AU759925B2

AU759925B2 - Oral contraceptive preparation having a first phase comprising progestin/estrogen and a second phase comprising progestin

Info

Publication number: AU759925B2
Application number: AU92286/98A
Authority: AU
Inventors: Michael Jay Gast
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 1997-09-12
Filing date: 1998-09-09
Publication date: 2003-05-01
Anticipated expiration: 2018-09-09
Also published as: CN1270521A; AU9228698A; CA2301162A1; JP2001516720A; EP1011681A1; WO1999013882A1

Description

WO 99/13882 PCT/US98/18850 ORAL CONTRACEPTIVE PREPARATION HAVING A FIRST PHASE COMPRISING PROGESTIN/ESTROGEN AND A SECOND PHASE COMPRISING PROGESTIN BACKGROUND OF THE INVENTION The vast majority of oral contraceptives consist of a combination of a progestin and estrogen that are administered concurrently for 21 days followed either by a 7 day pill free interval or by the administration of a placebo for 7 days in each 28 day cycle.

The most important aspects of a successful oral contraceptive product are effective contraception, good cycle control (absence of spotting and breakthrough bleeding and occurrence of withdrawal bleeding), and minimal side effects. Combination oral contraceptives have traditionally acted by suppression of gonadotropins. In addition, it appears that the progestin component is primarily responsible for contraceptive efficacy through inhibition of ovulation, and other peripheral effects which include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). The estrogenic component intensifies the anovulatory effect of the progestin, and is also important for maintaining cycle control.

Since the introduction of oral contraceptives (OCs) over a quarter-century ago, research has been directed toward developing preparations that minimize the potential for side effects while maintaining efficacy and normal menstrual patterns. The firstgeneration OCs contained more progestin and estrogen than was necessary to prevent conception. Adverse hemostatic and metabolic changes, clinical problems, and side effects were associated with these high-dose preparations. In 1978, the World Health Organization (WHO) recommended that the focus of OC research should be the development of products containing the lowest possible dose levels of estrogen and progestin.

The first reductions in steroid content in a combination pill were focused on estrogen because it, rather than progestin, was thought to be related to the most serious side effects. Reduction in progestin content followed, as evidence mounted that lowering progestin intake might lower the risk of cardiovascular complications such as stroke and ischemic heart disease. [Kay CR, Am J Obstet Gynecol 142:762 (1982)].

However, this evidence was not as clear as that implicating estrogen in thromboembolic disorders. [Inman WHW, Br Med J 2:203 (1970); Stolley PD, Am J Epidemiol 102:197 (1975)]. The need for a balance between estrogens and progestins to minimize adverse effects on carbohydrate metabolism and on lipid and lipoprotein levels was also recognized. [Bradley DD, N Engl J Med 299:17 (1978); Wynn V, Lancet 1:1045 (1979)]. Researchers then found that the synergistic action between progestin and WO 99/13882 PCT/US98/18850 -2estrogen in a balanced ratio successfully inhibited ovulation at low levels of both components.

Research into low-dose progestins was advanced significantly by the development of norgestrel (Ng) and levonorgestrel (LNg). Levonorgestrel is the biologically active moiety of racemic norgestrel. It is strongly progestational, has no inherent estrogenic activity, is antiestrogenic, and possesses good biologic activity.

The contraceptive effects of levonorgestrel are manifested throughout the hypothalamicpituitary-gonadal-target organ axis.

Ethinyl estradiol (EE) is the estrogen most frequently used in combination OCs.

In attempts to fulfill the WHO objective, the dosage of EE in marketed OC formulations has been steadily reduced from that found in earlier OCs. Thromboembolic mortality decreased when the amount of synthetic estrogen in OC formulations was reduced from 100 pg to 50 pg. Subsequently, a significant reduction in fatal myocardial infarctions was reported for women using OCs with 30 pg of EE rather than 50 pg of EE. [Meade TW, Br Med J 280:1157 (1980)].

