The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids

Patients taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine together with their oral contraceptive steroid may suffer contraceptive failure because of the enzyme-inducing properties of these anticonvulsants. We have examined, in six women, the effect of sodium valproate, an effective broad spectrum anticonvulsant, on the area under the plasma concentration versus time profile (AUC) of ethinyloestradiol (EE2) and levonorgestrel (Ng). Prior to sodium valproate therapy the mean AUC for EE2 was 880 +/- 109 pg/ml X h (+/- S.E.) and for levonorgestrel it was 29.1 +/- 2.9 ng/ml X h (n = 4). Between two and four months after sodium valproate therapy the mean AUC figures had not changed significantly, the figure for EE2 being 977 +/- 130 pg/ml X h and for levonorgestrel 29.2 +/- 1.9 ng/ml X h (p greater than or equal to 0.1 in each case). We conclude that sodium valproate in the dose used (200 mg b.d.) does not interact with oral contraceptive steroids.     

The effect of cotrimoxazole on oral contraceptive steroids in women

Nine women taking long-term oral contraceptive steroids (Trinordiol) were studied during a cycle while taking cotrimoxazole (1 gm twice daily) and the results were compared to the previous control cycle. During the cotrimoxazole cycle, there was a significant increase in the plasma concentration of ethynylestradiol (EE). In plasma samples taken on 4 successive days 10-12 hours after dosing, the plasma EE concentration rose from 29.3 +/- 5.0 pg/ml to 38.2 +/- 5.8 pg/ml (mean +/- S.E. P less than or equal to 0.02). In samples taken 24 hours after dosing, the increase was from 18.9 +/- 2.5 pg/ml to 27.8 +/- 4.0 pg/ml (P less than or equal to 0.05). Plasma F.S.H. values in these latter samples, decreased from 4.8 +/- 0.6 mIu/ml to 3.4 +/- 0.5 mIu/ml (P less than or equal to 0.01). No significant changes were noted in the plasma concentrations of levonorgestrel or progesterone. The rise in plasma concentration of EE during cotrimoxazole therapy is attributed to an inhibition of the metabolism of EE by cotrimoxazole as has been shown with other drugs. Short courses of cotrimoxazole are unlikely to cause any adverse effects on contraceptive control when given to women taking long-term oral contraceptive steroids.     

The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy

In a group of 5 women on long-term anticonvulsant and oral contraceptive therapy, the plasma ethynylestradiol (EE) concentration on 50 μg EE daily was 11.1 ± 4.5 pg/ml. These values were at the lower end of the range found in normal women in this laboratory taking 30 μg EE daily (6–190 pg/ml). Four women have been studied prospectively for 3 months, over 1 cycle before and 2 cycles during phenobarbital 30 mg b.i.d. therapy. Significant falls in the plasma EE concentration were seen in two women (from 104.8 ± 13.4 to 37.7 ± 2.0 pg/ml and from 125.6 ± 23.8 to 34.8 ± 6.7 pg/ml p < 0.01) and breakthrough bleeding was seen in both women. No changes in plasma concentrations of follicle stimulating hormone, progesterone, norethindrone or norgestrel were seen. There was a significant increase in the sex hormone binding globulin capacity from 100.7 ± 5.8 to 133.3 ± 1.2 nmoles/1 (p < 0.05). These changes are consistent with the known microsomal enzyme inducing effect of phenobarbital.     

The effect of extending the pill-free interval on follicular activity: triphasic norgestimate/35 micro g ethinyl estradiol versus monophasic levonorgestrel/20 micro g ethinyl estradiol

This study was designed to evaluate follicular activity in women taking oral contraceptives with imposed imperfect compliance. After completing a 28-day cycle of either triphasic norgestimate/EE (NGM/EE) (Ortho Tri-Cyclen, Ortho-McNeil Pharmaceutical, Raritan, NJ) or monophasic levonorgestrel/EE (LNG/EE) (Alesse, Wyeth-Ayerst Laboratories, Philadelphia, PA), women were instructed to intentionally "miss" the first two active pills of the next pack. The first two tablets in the second treatment cycle were deliberately omitted, thereby extending the pill-free interval from 7 days to 9 days. Subjects were randomized to take NGM/EE (n = 40) or LNG/EE (n = 39) for two consecutive cycles. The mean maximum follicular diameter was significantly greater in women taking LNG/EE than in those taking NGM/EE (16.4 +/- 7.1 mm vs. 12.6 +/- 8.3 mm, p = 0.047). The LNG/EE group had significantly higher median serum estradiol concentrations compared to women taking NGM/EE on pill Days 10 [29.5 pg/mL (range: 10.0-540.0 pg/mL) vs. 2.5 pg/mL (range: 2.0-6.0 pg/mL), p < 0.001] and 14 [11.0 pg/mL (range: 2.0-416.0 pg/mL) vs. 2.0 pg/mL (range: 2.0-3.0 pg/mL), p = 0.001]. Two women in the NGM/EE group and three women in the LNG/EE group had at least one progesterone level > or =3 ng/mL; none of these women demonstrated a maximum follicular diameter >13 mm. Significantly greater follicular activity was observed after an extended pill-free interval in women taking LNG/EE compared to those taking triphasic NGM/EE. The clinical implications of these findings require further study.     

