MXPA06003682A - Extended triphasic contraceptive regimens - Google Patents

Abstract

An extended triphasic oral contraceptive regimen is disclosed. According to the disclosed regimen, a combination of an estrogen and a progestin is administered for at least 42 consecutive days followed by a hormone-free period of from 4 to 8 days. The estrogen and progestin are administered in a contraceptively effective daily dosage for a sequence of at least two cycles of at least 21 days, wherein the estrogen dosage remains constant over each cycle and the progestin dosage increases in three phases over each cycle.

Description

Published: For two-letter codes and other abbreviations, refer to the "Guid- - with intemational search report" Notes on Codes and Abbreviations "appearing at the begin- - before the expiration of the time limit for amending the ning ofeach regular issue ofthe PCT Gazette. claims and to be republished in the event of receipt of amendments EXTENDED THREE-PHASE CONTRACEPTION REGIMES CROSS REFERENCE WITH RELATED APPLICATION This application claims the benefit in accordance with 35 U.S.C. § 119 (e) of provisional application Serial No. 60 / 507,536, filed on October 1, 2003, which is hereby incorporated in its entirety.

FIELD OF THE INVENTION The present invention relates to extended cycle oral contraceptive regimens for women of menstrual age. In particular, the present invention relates to extended multiphasic oral contraceptive regimens containing a progestin and an estrogen.

BACKGROUND OF THE INVENTION Multiphase oral contraceptive regimens that combine a progestin and an estrogen are known in the art. Usually, these combination type products are administered to increase or decrease the dosage of one or both of the components during the menstrual cycle. An oral contraceptive regimen of three-stage or three-phase combination type is marketed by Ortho-McNeil Pharmaceuticals, Inc. under the trademark ORTHO TRI-CYCLEN LO. In the first stage of this regimen, a tablet containing 25 μg of ethinyl estradiol (EE) and 0.180 mg of norgestimate (NGM) is administered for 7 days. This is followed by a second step, where a tablet containing 25 μg of ethinyl estradiol and 0.215 mg of norgestimate is administered for 7 days. In the third stage of the regimen, a tablet containing 25 μg of ethinyl estradiol and 0.250 mg of norgestimate is administered for 7 days. After completing all three stages, a placebo is administered for 7 days to allow bleeding of deprivation. Accordingly, the regimen is administered in a standard 28-day cycle to mimic the natural menstrual cycle, waiting for menstruation to occur after each period of 21 consecutive days of hormonal administration. Extended administration of contraceptive hormones (also referred to herein as "continuous administration"), where there is no hormone-free interval after the traditional 21-day hormone administration cycle, is a common practice among women who wish to delay or avoid the bleeding of deprivation. Frequently, this is done for convenience, for example, to avoid bleeding deprivation during vacation periods or to participate in sports. In addition to the convenience of delaying withdrawal bleeding, the omission of the hormone-free interval or placebo of cyclic administration reduces many menstruation-related symptoms that occur more frequently during the hormone-free interval than during the rest of the cycle. These symptoms include headaches, pelvic pain, breast tenderness, swelling and inflammation. Extended regimens for administering oral contraceptive hormones have been shown to be well tolerated and effective to prevent pregnancy and to reduce the number of periods of withdrawal bleeding experienced during the course of extended hormone administration. Although most studies on extended use of oral contraceptives have examined single-phase regimens, there has been a general lack of interest in searching busily for a three-phase oral contraceptive as an extended regimen. Those skilled in the art have reasoned that the ascending and descending progestin levels employed in the three phase model will result in unexpected bleeding which would make this model unacceptable for women who take oral contraceptives. Contrary to the reasoning that has hitherto guided the prior art, the present invention provides a safe and effective extended three-phase oral contraceptive regimen that will achieve acceptable cycle control.

BRIEF DESCRIPTION OF THE INVENTION The invention provides an extended three-phase oral contraceptive regimen comprising administering to a woman of child-bearing age a combination of an estrogen and a progestin for at least 42 consecutive days. This is followed by a hormone-free period of 4 to 8 days to allow for withdrawal bleeding. Once the hormone-free period is completed, extended hormone administration is resumed. Estrogen and progestin are administered in a daily contraceptively effective dosage during a sequence of at least two cycles of at least 21 days for a total of at least 42 consecutive days of hormonal administration. The dosage of estrogen remains constant during each cycle; however, the progestin dosage increases in all three stages or phases during each cycle. Preferably, estrogen is administered in a daily dosage equivalent to 23-28 μg of ethinyl estradiol (EE) during each cycle. Thus, for example, if a sequence of two 21-day cycles is administered for a total of 42 consecutive days of hormonal administration, the equivalent of 23-28 μg of ethinyl estradiol is administered daily for the entire 42-day period. As indicated above, the progestin dosage increases in three phases during each cycle. During a first phase, a daily dosage of progestin equivalent to 0.03-0.25 mg norgestimate (NGM) is administered. This is followed by a second phase during which a daily progestin dosage of 0.1-0.35 mg of norgestimate is administered. In a third phase, a daily dosage of progestin equivalent to 0.15-0.50 mg of norgestimate is administered. Thus, in the case where a sequence of two 21-day cycles is administered for a total of 42 days of hormonal administration, two three-phase progestin dosing regimens are provided.

