreciate the variety of planning tools that would be appropriate for use with the present invention.

[0096] The kit can also include a container for storing the other components of the kit.

The container can be, for example, a bag, box, envelope or any other container that would be suitable for use in the present invention. The container can be large enough to accommodate each component and/or any administrative devices that can be necessary for use of the dosage units of the kit according to the methods of the present invention. However, in some cases, it can be desirable to have a smaller container which can be hidden in a patient's pocketbook, briefcase or pocket.

(0097] The present invention is also directed to a method of delivery of a regimen disclosed herein according to the methods of the present invention (e.g., a method of treating osteopenia) to a patient in need thereof, the method comprising (a) registering in a computer readable medium the identity of a physician permitted to prescribe the formulation; (b) providing the patient with counseling information concerning the risks attendant to the regimen; (c) obtaining informed consent from the patient to receive the regimen despite the attendant risks; (d) registering the patient in a computer readable medium after obtaining their informed consent; and (e) permitting the patient access to the regimen.

[0098] The drug delivery methods of the present invention involve, inter alia, registering in a computer readable storage medium physicians who are qualified to prescribe the regimen to be used according to the methods of the present invention. Once registered in the computer readable storage medium, the physician can be eligible to prescribe a regimen according to the methods of the invention to a patient in need thereof. Generally speaking, in order to become registered in the computer readable storage medium, the physician can be required to comply with various aspects of, for example, providing patient education and counseling. Registration of the physician in the computer readable storage medium can be achieved by providing the physician, for example, by mail, facsimile transmission, or on-line transmission, with a registration card or form, preferably together with educational materials concerning the regimen. The physician can complete the registration card or form by providing information requested therein, and the registration card or form can be returned to the manufacturer or distributor of the regimen, or other authorized recipient of the registration materials, for example, by mail, facsimile transmission or on-line transmission. The physician's information in the registration card or form is then entered into the computer readable storage medium. Suitable computer readable storage media which can be employed for registration of the physicians (as well as patients, as discussed below) will be apparent to one of ordinary skill in the art, once in possession of the teaching of the present application.

[0099] In the course of examination of a patient, the physician may determine that administration of one of the regimens of the present invention is appropriate for the patient, or the physician may determine that the patient's condition (e.g., the patient may be suffering from amenorrhea) can be improved by the administration of one of the regimens of the present invention according to the methods of the present invention. Prior to prescribing the regimen, the physician can counsel the patient, for example, on the various risks and benefits associated with the regimen. The patient can be provided full disclosure of all the known and suspected risks associated with the regimen. Such counseling can be provided verbally, as well as in written form. In some embodiments, the physician can provide the patient with literature materials on the regimen, such as product information, educational materials, and the like.

[0100] In addition to receiving counseling on the risks attendant to administration of the regimens disclosed herein, the methods of the present invention further require the patient to fill out an informed consent form which is signed by the patient. Upon the completion of the informed consent form, the patient can be registered in a computer readable storage medium. The computer readable storage medium in which the patient is registered can be the same as, or different from, the computer readable storage medium in which the physician is registered.

[0101] The registration into one or more computer readable storage media of the physician and patient, according to the methods describe herein, provides a means to monitor and authorize access to the regimen administered according to the methods of the present invention. Thus, the computer readable storage medium can serve to deny access to patients who fail to abide by the methods of the present invention. In some embodiments, access to the regimen is in the form of a prescription, wherein the prescribing physician is registered in a computer readable storage medium, has provided counseling to the patient concerning the attendant risks of the regimen, and has obtained informed consent from the patient, prior to prescribing the regimen to the patient in need thereof according to the methods of the present invention.

[0102] The present invention is also directed to methods of educating consumers about the use of the regimens of the present invention, the method comprising distributing the regimen with consumer information at a point of sale. In some embodiments, the distribution will occur at a point of sale having a pharmacist or healthcare provider.

[0103J The term "consumer information" can include, but is not limited to, an English language text, non-English language text, visual image, chart, telephone recording, website, and access to a live costumer service representative. In some embodiments, consumer information will provide directions for use of the regimens according to the methods of the present invention, appropriate age use, indication, contraindications, appropriate dosing, warnings, telephone number of website address. In some embodiments, the method further comprises providing professional information to relevant persons in a position to answer consumer questions regarding use of the disclosed regimens according to the methods of the present invention.