Evaluation of plasma levels of renin-aldosterone and blood pressure in women over 35 years treated with new oral contraceptives.

Increases in blood pressure and weight are consequences of increased fluid retention following oral contraceptives administration. Hypertension and weight increase are particularly frequent in women over 35 years of age. The aim of the present study was to evaluate the clinical and hormonal effects of a new extra-low dose oral contraceptive [15 microg ethinyl estradiol (EE) and 60 microg gestodene (GSD)] on the renin-aldosterone system in a group of women aged 35-39 years treated for 3 months compared with a formulation containing the same hormones at a higher dose. Eighteen healthy women, age 35-39 years, were divided into two groups. The first group (10 women) used Arianna, Schering, 15 microg EE/60 microg GSD (EE15/GSD60); the second group (8 women) used Fedra, Schering, 20 microg EE/75 microg GSD (EE20/GSD75). Blood samples were obtained before the study and after 3 months of contraceptive use for assay of renin and aldosterone. Blood pressure was also measured on both occasions. No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 3 months of contraceptive use. The mean increase in body weight after 3 months of contraceptive use was 350 +/- 100 g for EE20/GSD75 and 300 +/- 50 g for EE15/GSD60. There was a mean increase of 4 mm Hg for systolic pressure and 2 mm Hg for diastolic pressure in women on EE20/GSD75 and corresponding increases of 3 and 2 mm Hg in women on EE15/GSD60. The changes were not significant in any case. The results of the present study show that the formulations were well tolerated and provided good control of the menstrual cycle in all 18 women. The contraceptive formulations EE20/GSD75 and EE15/GSD60 have no clinical impact on blood pressure, PRA, or aldosterone in this age group.     

The effect of rifampicin oh the pharmacokinetics of ethynylestradiol in women

A single dose of Minovlar^R (50 μg ethynylestradiol (EE) and 1 mg norethindrone acetate) was given to seven women during treatment with rifampicin (450–600 mg/day) and again one month after stopping rifampicin. Blood samples were taken at intervals over a 24-hour period. The area under the plasma EE versus time curve increased significantly on stopping rifampicin from 1014 ± 317 pg/ml × h (mean ± SE) to 1747 ± 218 pg/ml × h (p < 0.01). The terminal plasma half-life increased from 2.9 ± 0.8 h to 6.3 ± 1.4 h (p < 0.005). The sex hormone binding globulin (S.H.B.G.) capacity was also reduced from 213.4 ± 11.5 nmoles to 129.0 ± 7.7 nmoles/1 after stopping rifampicin. In one patient starting rifampicin who was taking Minovlar as a long-term oral contraceptive, a fall in the plasma EE concentration was associated with a rise in the plasma follicle stimulating hormone concentration. These effects of rifampicin on EE pharmacokinetics are consistent with induction of the microsomal enzymes that metabolise EE.     

Pharmacokinetics of oral contraceptive steroids in Egyptian women: studies with Ovral, Nordette and Norminest