In keeping with the goal of reducing the total steroidal dosage, while maintaining contraceptive efficacy, good cycle control, and minimizing side effects, numerous regimens have been developed in which the progestin/estrogen combination is administered either as a fixed dosage combination (monophasic) or as biphasic or triphasic regimens in which the dosage of the combination is varied either once or twice throughout the menstrual cycle. In these regimens, the progestin/estrogen combination is typically administered for 21 days followed by either a 7-day pill free period or the administration of a non-contraceptive placebo (or iron supplement) for 7 days. In these regimens, 3-ketodesogestrel (3-KDSG), desogestrel (DSG), levonorgestrel (LNg), gestodene (GTD), norgestrel and norethindrone (NE) are typically used as the progestin while ethinyl estradiol 17p-estradiol, and mestranol are typically the estrogenic components.

Several examples of attempts at reducing the total steroidal dosage by using bridged or 24-day regimens are provided below.

De Jager (European Patent Application 368,373 A) discloses 22-30 day bridged regimens consisting of the administration of 20-22 (preferrably 21) days of a progestin/estrogen combination followed by 2-10 (preferrably 7) days of a progestin.

Specifically disclosed regimens include a combination of 150 .jg DSG and 2.0 mg 17p-estradiol for 21 days, followed by 30 pg desogestrel for 7 days; a combination of 150 tg DSG and 30 gg EE for 21 days, followed by 30 ug desogestrel for 7 days; a combination of 50 p.g DSG and 3 mg 17p-estradiol for 7 days, followed by a WO 99/13882 PCT/US98/18850 -3combination of 150 ig DSG and 2 mg 17p-estradiol for 14 days, followed by 30 ug DSG for 7 days; a combination of 50 gg DSG and 35 lg EE for 7 days, followed by a combination of 150 gg DSG and 30 gg EE for 14 days, followed by 30 pg DSG for 7 days; a combination of 50 gg DSG and 3 mg 17p-estradiol for 7 days, followed by a combination of 100 gg DSG and 2 mg 17p-estradiol for 7 days, followed by a combination of 150 gg DSG and 1.5 mg 17p-estradiol for 7 days, followed by 30 gg DSG for 7 days; a combination of 50 lg DSG and 3 mg 173estradiol for 7 days, followed by a combination of 100 pg DSG and 2 mg 17p-estradiol for 7 days, followed by a combination of 150 gg DSG and 1.5 mg 17p-estradiol for 8 days, followed by 30 pg DSG for 6 days; a combination of 50 g LNG and 2 mg 17p-estradiol for 11 days, followed by a combination of 150 g LNG and 2 mg 173estradiol for 11 days, followed by 125 jig LNg for 2 days; and a combination of ig LNG and 2 mg 17p-estradiol for 6 days, followed by a combination of 75 g LNG and 2.5 mg 17p-estradiol for 5 days, followed by a combination of 125 gg LNG and 2 mg 17p-estradiol for 10 days, followed by 70 gg LNg for 2 days, followed by 50 jig LNg for 2 days.

Endrikat (PCT Publication WO 97/23228) discloses bridged regimens consisting of the squential administration of an ovulation inhibiting dose of a progestin for at least 28 days and a natural estrogen during the last 5-10 days of the at least 28 day sequential administration. A preferred contraceptive kit consists of 28 daily dosage units with a first phase having 18-23 daily dosage units of a progestin and a second phase having 5-10 daily dosage units of a prigestin in combination with a natural estrogen. Specific disclosed regimens include: administration of 100 gg LNg for 28 days, with 2.5 mg 17p-estradiol concomitantly adminsistered for the last 10 days of the 28-day administration; administration of 100 jig LNg for 28 days, with 2.5 mg 17p-estradiol concomitantly adminsistered for the last 8 days of the 28-day administration; administration of 100 gg LNg for 56 days, with 2.5 mg 173estradiol concomitantly adminsistered for the last 10 days of the 56-day administration; administration of 100 glg LNg for 84 days, with 2.5 mg 17p-estradiol concomitantly adminsistered for the last 10 days of the 84-day administration; and equivalent regimens using 75 ag GTD as the progestin.