The three phases of progestin administration in each cycle may have the same length or a different length. Accordingly, in one embodiment of the invention, a daily dosage of progestin equivalent to 0.03-0.25 mg of norgestimate (NGM) is administered in a first phase of 5 to 8 days. This is followed by a second phase of 7-11 days during which a daily progestin dosage of 0.1-0.35 mg of norgestimate is administered. In a third phase of 3 to 7 days, a daily dosage of progestin equivalent to 0.15-0.50 mg of norgestimate is administered. Thus, in the case where a sequence of two 21-day cycles is administered for a total of 42 days of hormonal administration, two three-phase progestin dosing regimens are provided. In the case where the progestin administration phases in a cycle are of equivalent length, each cycle extends for at least 21 days and is a multiple of 3. Thus, the invention encompasses a sequence of cycles wherein each cycle is extends for 21 days, 24 days, 27 days, 30 days, etc. Each phase of progestin administration within a cycle is determined by dividing the total days in the cycle by 3. For example, if each cycle has a length of 42 days, the progestin is administered in three phases of 14 days each. In a particularly preferred embodiment of the invention, the combination of estrogen and progestin is administered during a four-cycle sequence of 21 days for a total of 84 days of uninterrupted hormonal administration. A daily dosage of 25 μg of ethinyl estradiol is administered during each 21-day cycle, and consequently, during the entire 84-day period of hormonal administration. A four-cycle sequence of 21 days of triphasic progestin administration is provided. Each cycle includes a first phase of 7 days in which 0.180 mg of norgestimate is administered daily, followed by a second phase of 7 days in which 0.215 mg of norgestimate is administered daily., followed by a third phase of 7 days in which a daily dosage of 0.250 mg of norgestimate is administered. This dosing program is then repeated every 21 days up to 84 days. Therefore, during the full period of 84 consecutive days of hormonal administration, four three-phase norgestimate cycles are provided. The 84-day period of hormone administration is followed by a hormone-free period of 4 to 8 days to allow bleeding of deprivation, after which extended administration is resumed.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the average number of days of recurrent bleeding and / or staining during the treatment phase of the extended regimen of the study described in example 1; and Figure 2 illustrates the percentage of subjects with bleeding and / or spotting during days 1 to 140 of the study described in example 1.

DETAILED DESCRIPTION OF THE INVENTION As indicated above, multiphasic oral contraceptives have not been used for extended hormonal administration. In the particular case of triphasic oral contraceptives, those skilled in the art have reasoned that the stepped levels of progestin and downstream employed in the triphasic model will result in bleeding unexpected, thus making an extended triphasic regimen unacceptable to women taking oral contraceptives. The present invention is based on the reasoning that the critical element for cycle control with an oral contraceptive is a stable dose of estrogen, while progestin provides the main contraceptive effect through the inhibition of ovulation, thickened cervical mucus and an atrophic endometrium Progestin, norgestimate, has been studied extensively. It is a progestin with a high affinity for endometrial progesterone receptors and low androgenicity, reflected by its relative lack of binding to androgen receptors and minimal effect on levels of sex hormone binding globulin (SHBG). It is also referred to in the art as a "conservative endometrium" progestin because in animal models the endometrium remains relatively thick and supported compared to other more androgenic progestins. In the ovariectomized rat, norgestimate maintains pregnancy as well as progesterone.

In the clinical setting, there is no difference in endometrial thickness between oral contraceptives containing monophasic and triphasic norgestimate. Oral contraceptives containing norgestimate appear to have less endometrial suppression than other oral contraceptive progestins such as desogestrel and levonorgestrel. Based on these properties, it has been speculated that norgestimate may contribute to improved cycle control in women. In the case of a three-phase regime with a daily dosage of 25 ug of ethinyl estradiol with norgestimate, the advantages are twofold: a total exposure reduced to ethinyl estradiol and norgestimate, as compared to a mofásico providing a daily dosage of 35 mg of ethinyl estradiol. In addition to providing cycle control, the pharmacological profile of norgestimate offers other benefits such as a progestin, especially, low androgenicity and a good metabolic and coagulation profile. For these reasons, the single-arm study described in Example I was carried out to test the bleeding profile and patient satisfaction with an extended three-phase oral contraceptive regimen. The study established that this regimen does not result in reduced cycle control, ie, increased bleeding and recurrent staining, where the progestin dose is executed in phases while the daily dose of ethinyl estradiol remains constant at 25 μg throughout the extended period of hormonal administration.