Plasma concentration profiles and pharmacokinetic parameters have been obtained following single dose administration of three commonly used oral contraceptive steroid preparations, Ovral, Nordette and Norminest to Egyptian women. The constituents of the preparations are as follows: Ovral (50 micrograms ethinyloestradiol, EE2 and 500 micrograms levonorgestrel, LNG); Nordette (30 micrograms EE2 and 150 micrograms LNG); and Norminest (35 micrograms EE2 and 500 micrograms norethisterone, NOR). Peak plasma concentrations of EE2 ranged between 116-160 pg ml-1 for Ovral, 55-78 pg ml-1 for Norminest and 30-70 pg ml-1 for Nordette. There was no significant difference in half-life (t1/2), oral clearance (CL) or apparent volume of distribution (Vd). The relative values of the area under the plasma concentration-time curve (AUC) reflected well the different amounts of oestrogen in each preparation. There was no significant difference in t1/2, CL or Vd for LNG in the 2 preparations containing this progestogen. The mean AUC following Nordette (150 micrograms LNG) was 40% of that following Ovral (500 micrograms LNG; p less than 0.001). Comparing pharmacokinetic parameters for the same dose of LNG (Ovral) and NOR (Norminest) showed the AUC to be decreased and CL and Vd increased in the latter group. The study indicates that the kinetic profile of the OCS in healthy Egyptian women are similar to other ethnic populations.     

Contraceptive steroid concentrations in women with early active schistosomiasis: lack of effect of antischistosomal drugs

Plasma concentrations of the oral contraceptive steroids (OCS) ethinyloestradiol (EE2) and levonorgestrel (LNG) have been determined in women with early active schistosomiasis and compared to those obtained in healthy volunteers. Steroid concentrations following a single dose of Ovral (500 micrograms LNG, 50 micrograms EE2) or during a multiple dose regimen were unaffected by the disease. There was no significant effect of the antischistosomal drugs praziquantel (40 mg X kg-1) or metrifonate (10 mg X kg-1 X 3 at 2-week intervals) on plasma steroid concentrations. In regular users of OCS, significantly higher concentrations of LNG were observed than in women who received only a single dose. We conclude that there is no pharmacokinetic reason for withholding OCS from patients with early active schistosomiasis who are also receiving either praziquantel or metrifonate.     

Vaginal administration of ethinylestradiol: effects on ovulation and hepatic transcortin synthesis

Ethinylestradiol (EE) was given vaginally to circumvent the intestinal metabolism and initial liver passage which follow oral intake. This route of administration was chosen in an effort to enhance the antiovulatory potency of EE, while decreasing adverse hepatic reactions. Vaginal tablets containing 20-30 micrograms of EE were taken daily by 7 ovulating volunteers from day 5 to day 25 of the menstrual cycle. The regimen resulted in serum EE levels of 62 +/- 27 pg/ml (mean +/- S.D.) 8-10 hours after insertion. Ovulation was inhibited in 5 women (monophasic basal body temperature curves, serum progesterone levels of 0.9 +/- 1.1 ng/ml during the second half of the treatment cycle). The cortisol-binding capacity of transcortin was significantly elevated in all subjects (52.3 +/- 6.4 micrograms/100 ml; controls 25.7 +/- 2.2 micrograms/100 ml). These findings indicate that intravaginal EE is twice as potent as oral EE in regard to inhibition of ovulation as well as stimulation of the hepatic transcortin synthesis. Vaginal administration apparently increases the bioavailability of EE; it does not facilitate a selective reduction of estrogenic effects upon the liver.     

An investigation of the pharmacokinetics of ethynylestsadiol in women using badioimmunoassay

A radioimmunoassay for ethynylestradiol (EE) which is applicable to plasma samples obtained from women, who have taken a combination type oral contraceptive, has been developed and fully validated. Plasma concentrations of EE rise to a peak of 128 pg/ml following the oral administration of 50 μg EE. Following the intravenous administration of the same dose of EE, plasma concentration's of the steroid declined biexponentially, the two half-lives being 0.83 and 6.75 hours. Comparison of the results of the intravenous and oral administration of the steroid suggested that its oral bioavailability is 42%. Although EE thus has a lower bioavailability than norethindrone, the pharmacokinetics of the two steroids, as reflected by half-lives, plasma clearance and volume of distribution, are very similar. The occurrence of a secondary peak in plasma at around 12 hours after dosing gave strong evidence that EE undergoes enterohepatic circulation in women; an event that may have considerable clinical significance.     

Milk and plasma concentrations of the progestin ST-1435 in women treated parenterally with ST-1435

A subcutaneous contraceptive capsule releasing progestin ST-1435 was used by 6 breast-feeding women. One to three paired milk and plasma samples were collected over a one-month period and the concentrations of ST-1435 were determined by radioimmunoassay. An improved and sensitive method for determination of ST-1435 in milk was developed. A column chromatographic purification of milk prior to radioimmunoassay decreased the blank and improved sensitivity. The average plasma concentration of ST-1435 was 62 +/- 20 pg/ml (mean +/- SD). The average milk concentration of ST-1435 was 38 pg/ml (ranging from 7 to 73 pg/ml), while the average milk to plasma ratio was 0.60 (ranging from 0.25 to 0.91). There was a significant correlation between ST-1435 concentrations in breast milk and plasma, indicating that the concentration in plasma is the major determinant for the amount of ST-1435 excreted into milk. Since studies with this drug have shown good contraceptive efficacy and low bioavailability after oral intake, ST-1435 is a good candidate for lactational contraception.     