Erlich (German Patent DE 4,104,385 Cl and U.S. Patent 5,280,023) discloses sequential contraceptive regimens consisting of the administration of an estrogen which effects a disturbance of follicle stimulation, followed by the administration of a combination of a progestin/estrogen in a dose at least adequate to inhibit ovulation.

The regimen is administered for a total of 28 days per cycle. It is preferred that the estrogen is administered for 5-14 days per cycle and the progestin/estrogen combination WO 99/13882 PCT/US98/18850 -4is administered for 23-14 days per cycle, so that the total administration is for 28 days per cycle. Specific regimens include 4 mg estradiol for 7 days followed by 21 days of the combination of 1 mg norethisterone acetate and 4 mg estradiol; 2 mg estradiol valerate for 7 days followed by 21 days of the combination of 2 mg chlormadinone acetate and 4 mg estradiol valerate; and 20 gg EE followed by 18 days of the combination of 150 glg LNg and 20 jg EE. Regimen in Erlich provides a total steroidal load of 2.7 mg of LNg and 560 jlg EE per 28 day cycle.

Lachnit (PCT Publication WO 95/26730) discloses bridged regimens consisting of the administration of a combination of a progestin/estrogen combination (50 125 lg LNg and 10 40 jgg EE) for the first 23-24 days of the menstrual cycle followed by the administration of an estrogen (2 40 glg EE) for 4-10 days for a total administration of at least 28 days per cycle. The use of 100 300 gg drospirenone and 10 40 gg EE as the 23-24 day progestin/estrogen combination is disclosed. Lachnit also discloses a triphasic plus bridging regimen (4-9 days, 4-9 days, 9-13 days, and 28 days for the three phases and estrogen phase, respectively) in which a combination of 50 gg LNg and 20 gg EE are administered in the first phase, a combination of 75 lg LNg and gg EE are administered in the second phase, a combination of 100 glg LNg and 20 jg EE are administered in the third phase, and 10 gg EE is administered in the estrogen phase. Other progestins disclosed include GTD, DSG, 3-KDSG, DRSP, cyproterone acetate, norgestimate, and norethisterone.

Moore (DE 4313926 Al) discloses bridged triphasic regimens consisting of the administration of a combination of 10 50 Lg LNg and 5 20 Lg EE from days 1-7 of the menstrual cycle; of 50 75 gg LNg and 5 20 gg EE from days 8-14 of the menstrual cycle; of 75 125 gg LNg and 5 20 jg EE from days 15-21 of the menstrual cycle; and 5 20 gg EE from days 22-28 of the menstrual cycle.

Spona Patent 5,583,129 and PCT Publication WO 95/17194) discloses contraceptive regimens which consist of the administration of a combinaton of a progestin (50 75 gg GTD, 75 125 jig LNg, 60 150 jg DSG, 60 150 jg 3- KDSG, 100 300 g DRSP, 100 200 gg cyproterone acetate, 200 300 gg norgestimate, or >350 750 jlg norethisterone) and an estrogen (15 20 gg EE or 2 6 mg 17P-estradiol) for 23-24 days per cycle.

Upton (EP Patent Specification 253,607 B1) teaches the use of low dose progestin/estrogen combinations for combined hormone replacement therapy and contraception in climacteric women. Climacteric women are defined in Upton as premenopausal women around 40 years of age whose hormone levels are waning. The climacteric woman still ovulates (albeit may have irregular ovulation), but she still experiences many of the symptoms of the hypoestrogenic menopausal woman, such as WO 99/13882 PCT/US98/18850 insomnia, hot flushes, and irritability. Upton teaches the administration of a 23-26 day monophasic regimen of progestin/estrogen followed by a pill free or placebo interval of days; with 24 days of progestin/estrogen administration followed by a 4-day pill free or placebo administration being preferred. Upton teaches the use of a progestin selected from 25 100 gig LNg, 10 70 gg GTD, 25 100 tg DSG, 25 100 gg 3- KDSG, and 85 350 gjg NE used in combination with an estrogen selected from 500 2000 gig 17-estradiol, 8 30 gLg EE, and 15 60 gg mestranol. Based on relative potencies, Upton teaches that a dose of 75 gg LNg is equivalent to 35 pLg of GTD, gg of 3-KDSG or DSG, and 250 gg NE and that a dose of 1000 jtg of 17p-estradiol is equivalent to a dose of 15 gig EE and 30 gjg mestranol. Upton also teaches that NG may be substituted for LNg, but at twice the dose.