EXAMPLE I Overview of Study Design This is an open label study evaluating the bleeding profile of ORTHO TRI-CYCLEN LO (available from Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) given in an extended regimen, following a traditional regimen ORTHO TRI-CYCLEN LO. Approximately 50 female subjects were registered. All subjects received ORTHO TRI-CYCLEN LO in a traditional regimen of two 28-day cycles. After the treatment phase of the traditional regimen, all subjects received ORTHO TRI-CYCLEN LO in a treatment phase of the extended regimen, which consists of 84 days of treatment with ORTHO TRI-CYCLEN LO. The treatment phase of the traditional regimen consisted of two cycles of ORTHO TRI-CYCLEN LO administered as follows: 180 μg NGM / 25 μg EE taken daily for a week (7 days), followed by 215 μg NGM / 25 μg EE taken daily for one week (7 days), followed by 250 μg NGM / 25 μg EE taken daily for one week (7 days), followed by placebo taken daily for one week (7 days) ). After the treatment phase of the traditional regimen, subjects received ORTHO TRI-CYCLEN LO given in an extended regimen, which is defined as: 180 μg of NGM / 25 μg of EE, taken daily for a week (7 days), followed by 215 μg NGM / 25 μg EE taken daily for one week (7 days), followed by 250 μg NGM / 25 μg EE taken daily one week (7 days). This sequence was repeated three more times for a total of 84 days. The treatment phase of the extended regimen was followed by one week (7 days) without medication. The subjects were women of 18-45 years of age, in good health and postmenarcheal / premenopausal. The subjects did not have a history or presence of commonly accepted disorders as contraindications for steroidal hormone therapy. Subjects were treated at a screening visit up to 28 days before dosing for a physical examination, gynecological examination (including a breast exam), medical history, and vital signs. In addition, a Papanicoiau rub at the screening visit was performed unless a Pap smear was performed in the previous 6 months that showed no evidence of dysplasia or malignancy. Subjects who met the eligibility criteria for this study returned to visit 2, which was scheduled up to 7 days (day -7 to day 1, defined as the first day the study medication was taken) before the expected start of her next menstruation. In this visit, the vital signs of the subjects were taken, a pregnancy test was performed (to occur no more than 7 days before the administration of the first dose of the medication), adverse events were recorded and diaries were delivered and the study medication. Subjects were instructed to start their study medication on the first day of their next menstruation. Urine pregnancy tests were administered to all subjects at visits 2, 3, 4 and 5. The subjects returned for visit 3 between days 50-56. All procedures of visit 2 were repeated. In addition, subjects received four 28-day dialpaks (eliminating the 7 tablets of inert medication) as well as a backup dialpak for replacement medication. The subjects returned for visit 4 between days 88-94. All procedures of visit 3 were repeated. (Subjects received another backup dialpak when necessary). The final visit (visit 5) occurred between days 141-147. All subjects underwent a physical examination, gynecological examination (including a chest examination), and vital signs. All unused study medication and subjects' diaries were collected and reviewed. The subjects and the principal investigator also completed a global evaluation. The questionnaires of treatment satisfaction and quality of life of the subjects were administered in visit 3, and in the final visit.

Efficacy assessments Subjects were given a diary to record the bleeding data. The number of pads, tampons, and pantiliners used was recorded on their daily cards.

Subjects were given validated quality of life (QOL) questionnaires SF12 and MHI-5. SF12 consists of 12 elements from which scores are derived for the following domains: physical functioning, physical function, body pain, general health, vitality, social functioning, emotional function, mental health. The MHI-5 consists of 5 elements from which the score for a domain, mental health, is derived. Subjects were also provided with a validated treatment satisfaction questionnaire which includes evaluations of various aspects of satisfaction with hormonal contraceptive methods. The investigator in charge of the study and each subject provided an overall evaluation of the treatment phase of the extended regimen. The rating scale for the final evaluation by the researcher and the subject includes excellent, good, fair or poor.