Dose finding in a low-dose 21-day combined oral contraceptive containing gestodene.

An open label, non-comparative study was carried out in 22 women over a total of five cycles. After an untreated cycle, oral administration of 20 microg ethinyl estradiol (EE) with 50 microg gestodene (GST) (tablets taken daily for 21 days with a break of 7 days) was commenced, and three treatment cycles were followed by an untreated follow-up control cycle. The ability of this formulation to inhibit ovulation and suppress ovarian activity was assessed by using hormonal parameters and ultrasound. One ovulation occurred during treatment. Luteinized unruptured follicles were observed in three cases in the second treatment cycle and in one case during the third treatment cycle. Follicle-like structures larger than 13 mm associated with a serum estradiol level of more than 30 pg/mL were noted in 19% of the women in the first treatment cycle. The rate of active follicle-like structures was 43% in the second treatment cycle and 28% in the third treatment cycle. The results were compared with previously reported findings of a preparation containing 20 microg EE and 75 microg GST. With regard to ovarian grading and endogenous hormone secretion, considerably more residual ovarian activity, with all parameters examined, was found in the 20 microg EE and 50 microg GST preparation compared to the 20 microg EE and 75 microg GST preparation. It was concluded that the 20 microg EE and 50 microg GST preparation administered for 21 days does not meet the requirements of a combined oral contraceptive with respect to ovulation inhibition.     

A study of interaction of a low-dose combination oral contraceptive with anti-tubercular drug

Low-dose combination contraceptive (containing norethisterone acetate 1 mg and ethinyl estradiol 30 μg) was administered to women receiving concurrent therapy with either Rifampicin or “triple” antitubercular treatment consisting of paraaminosalicylic acid (PAS), isonicotinic acid hydrazide (INH) and streptomycin. Plasma levels of norethisterone (NET) and ethinyl estradiol (EE), PAS and INH were measured and the area under curve (AUC) was calculated for NET and EE. Rifampicin treatment (9 women) caused a statistically significant reduction of the plasma NET levels as well as the AUC of NET. In this group of women, though a trend for reduction in EE levels was observed in individual subjects, it was not statistically significant. Out of 7 regularly menstruating women on Rifampicin therapy, 2 showed a premenstrual rise of plasma progesterone (P) levels (> 4 ng/ml) suggesting an ovulatory cycle and 3 experienced menstrual irregularities. In contrast, plasma levels of NET and EE as well as their AUCs were not altered in 8 women receiving “triple” antitubercular therapy. Only one women out of 8, had menstrual irregularity and all women had P levels in the anovulatory range. Furthermore, oral contraceptive treatment did not alter the plasma levels of PAS and INH.     

Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Lunelle Study Group

An open-label, nonrandomized, parallel, controlled study compared the efficacy, safety, and cycle control of a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) with that of a norethindrone 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol (NET/EE) triphasic oral contraceptive (Ortho-Novum 7/7/7). At study enrollment, women chose either the injections or the oral contraceptive. A higher proportion of women in the NET/EE group (65.1%) than in the MPA/E2C group (48.7%) had used hormonal contraception during the month before the study (p < 0.01). Overall, 55.5% (434/782) of MPA/E2C users and 67.6% (217/321) of NET/EE users completed the 60-week trial. One-year contraceptive efficacy (13 cycles of 28 days) for MPA/E2C and NET/EE was based on 8008 and 3434 woman-cycles of use, respectively. During the first year, one pregnancy occurred in an NET/EE user for a life table rate of 0.3; no pregnancies occurred in users of MPA/E2C. One additional pregnancy in the NET/EE group occurred during the 15th treatment cycle. After the first treatment cycle, women in both groups experienced regular menses, with an average cycle length of 28 days in MPA/E2C users and 27 days in NET/EE users. Although MPA/E2C users were more likely to experience bleeding irregularities, only 2.5% (19/775) cited metrorrhagia as a reason for discontinuing treatment. The adverse events reported in both treatment groups are consistent with those expected with the use of combined hormonal contraceptives. Overall, the results of this first Phase III US clinical trial of MPA/E2C confirm this method's high contraceptive efficacy and safety, as shown in previous studies by the World Health Organization. These results suggest that a monthly combination injectable would represent a welcome new contraceptive option for women in the US.     

Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial

BackgroundThis study evaluated the ethinyl estradiol (EE) and levonorgestrel (LNG) pharmacokinetic profiles of AG200-15, a transdermal contraceptive delivery system, compared with a combination oral contraceptive (COC) containing EE 35 mcg and norgestimate 250 mcg.Study designA Phase 1, open-label, single-center study in 36 healthy women was conducted over three cycles with a randomized crossover design. After a run-in cycle of 21 days on and 7 days off with AG200-15, participants were randomized to receive one of two treatments: a 21/7-day cycle of AG200-15 either followed or preceded by one cycle of the COC. This trial is registered on ClinicalTrials.gov under the identifier NCT01243580.ResultsDuring the third week of AG200-15 use, mean (±standard deviation) maximum serum concentration (C_max), area under the curve_{0–168 h} and steady-state concentration (C_{ss48–168 h}) for EE were 51.3±17.3 pg/mL, 6.26±2.46 ng h/mL and 35.7±14.5 pg/mL, respectively; for LNG, the corresponding values were 2400±1140 pg/mL, 317±159 ng h/mL and 1847±930 pg/mL, respectively. The AG200-15 EE C_max was approximately 60% lower and the EE C_ss was 15%–20% lower than those obtained with the COC. The calculated daily dose of AG200-15 was equivalent to a 30-mcg EE COC. The most common adverse events (AEs; >10%) in the AG200-15 group were headache, nausea and application-site irritation. All drug-related AEs were mild, and no serious AEs were reported.ConclusionsEE and LNG daily exposure during AG200-15 treatment was within the range reported for a low-dose COC. The daily EE dose with AG 200-15 was equivalent to a 30-mcg COC and was safe and well tolerated.     

Levonorgestrel in milk and plasma of breast-feeding women with a levonorgestrel-releasing IUD

A levonorgestrel-releasing intrauterine contraceptive device was used by 10 breast-feeding women beginning 6 weeks after delivery. Two models of IUD were used. One released 10 microgram (5 patients), the other 30 microgram (5 patients) of levonorgestrel per day. Plasma and milk samples were collected 8 times over a 3-month period and the concentrations of levonorgestrel determined by radioimmunoassay. An improved and sensitive method for the determination of levonorgestrel in milk was developed. A column chromatographic purification of a milk extract before radioimmunoassay made possible the use of large milk samples in order to improve the sensitivity. The plasma concentrations during the follow-up period were 207 +/- 64 pg/ml (mean + SD) in the 10 microgram and 235 +/- 87 pg/ml in the 30 microgram/day releasing IUD groups. The milk levonorgestrel concentrations were 56 +/- 35 and 57 +/- 34 pg/ml, respectively. The plasma to milk ratio of levonorgestrel was initially 100:15 and at the end of the 3-month follow-up period 100:25. There were no significant differences in the milk and plasma concentrations between the study groups. The total amount of levonorgestrel excreted per day in 600 ml breast milk is approximately 0.1 per cent of a daily dose of 30 microgram.     

Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a low-dose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation.

The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 9 healthy women (age 23 to 42 years), during a treatment period of three months with a low-dose oral contraceptive, containing 0.15 mg LNG together with 0.03 mg EE2 (Microgynon). After a wash-out period of 3 months, 8 of these women received a single administration of the same formulation. The results showed that there was an increase in serum trough levels of LNG, reaching steady-state in the second half of each treatment cycle. The LNG levels achieved were about 3 to 4 times higher than anticipated on the basis of single dose administration. At the end of treatment cycles one and three, the terminal half-life of LNG was in the range of 24-26 h, while a mean value of 20 h was observed following single dose administration. An EE2-induced increase in the SHBG concentration of about 50% as compared to pretreatment values was observed during a treatment cycle. Pretreatment values were reached following the drug-free interval of 7 days between two cycles. After single dose administration, the free fraction of LNG was 1.3 +/- 0.2% and the fractions bound to SHBG and albumin were 64.1 +/- 4.2% and 34.6 +/- 4.0%, respectively. Serum protein binding of LNG did not change during chronic treatment. An about 50% reduction in total and unbound clearance of LNG was observed during chronic treatment, as compared to single dose administration. Increased SHBG binding capacity and a reduced hepatic metabolic capacity were discussed as possible causes of accumulating LNG concentrations in the serum. On the last day of treatment cycles one and three, the AUC(0-24h) values of EE2 were 728 +/- 314 and 778 +/- 318 pg x ml-1 x h, respectively, and were in keeping with data reported from others.     