Bergink Patent 5,262,408) discloses a 24 day triphasic combination regimen in which the first 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 100 jg DSG and an estrogen at a daily dosage equivalent to 25 gg EE, the second 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 125 gg DSG and an estrogen at a daily dosage equivalent to jig EE, and the third 7-9 day phase consists of the administration of a progestin at a daily dosage equivalent to 50 gg DSG and an estrogen at a daily dosage equivalent to gg EE. It is preferred that the three phases be 8 days each. Following the 24 day contraceptive steroid administration, a placebo may be administered for 4 days, the 4 day interval may be pill free, or a progestin at a dosage equivalent to 25-35 glg DSG may be administered.

DESCRIPTION OF THE INVENTION This invention provides a progestin bridged combination progestin/estrogen oral contraceptive regimen for females of child-bearing age that provides effective contraception, good cycle control, and minimal side effects while greatly reducing the total contraceptive steroid administered per 28-day cycle. To achieve the substantial reduction in the total contraceptive steroid administered per cycle while maintaining good cycle control, the low dose progestin/estrogen combination is administered for 23per cycle followed by the administration of a progestin for the remaining days of the cycle. Administration of the contraceptive progestin/estrogen combination is begun on the first day of menses (day and continued for 23-25 consecutive days.

Following the 23-25-day administration period, a progestin is administered for 3-5 days to assist in maintaining good cycle control. The total administration during each cycle is 28 days.

WO 99/13882 PCT/US98/18850 -6- More particularly, this invention provides a method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent in progestational activity to 40-150 jtg levonorgestrel and an estrogen at a daily dosage equivalent in estrogenic activity to 10-20 gLg ethinyl estradiol for 23-25 days beginning on day 1 of the menstrual cycle. Following the 23period, a progestin at a daily dosage equivalent to 10-100 gg levonorgestrel is administered for 3-5 days. The total administration during each cycle is 28 days.

Preferred progestins include, but are not limited to levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone. It is more preferred that the progestin is levonorgestrel. When levonorgestrel is used as the progestin during the first 23-25 days of the cycle, it is preferred that the daily dosage of levonorgestrel is 30-150 pg, with 50-100 jg being more preferred, and 90 jg being most preferred. When levonorgestrel is used as the progestin during the last 3-5 days of the cycle, it is preferred that the daily dosage be 10-100 g, with 20-50 ug levonorgestrel being more preferred, and 37.5 gg most preferred. Preferred dosages of the preferred progestins are provided in the table below.

PREFERRED DAILY DOSAGE RANGES Progestin First 23-25 Cycle Days Last 3-5 Cycle Days Levonorgestrel 30-150 gg 10-100 jig Norgestrel 60-300 g 20-200 g Desogestrel 45-225 glg 15-150 gg 3-Ketodesogestrel 45-225 jg 15-150 gg Norethindrone 200 g 1 mg 65-650 Lig Norethisterone Acetate 200 g 1 mg 65-650 lig Gestodene 20-115 lig 7.5-75 gg Norgestimate 75-375 jlg 25-250 Lg Osaterone 250 gg 2.5 mg 100 gg 1.5 mg Trimegestone 75-375 ag 25-250 gg Dienogest 500 jg 3.75 mg 100 g 2.5 mg Drospirenone 500 glg 3.75 mg 100 gg 2.5 mg Cyproterone Acetate 450 gg 2.5 mg 150 gg 1.5 mg WO 99/13882 PCT/US98/18850 -7- Preferred estrogens include, but are not limited to ethinyl estradiol; 173estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol; with ethinyl estradiol being more preferred. When ethinyl estradiol is used as the estrogen the preferred daily dosage is 10-20 pLg, with 15 ltg being more preferred. When 173estradiol is used as the estrogen, it is preferred that the daily dosage of 173-estradiol is 1-3 lg. Preferred salts of estrone include, but are not limited to the sodium and piperate salt. When conjugated estrogens, USP are used as the estrogen, it is preferred that the daily dosage is 0.3-5 mg, with a daily dose of 1.25 mg conjugated estrogens, USP being equivalent to a daily dose of 15 jig ethinyl estradiol.

