Drugs (2015) 75:1019–1026 DOI 10.1007/s40265-015-0407-9

ADIS DRUG EVALUATION

Extended-Cycle Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol (SeasoniqueÒ): A Review of Its Use as an Oral Contraceptive Celeste B. Burness1

Published online: 28 May 2015 Ó Springer International Publishing Switzerland 2015

Abstract A 91-day extended-cycle oral contraceptive (OC) consisting of levonorgestrel/ethinylestradiol 150/30 lg for 84 days and ethinylestradiol 10 lg for 7 days (SeasoniqueÒ) has recently been approved for the prevention of pregnancy in adult women in the EU. This regimen allows for a reduction in the number of withdrawal bleeding episodes to four per year, compared with 13 episodes per year with conventional 28-day regimens. SeasoniqueÒ was effective in preventing pregnancy in a large (n = 1006), noncomparative trial of healthy, sexually active women. In this trial, the overall Pearl index (pregnancies per 100 woman-years of use) in women aged 1835 years (n = 621) was 0.76 and the Pearl index for method-failure (compliant use) was 0.26. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with a mean of 2 days of bleeding and 1 day of spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting was highest during the first few cycles of use and decreased thereafter. SeasoniqueÒ was generally well tolerated, with a tolerability profile in line with that expected for OCs. SeasoniqueÒ extends the contraceptive options currently available to The manuscript was reviewed by: H-J Ahrendt Practice for Gynaecology and Clinical Research, Magdeburg, Germany; A. Cagnacci, Department of Obstetrics Gynecology and Pediatrics, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy; A. M. Kaunitz, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, FL, USA; A. M. Paoletti, Department of Obstetrics and Gynaecology, University of Cagliari, University Hospital of Cagliari, Italy. & Celeste B. Burness [email protected] 1

Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland, New Zealand

women, particularly in those who desire fewer withdrawal bleeding episodes.

SeasoniqueÒ for the prevention of pregnancy: a summary Extended cycle birth control option allowing women to have four scheduled withdrawal bleeding episodes a year Effective for the prevention of pregnancy Generally well tolerated; most frequently reported adverse events include irregular and/or heavy uterine bleeding, weight gain and acne The incidence of unscheduled bleeding and/or spotting was highest during the first few cycles of use and decreased thereafter Scheduled bleeding episodes are short (&3 days) and light (2 out of 3 days are bleeding; 1 out of 3 days is spotting)

1 Introduction Oral contraceptive (OC) pills have been available for over 50 years and are one of the most commonly used methods of contraception [1, 2]. Traditional OC regimens consist of a 28-day schedule of 21–24 days of active hormone pills followed by 4–7 days of placebo pills (hormone-free interval), which induces monthly withdrawal bleeding [1, 2].

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This regimen was originally created to mimic the natural menstrual cycle and help women feel comfortable in accepting OCs and was not based on any biological requirement for monthly bleeding [3]. The more recently introduced extended-cycle OCs have increased in popularity as they offer the option of fewer overall scheduled withdrawal bleeding episodes, a benefit preferred by many women [2, 4, 5]. The first 91-day extended-cycle OC formulation contained 84 active hormone tablets (levonorgestrel 150 lg and ethinylestradiol 30 lg) and 7 hormone-free tablets (placebo) [6]. This regimen allowed for a reduction in scheduled bleeding to four episodes per year and was shown to be effective, safe and generally well tolerated [7]. However, women receiving the extended-cycle regimens, regardless of type of progestin, are more likely to experience breakthrough bleeding than those receiving a traditional regimens, particularly during the first few cycles of treatment [7]. A variation of this regimen, utilizing low dose ethinylestradiol (10 lg) monotherapy during the typical hormone-free interval (SeasoniqueÒ) has been developed to lessen the withdrawal symptoms that result from a sudden, sharp decrease in hormones [5, 8]. This formulation has been available in the USA for the prevention of pregnancy since 2006 [8] and has been recently approved in the EU [9]. This narrative review focuses on the efficacy and tolerability of SeasoniqueÒ for the prevention of pregnancy from an EU perspective, and overviews its pharmacological properties. The use of other 91-day extended-cycle OCs containing levonorgestrel/ethinylestradiol (e.g. SeasonaleÒ, LoSeasoniqueÒ) [6, 10] are beyond the scope of the review.