[0104] The term "professional information" includes, but is not limited to, information concerning the regimen when administered according to the methods of the present invention that is designed to enable a healthcare professional to answer costumer questions.

[0105] A "relevant person," includes, for example, a physician, physician assistant, nurse practitioner, pharmacist and customer service representative.

[0106] All of the various aspects, embodiments and options described herein can be combined in any and all variations. The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the below-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents. Example 1

[0107] This study will be a randomized, multicenter, double blind, placebo-controlled study designed to evaluate the effects of a 91 -day extended cycle contraceptive regimen on bone mineral density in postmenarcheal, adolescent females with secondary amenorrhea who also have osteopenia. This example provides a protocol for evaluating the effects of a 91 -day extended cycle oral contraceptive (OC) containing 84 days of 30 μg ethinyl estradiol (EE) and 150 μg levonorgestrel (LNG), followed by 7 days of placebo, on bone mineral density in postmenarcheal, adolescent females with secondary amenorrhea who also have osteopenia.

[0108] The overall study duration for each patient will be approximately 2 years (eight consecutive 91 -day extended cycles). Patients will be randomized in a 1:1 fashion to receive either 91 -day extended cycle regimen or a matching placebo. Approximately 100 patients will be randomized between the regimen and placebo, to achieve approximately 20 patients completing the 91 -day extended cycle regimen treatment arm, and 20 patients completing the placebo arm. The study will consist of a Screening Period of up to four weeks, a Randomization Visit, Study Visits at 3-month intervals following the initiation of study medication, and an End of Study Visit approximately 30 days following the last dose of study medication.

[0109] The purpose of the study will be to determine the effect of the 91 -day extended cycle combination oral contraceptive in adolescent females with secondary amenorrhea and osteopenia on:

1. lumbar spine bone mineral content (BMC) and bone mineral density (BMD);

2. proximal femur (hip) BMC and BMD;

3. total body BMC and BMD;

4. biochemical markers of bone resorption and bone formation;

5. body weight and bleeding patterns; and

6. to determine the safety and tolerability of the 91 -day extended cycle combination oral contraceptive in this population

Study Population

[0110] Sexually-naϊve postmenarcheal female patients with secondary amenorrhea who also have osteopenia and are aged 12 to less than 18 years at the time of screening who consent to participate (patient's legally authorized guardian will also provide written consent/assent), will be evaluated for eligibility during the screening period.

Description of Study Medication

[0111] Active Treatment regimen: 84 white unembossed tablets, each tablet containing

150 μg levonorgestrel/ 30 μg ethinyl estradiol, and 7 green placebo tablets in each 13- week (91 -day) cycle. The active treatment study medication will be identical in appearance to the placebo study medication. One tablet will be taken each day for 8 consecutive 91 -day cycles.

[0112] Blinded Placebo regimen: 84 white unembossed placebo tablets and 7 green placebo tablets in each 13-week (91 -day) cycle. The placebo study medication will be identical in appearance to the active treatment study medication. One tablet will be taken each day for 8 consecutive 91 -day cycles.

[0113] Regardless of treatment arm, each patient-specific kit will contain four white blister cards; each blister card will contain 13 weeks of 7 tablets each. Each blister card pack will be sealed in a foil pouch along with an oxygen absorber and will be labeled with a patient-specific label. All study medication for both treatment arms will be blinded and identical in appearance. Each sealed foiled pouch will be labeled with a 2- part double-blind label, affixed to the outside of the foil pouch, and will have the following information printed on it: protocol identification number, unique patient identification number, storage directions, caution statement required by regulations, and Sponsor identification information.

[0114] Designated study personnel will dispense all study medications. All study medication will be kept in a secured area at a temperature ranging from approximately 15-25 ⁰C (59-77 ⁰F). Patients will receive a 13-week supply (Study Medication Card 1, Cycle 1 : weeks 1 through 13) of study medication at the Randomization Visit. During subsequent visits patients will receive Study Medication Cards 2-8 (containing study medication for Cycles 2-8: weeks 14 through 26; weeks 27 through 39; . . . weeks 79 through 91 ; and weeks 92 through 104). Each blister card will be dispensed to the patient in a child-resistant pouch along with a copy of a Patient Information Sheet.