Ethynyl-estradiol (EE-2) retained in blood and endometrium during and after steroidal contraception

Thirty-six women under norgestrel + EE-2 interrupted the medication after 2 to 36 months of regular use. A single venous blood and a single endometrial sample were simultaneously obtained from each subject on different days of the cycle to measure the synthetic estrogen content. Samples were collected during the last month of contraception and in the month after the medication. The EE-2 values (means +/- SE) during and after the "pill" were as follows: endometrial = 90 +/- 18 vs 234 +/- 5 ng/g wet tissue (P less than 0.001), and in blood = 90 +/- 18 vs 234 +/- 32 pg/ml (P less than 0.001). In a hysterectomized woman 30 micrograms of oral EE-2/d/20 d, yielded plasma EE-2 concentrations up to 979 pg/ml, descending to 30 pg/ml under no treatment. The results demonstrate that in intact women, exfoliation of the endometrium after one month of no steroidal ingestion, did not achieve the complete synthetic estrogen elimination from tissue, while blood levels of EE-2 increased during the same period of observation.     

Presence of ethynyl-estradiol (EE-2) in blood and endometrium after interrupting steroidal contraception for three months

Serial studies were conducted in five women under norgestrel + EE-2 after interrupting 11-34 months of regular use of the medication. A venous blood and an endometrial sample were simultaneously obtained from each subject between the 22nd and 25th day of the pseudocycle (last month of contraception) and on the same days of the following three cycles under no treatment for the measurement of EE-2 content. Values during and after the first month of no medication were: plasma = 85 +/- 6 versus 218 +/- 36 (pg/ml; P less than 0.001) and endometrium = 93 +/- 10 versus 29 +/- 7 (ng/g wet tissue; P less than 0.001). A decrement of circulating EE-2 from 346 pg/ml in the first month with no medication to 14 pg/ml in the third month off the treatment was observed. The EE-2 endometrial uptake of 93 +/- 10 (last month of steroidal ingestion) decreased to 29 +/- 7, 7 +/- 2 and 4 +/- 0.9 ng/g wet tissue in the following three months of no treatment. In 3/15 instances after interrupting contraception, circulating EE-2 was below the detection limit of the assay, while endometrial EE-2 uptake was in the range of 3-19 ng/g wet tissue. These data confirm our apparent controversial report that EE-2 plasma levels increased during the first month after interrupting medication and support the presence of the exogenous estrogen in plasma and endometrium after interrupting the steroidal contraceptive for three months.     

Efficacy and safety of an ascending-dose,extended-regimen levonorgestrel/ethinyl estradiol combined oral contraceptive

Objective

To evaluate the efficacy and safety of an ascending-dose, extended-regimen (ADER) combined oral contraceptive consisting of levonorgestrel (LNG) 150 mcg/ethinyl estradiol (EE) 20 mcg for 42 days, LNG 150 mcg/EE 25 mcg for 21 days, LNG 150 mcg/EE 30 mcg for 21 days and EE 10 mcg for 7 days.

Study Design

This was a multicenter, open-label, phase 3, single-arm study. Sexually active women aged 18–40 years were enrolled and received ADER for up to 1 year (4 consecutive 91-day cycles). Participants kept diaries to record adherence, bleeding/spotting and other contraceptive use. Efficacy was measured using the Pearl Index and the life-table method; safety and tolerability were assessed through reported adverse events (AEs).

Results

A total of 3701 women were enrolled and 2144 completed the study. The Pearl Index was 3.19 [95% confidence interval (CI), 2.49–4.03], based on 70 pregnancies that occurred after ADER initiation and ≤ 7 days after the last LNG/EE or EE-only pill in women aged 18–35 years, excluding cycles in which another contraceptive method was used. Life-table pregnancy rate was 2.82% (95% CI, 2.23%–3.57%) for all users aged 18–35 years. Unscheduled bleeding/spotting decreased with increasing EE doses within each cycle and decreased after cycle 1. No unexpected AEs or changes in laboratory parameters were reported.

Conclusion

This study demonstrated that ADER effectively prevented pregnancy with a favorable safety and tolerability profile.