Efficacy criteria The following definitions were used in the evaluation of effectiveness criteria: Bleeding: vaginal bleeding requiring sanitary protection of at least one pad or tampon per day. Stained: vaginal bleeding that does not require sanitary protection (the use of pantyhose is acceptable) Day of bleeding: a day in which bleeding is registered.

Spotting day: a day in which only spotted is recorded. If spotting and bleeding occur on the same day, bleeding is the dominant event and the day should be recorded as a bleeding day. Day without bleeding: a day in which no bleeding or spotting is recorded. Bleeding / spotting episode: any set of one or more consecutive days of bleeding or spotting linked by days without bleeding. Bleeding and / or recurrent staining: bleeding or spotting during the drug administration interval of the study that is not continuous with bleeding or drug-free staining of the previous cycle, or continuous without interruption in the drug-free interval. Day 1: the first day with study medication. The main efficacy variables are the number of days of bleeding and / or spotting and the number of bleeding days for specified time intervals within 84 days of the extended regimen. In particular, the final point of interest is the comparison of bleeding / spotting between week 3 and week 4; week 6 and week 7; and week 9 and week . It is during these weeks that the subject will experience a decrease in the highest to the lowest dose of progestin.

Safety assessments The following safety assessments will be conducted during the study to measure the safety and tolerability of ORTHO TRI-CYCLEN LO: Adverse events: (EA): The EAs were reported by the subject (or when appropriate by the legally authorized representative of the subject) during the study. Urine pregnancy test: The subjects were given a urine pregnancy test no more than 7 days before the administration of the first dose of the study medication. The subjects underwent a urine pregnancy test at each visit, after visit 1. Any persistent clinically important abnormalities at the end of the study were followed until resolution, or until reaching a clinically stable endpoint.

Termination A subject was considered to have finished the study if he arrived at day 147 of the study. Subjects who withdrew from the study for any reason before completing the treatment phase of the extended regimen were not considered to have completed it.

Results of the study Figure 1 illustrates the average number of days of bleeding and / or recurrent staining in the transition between consecutive cycles during the treatment phase of the extended regimen. It is in these transitions where the most important change in progestin dosage occurs, that is, the dosage of norgestimate was reduced from 250 μg per day in the third week of a previous cycle to 180 μg per day in the first week of the next consecutive cycle. According to the understanding of those skilled in the art, it is in the transition between consecutive cycles where the most important amount of bleeding and / or spotting occurs. The data presented in Figure 1 unexpectedly show that this is not the case. A significant increase in the average number of days of recurrent bleeding and / or spotting occurred only during the transition from the first cycle to the second cycle in the treatment phase of the extended regimen. No significant change occurred in the average number of days of spotting and / or bleeding during the transition from the second to the third cycle, or during the transition from the third to the fourth cycle in the treatment phase of the extended regimen. Figure 2 illustrates the percentage of subjects with bleeding and / or spotting during the 1 to 140 of the study. The data in figure 2 show that the large peak in bleeding and / or recurrent staining that occurs in the third week of each cycle administered in the treatment phase of the traditional regimen is not present during transitions between cycles administered in the phase of treatment of the extended regime.

Claims (5)

NOVELTY OF THE INVENTION CLAIMS

1. - A method of contraception comprising the steps of: administering to a woman of child-bearing age a combination of an estrogen and a progestin for at least 42 consecutive days followed by a hormone-free period of 4 to 8 days, said estrogen and progestin being administered in a daily contraceptively effective dosage during a sequence of at least two cycles of at least 21 days, wherein the dosage of estrogen remains constant during each cycle and the dosage of progestin increases in all three phases during each cycle.

2. The method according to claim 1, further characterized in that for each cycle, the estrogen is administered in a daily dosage equivalent to 23-28 μg of ethinyl estradiol, and the progestin is administered in a first phase in a daily dosage equivalent to 0.03-0.25 mg of norgestimate, followed by a second phase in a daily dosage equivalent to 0.1-0.35 mg of norgestimate, followed by a third phase in a daily dosage equivalent to 0.15-0.50 mg of norgestimate.

3. The method according to claim 1, further characterized in that each phase is of equal length.

4. - The method according to claim 2, further characterized in that the estrogen and progestin are administered in a sequence of four cycles of 21 days for a total of 84 days of uninterrupted administration of estrogen and progestin.

5. The method according to claim 4, further characterized in that for each cycle of 21 days, 25 μg of ethinyl estradiol is administered daily, and 0.180 mg of norgestimate is administered daily in a first phase of 7 days, followed by 0.215 mg of norgestimate administered daily in a second phase of 7 days, followed by 0.250 mg of norgestimate administered daily in a third phase of 7 days.