[0115] Patients will be instructed to take one tablet per day at approximately the same time each day. All patients will begin study medication at the Randomization Visit and will continue to take one tablet daily for eight (8) consecutive 91 -day cycles. Study Design

[0116] At the initial Screening Visit and prior to performing any study procedures, all patients and their legally authorized guardian will be informed of the study and will be required to sign the approved consent and assent forms for this study. Height, weight and vital signs (blood pressure and pulse) will be recorded. A complete medical history including menstrual history will be obtained and a physical examination will be performed. Patients will be queried regarding the use of all concomitant medication(s) including hormonal therapy. In addition, the following procedures will be performed:

• Bone mineral density of the lumbar spine and proximal femur will be determined using dual-energy x-ray absorptiometry (DEXA). Baseline DEXA scans will be shipped to the Central Reader for immediate analysis. Patients with osteopenia defined as posteroanterior total lumbar (L1-L4) BMD at least 2 SD below the mean of age-, race-, and weight-matched controls (z-score less than or equal to - 2) will be eligible for randomization into this study.

• Patients will complete a questionnaire (via 24-hour recall) to determine dietary calcium and Vitamin D intake, and, based on the results of this assessment, patients will receive nutritional counseling and Investigators will be permitted to supplement patients with a stable course of calcium and/or vitamin D throughout the course of the study;

[0117] The Randomization Visit will occur as soon as possible for patients whose baseline DEXA scan is consistent with BMD of lumbar spine of at least 2 SD below the mean of age-, race-, and weight-matched controls (z-score less than or equal to —2). Prior to randomizing eligible patients, clinical laboratory samples will be obtained for hematology, chemistry, lipid profile (total cholesterol and HDL-C, only), and biochemical markers of bone metabolism (Λf-telopeptide, deoxypyridinoline, bone specific alkaline phosphatase, osteocalcin, procollagen of type-I propeptide). A urine pregnancy test will also be done.

[0118] The designated member of the study team will randomize all eligible patients. All patients will initiate study medication at the Randomization Visit. As laboratory results become available, patients with any abnormality on the clinical laboratory assessment will have the test repeated and may be discontinued from participation in this study unless the Investigator determines that the results are not clinically significant and will not interfere with the conduct of this study. Each time study medication is dispensed, patients will be given a copy of a Patient Information Sheet which contains detailed information about the study medication, how to take it, and what to do if they miss pills.

[0119] Patients will be randomized in a 1:1 fashion to one of two double-blind treatment groups:

Treatment Group 1: Active regimen: levonorgestrel 150 μg and ethinyl estradiol 30 μg as a combination tablet taken for 84 days followed by placebo tablets for 7 days, in each 91 -day cycle, taken for a total of eight consecutive 91 -day cycles; and

Treatment Group 2: Placebo regimen: 91 placebo pills in each 91 -day cycle, taken for a total of eight consecutive 91 -day cycles

[0120] Regardless of treatment arm, each patient will take one pill daily. To ensure consistency of randomization to treatment arms, each site will target to randomize a minimum of 4-8 patients. Patients will be randomized sequentially to a blinded treatment arm in the order in which they meet protocol eligibility for study randomization at each clinical site. Both of the study medications will be prepared and packaged to be visually indistinguishable from one another. Blinding will be strictly maintained until completion of the study. If needed to treat a patient in a medical emergency, blinding information regarding study medication for the individual patient is immediately available to the Investigator by means of a scratch-off label.

[0121] The patient will take her first pill at the Randomization Visit and will take one pill daily thereafter for approximately two years (eight consecutive 91 -day cycles). No dosage adjustments will be allowed. Compliance will be assessed at each study visit by examination of the pill packs. Patients will receive instructions for missed doses.