It is preferred that the progestin/estrogen combination be administered for 24 days beginning on day 1 of the menstrual cycle, and following this 24-day period, it is preferred that the progestin be administered for 4 days.

The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are preferred for contraception when administered for 23-25 consecutive days beginning on the first day of menses, followed by the administration of levonorgestrel for 3-5 days. The total administration during each cycle is 28 days.

Regimen

A

B

C

D

E

F

G

H

I

J

K

L

PREFERRED DAILY DOSAGES First 23-25 Cycle Days Last 3-5 Cycle Days Levonorgestrel Ethinyl Estradiol Levonorgestrel 100 lg 15 gg 20-50 Lg 90 glg 15 gg 20-50 .tg 75 gg 15 jg 20-50 Lgg 60 gg 15 gg 20-50 Lgg 50 gg 15 gg 20-50 gg 40 gg 15 gg 20-50 jg 100 gg 10 g.g 10-40 gg 90 Lg 10 gg 10-40 lgg 75 jg 10 Lg 10-40 gg 60 gg 10 gg 10-40 g 50 glg 10 gg 10-40 jg 40 gg 10 Lg 10-40 gg The following daily dosages of a combination of levonorgestrel and ethinyl estradiol are more preferred for contraception when administered for 24 consecutive days beginning on the first day of menses, followed by the administration of WO 99/13882 PCT/US98/18850 -8levonorgestrel for 4 days. The total administration during each cycle is 28 days. Of the regimens listed below, Regimens M-O are more preferred, with Regimen N being most preferred.

MORE PREFERRED DAILY DOSAGES First 24 Cycle Days Last 4 Cycle Days Regimen Levonorgestrel Ethinyl Estradiol Levonorgestrel M 75 g.g 15 gg 37.5 gg N 90 .g 15 gig 37.5 .tg O 100 gg 15 jg 37.5 Rg P 50 g 10 jg 25 Ig Q 60 g 15 Lg 37.5 tg R 75 ug 10 lg 25 ug S 40 Lg 15 Lg 37.5 ug For administration during the first 23-25 days of the menstrual cycle, it is preferred that the combination progestin/estrogen contraceptive be administered in unit dosage form tablet or pill, with each unit providing the entire daily dosage. It is preferred that the progestin and estrogen are admixed together in the same dosage unit.

Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the contraceptively active progestin and estrogen are combined with excipients, vehicles, pharmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable composition of a contraceptive progestin/estrogen combination of this invention.

EXAMPLE 1 Levonorgestrel, 75 gg Ethinyl estradiol, 15 gg Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF Magnesium Stearate Opadry Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP Wax E (Pharma) WO 99/13882 PCT/US98/18850 -9- For administration during the last 3-5 days of the menstrual cycle, it is preferred that the progestin be administered in unit dosage form tablet or pill, with each unit providing the entire daily dosage. Such dosage units can be prepared by conventional methodology that is well known to one skilled in the art. In each dosage unit, the estrogen is combined with excipients, vehicles, pharmaceutically acceptable carriers, and colorants. For example, the following illustrates an acceptable estrogen composition of this invention.