[0122] Study personnel will contact the patient by telephone beginning one week following initiation of study medication to query the patient regarding compliance with study medication use, incidence of adverse events, bleeding or spotting, level of physical activity, and use of concomitant medications including calcium supplements. In addition, as laboratory results become available, any patient with any abnormality on clinically laboratory assessment will have the test repeated and may be discontinued from the study as a result (Investigator's and Sponsor's discretion). [0123] Routine study visits will be conducted at 3-month intervals following the initiation of study medication. At these visits, weight, vital signs, and compliance with study medication will be assessed and recorded and patients will be queried regarding adverse events and concomitant medication use. In addition, a urine pregnancy test will be performed and patients will complete a questionnaire (via 24-hour recall) to determine dietary calcium and Vitamin D intake. Patients will also be contacted by telephone at designated time points between routine study visits and queried regarding adverse events, incidence of bleeding or spotting, compliance with study medication, concomitant medication use, and level of physical activity. During the study, patients will be instructed to bring their study medication to each study visit.

[0124] In addition to the above, bone mineral content and bone mineral density of the lumbar spine and proximal femur will be determined by dual-energy x-ray absorptiometry (DEXA), clinical laboratory tests (hematology, chemistry, and lipid panels), and biochemical markers of bone metabolism (Λ/-telopeptide, deoxypyridinoline, bone specific alkaline phosphatase, osteocalcin, procollagen of type-I propeptide) will be measured at Month 6 (Cycle 2/Week 26), Month 12 (Cycle 4ΛVeek 52), Month 18 (Cycle βrWeek 78), and Month 24 (Cycle 8/Week 104). Biochemical markers of bone metabolism will additionally be measured at Month 3 (Cycle I/Week 13).

[0125] For patients who complete the study, an End of Study Visit will be conducted approximately 30 days following the last dose of study medication (acceptable time window is 28-35 days). At the End of Study Visit, weight, vital signs, and compliance with study medication will be assessed and recorded and patients will be queried regarding adverse events and concomitant medication use. In addition, a urine pregnancy test will be performed.

Study-Specific Procedures

[0126] Diagnostic Evaluations: Bone Mineral Density Testing: A Bone Mineral Density

(BMD) test is also referred to as bone densitometry. BMD is an important diagnostic tool that not only measures the amount of calcium in certain bones (bone mineral content) but also can be used to estimate the risk of fracture. The test is easy, fast, painless, and noninvasive. This procedure will be a dual energy X-ray absorptiometry (DEXA) scan of the lumbar spine (Ll to IA) and proximal femur (hip). DEXA is the most accurate method for measuring bone mineral content and calculating bone mineral density. Two X-ray beams are projected onto the bones. The amounts of each X-ray beam that are blocked by bone and soft tissue (bone mineral content) are compared to calculate the bone density. DEXA scanning is fast and exposes the person to very low doses of radiation. A Central Reader will analyze DEXA scans performed for each patient at each time point throughout the course of the study. The study Sponsor will provide clinical sites with instructions for obtaining, processing, and shipping DEXA scans to the Central Reader. [0127] Clinical Laboratory Assessment: Serum and Urine Bone Markers: Serum and urine bone markers include the following: (Λf-telopeptide, deoxypyridinoline, bone specific alkaline phosphatase, osteocalcin, procollagen of type-I propeptide). Instructions regarding obtaining, processing, and mailing samples to the Central Laboratory will be provided to each clinical site in a Laboratory Manual provided by the Central Laboratory.

Efficacy Evaluation

[0128] The primary efficacy endpoint will be the comparison between active and placebo treatment groups in the mean percent change in the DEXA scan lumbar spine bone mineral density from baseline (obtained at screening) to Month 12 (Cycle 4/Week 52).

[0129] Secondary efficacy endpoints will be the comparison between the active and placebo treatment groups in 1) mean percent change from baseline in lumbar spine BMD (measured at Month 6, Month 18, and Month 24), 2) mean percent change from baseline in proximal femur (hip) BMD (measured at Month 6, Month 12, Month 18, and Month 24), 3) mean percent change from baseline in total body BMD (measured at Month 6, Month 12, Month 18, and Month 24), 4) mean percent change from baseline n lumbar spine, proximal femur, and total body BMC (measured at Month 12, Month 18, and Month 24), and 5) mean change in biochemical markers of bone resorption and bone formation between baseline and Month 6, Month 12, Month 18, and Month 24. An additional secondary endpoint will be the comparison between the active and placebo treatment groups in the change from baseline to Month 6, Month 12, Month 18, and Month 24 in body weight.

[0130] Having now fully described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All documents, e.g., scientific publications, patents, patent applications and patent publications recited herein are hereby incorporated by reference in their entirety to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference in its entirety. Where the document cited only provides the first page of the document, the entire document is intended, including the remaining pages of the document.

Claims

WHAT IS CLAIMED IS:

1. A method of treating osteopenia in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

2. The method of claim 1, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by a hormone free period for 2 to 8 consecutive days, wherein neither estrogen nor progestin are administered to the adolescent female during the hormone free period.

3. The method of claim 2, wherein the hormone-free period is achieved by administering a hormone-free placebo pill or tablet.

4. The method of claim 2, wherein the estrogen and the progestin administered during the period of 42 or more consecutive days are administered for about 56 to about 112 consecutive days.

5. The method of claim 4, wherein the estrogen is administered in a daily dosage equivalent to about 10 μg to about 30 μg of ethinyl estradiol, and the progestin is administered in a daily dosage equivalent to about 0.05 mg to about 0.15 mg of levonorgestrel.

6. The method of claim 1, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days.

7. The method of claim 6, wherein the estrogen and the progestin administered for the period of 42 or more consecutive days are administered for about 56 to about 112 consecutive days.

8. The method of claim 7, wherein the estrogen and the progestin administered during the period of 42 or more consecutive days are administered for at least 84 consecutive days.

9. The method of claim 8, wherein:

(a) the estrogen that is administered with the progestin for the period of about 56 to about 112 consecutive days is administered in a daily dosage equivalent to about 10 μg to about 30 μg of ethinyl estradiol;

(b) the progestin that is administered with the estrogen for the period of about 56 to about 112 consecutive days is administered in a daily dosage equivalent to about 0.05 mg to about 0.15 mg of levonorgestrel; and

(c) the estrogen that is administered without the progestin for the period of 2 to 8 consecutive days is administered in a daily dosage equivalent to about 10 μg to about 30 μg of ethinyl estradiol.

10. The method of claim 9, wherein the estrogen in (a) is administered in a daily dosage equivalent to about 30 μg of ethinyl estradiol.

11. The method of claim 10, wherein the estrogen in (c) is administered in a daily dosage equivalent to about 10 μg of ethinyl estradiol.

12. The method of claim 10, wherein the estrogen in (c) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol.

13. The method of claim 10, wherein the estrogen in (c) is administered in a daily dosage equivalent to about 30 μg of ethinyl estradiol.

14. The method of claim 9, wherein the estrogen in (a) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol and the estrogen in (c) is administered in a daily dosage equivalent to about 10-20 μg of ethinyl estradiol.

15. The method of claim 14, wherein the estrogen in (c) is administered in a daily dosage equivalent to about 10 μg of ethinyl estradiol.

16. The method of claim 15, wherein the estrogen in (c) is administered in a daily dosage equivalent to about 20 μg of ethinyl estradiol.

17. A method of reducing loss of bone mineral density in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

18. The method of claim 17, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of a hormone free period for 2 to 8 consecutive days, wherein neither estrogen nor progestin are administered to the adolescent female during the hormone free period.

19. The method of claim 17, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days.

20. A method of increasing bone mass or bone mineral density in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

21. The method of claim 20, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of a hormone free period for 2 to 8 consecutive days, wherein neither estrogen nor progestin are administered to the adolescent female during the hormone free period.

22. The method of claim 20, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days.

23. A method of treating hypoestrogenism in an adolescent female in need thereof, the method comprising administering to the adolescent female estrogen and progestin for a period of 42 or more consecutive days.

24. The method of claim 23, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of a hormone free period for 2 to 8 consecutive days, wherein neither estrogen nor progestin are administered to the adolescent female during the hormone free period.

25. The method of claim 23, wherein the administration of estrogen and progestin for the period of 42 or more consecutive days is followed by administration of estrogen without progestin for a period of 2 to 8 consecutive days.

26. The method of claim 1, the method further comprising administering another pharmaceutically active agent to the adolescent female.

27. The method of claim 26, wherein the another pharmaceutically active agent is an antidepressant.