EXAMPLE 2 Levonorgestrel, 37.5 pg Microcrystaline Cellulose Lactose, NF, Spray Dried Polacrillin Potassium, NF Magnesium Stearate Opadry Pink Polyethylene Glycol, 1500, Flakes Water, Purified, USP Wax E (Pharma) This invention also provides a contraceptive kit adapted for daily oral administration which comprises a total of 28 separate dosage units. In this kit, 23-25 dosage units each consisting of a combination of progestin at a daily dosage equivalent in progestational activity to 30-150 gig levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 gg ethinyl estradiol. The remaining 3-5 dosage units contain an progestin at a daily dosage equivalent to 10-100 gg levonorgestrel. The daily dosage arrangements are preferably arranged in a blister pack or in a dial pack type tablet dispenser. Specific referred progestins and estrogens and the specifically preferred dosages of each combination dosage unit are described above.

9A Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, integers or process steps.

The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

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Claims

1. A method of contraception which comprises administering to a female of child bearing age a combination of a progestin at a daily dosage equivalent to

30-150 jig levonorgestrel and an estrogen at a daily dosage equivalent to 10-20 gg ethinyl estradiol for 23-25 days per menstrual cycle beginning on day 1 of the menstrual cycle; wherein the same dosage of the progestin and estrogen combination is administered in each of the 23-25 days, followed by the administration of a progestin at a daily dosage equivalent to 10-100 gg levonorgestrel for 3-5 days; wherein the same dosage of the progestin is administered in each of the 3-5 days; such that the number of days of administration of the progestin and estrogen combination plus the number of days of administration of progestin is equal to 28 per menstrual cycle. 2. The method according to claim 1, wherein the combination of progestin and estrogen is administered for 24 days per menstrual cycle beginning on day 1 of the menstrual cycle, followed by the administration of progestin for 4 days per menstrual cycle. 3. The method according to claim 1 or 2, wherein the progestin is selected from the group consisting of levonorgestrel, norgestrel, desogestrel, 3-keto- desogestrel, norethindrone, gestodene, norethisterone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, and drospirenone. 4. The method according to claim 1, 2 or 3, wherein the estrogen is selected from the group consisting of ethinyl estradiol; 17p-estradiol; conjugated estrogens, USP; estrone or a salt thereof; and mestranol. The method according to any one of claims 1 to 4, wherein the progestin is levonorgestrel. 6. The method according to any one of claims 1 to 5, wherein the estrogen is ethinyl estradiol. 7. The method according to any one of claims 1 to 6, wherein levonorgestrel and ethinyl estradiol are administered for 24 days per menstrual cycle beginning on day 1 of the menstrual cycle, followed by the administration of levonorgestrel for 4 days per menstrual cycle. WO 99/13882 PCT/US98/18850 -11- 8. The method according to claim 7, wherein the daily dosage of levonorgestrel administered during the first 24 days of the menstrual cycle is 100 gig and 20-50 g.g during the last 4 days of the menstrual cycle. 9. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 90 gig; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 15 gig; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 pg. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 75 jig; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 15 gjg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 pLg. 11. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 100 jg; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 15 glg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 gig. 12. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 50 lAg; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 10 g.g; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 25 g. 13. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 60 gg; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 15 jtg; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5 lgg. 14. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 75 glg; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 10 jig; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 25 lg. The method according to claims 7 or 8, wherein the daily dosage of levonorgestrel in the combination that is administered for 24 days is 40ug; the daily dosage of ethinyl estradiol in the combination that is administered for 24 days is 15ug; and the daily dosage of levonorgestrel that is administered for 4 days following the 24-day combination is 37.5ug. 16. A method according to claim 1 substantially as hereinbefore described with reference to anyone of the Examples. 17. A dosage unit containipg a combination of progestin at a daily dosage equivalent to 30-150 plg levonorgestrel and estrogen at a daily dosage equivalent in estrogenic activity to 10-20 pg ethinyl estradiol, substantially as hereinbefore described with reference to the Examples. 18. A dosage unit containing a progestin and at a daily dosage equivalent to 10-100 jig levonorgestrel substantially as hereinbefore described with reference to the Examples. DATED: 28 February 2003 PHILLIPS ORMONDE FITZPATRICK Attorneys for: Wyeth Attrnys or 3 sped (28.1.03) (last page).doc