2 Pharmacodynamic Properties 2.1 Contraceptive Effects Combined OCs (COCs) decrease the risk of pregnancy by suppressing ovulation, which is a direct consequence of a decrease in luteinizing hormone levels [1, 9]. A thickening of cervical mucus (making sperm entry into the uterus more difficult) and changes to the endometrium (reducing the likelihood of implantation) also contribute to the drug’s contraceptive effects [1]. The use of low-dose ethinylestradiol 10 lg during the usual 7-day hormone-free interval resulted in greater suppression of the hypothalamic-pituitary–ovarian axis and decreased follicular development in women than OC regimens using placebo [11, 12]. A randomized, openlabel trial (n = 33) compared three OC regimens containing levonorgestrel/ethinylestradiol 150/30 lg: three cycles of a standard 21/7-day regimen with 7 days of

C. B. Burness

placebo (21/7 placebo), an extended 84-day regimen with 7 days of placebo (84/7 placebo) and SeasoniqueÒ [12]. During the usual 7-day hormone-free interval, follicle stimulating hormone (FSH) and estradiol levels were significantly (p \ 0.05) lower in the SeasoniqueÒ group compared with the 21/7 placebo or 84/7 placebo groups [12]. Inhibin-B levels remained low and unchanged throughout in the SeasoniqueÒ group, while levels differed over time in the other two treatment groups. Fewer developing follicles were seen on ultrasound in women who received SeasoniqueÒ than in those who received placebo (p \ 0.05) in the usual 7-day hormone-free interval [12]. In another study (n = 35), ovulation was detected in 0 out of 35 cycles during the first 28-day interval, in 2.9 % of cycles in the second 28-day interval and in 5.7 % of cycles in the final 35-day interval [13]. The ovarian activity rate for the entire 91-day period was 2.9 % and ovulation was suppressed in 97.1 % of cycles during treatment with SeasoniqueÒ [13]. Additionally, progesterone levels were generally low (1.8–3.1 nmol/L) during treatment (vs. 29.7 nmol/L during the pre-treatment cycle). Ovulation returned quickly after continuous suppression with SeasoniqueÒ for 91 days. Ovulation activity was restored in 77.1 % of women within 32 days of treatment discontinuation, as reflected by mean serum progesterone levels C15.9 nmol/L [13]. 2.2 Other Effects Histological evaluations of samples from 63 evaluable healthy, sexually active women who received SeasoniqueÒ for 1 year did not reveal any unexpected changes in the endometrium, either during active treatment with levonorgestrel/ethinylestradiol or during the 7-day low-dose ethinylestradiol interval and there were no reports of endometrial hyperplasia [14]. COCs may inhibit skeletal growth and development in adolescents [15]. In a randomized trial in healthy adolescent (postmenarcheal) females aged 12–18 years (n = 829), the mean percent increases from baseline in lumbar spine bone mineral density after 12 months did not differ to a clinically meaningful extent between those receiving SeasoniqueÒ, those receiving a 21/7-day regimen of levonorgestrel/ethinylestradiol 100/20 lg and 7 days’ placebo, and in healthy controls not using hormonal contraceptives [16]. COCs are associated with an elevated risk of venous thromboembolism (VTE) due to changes in procoagulant, anticoagulant and fibrinolytic activity, mainly due to the effects of the estrogen component of the COC [2, 17]. However, in low-dose-estrogen COCs, the incidence of VTE appears to vary with the progestin component [18, 19]. The risk is lower in those containing second-

Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol: A Review

generation progestins (e.g. levonorgestrel) compared with those containing third-generation progestins (e.g. desogestrel and gestodene) [18, 19]. In a randomized, open-label study in 187 women (perprotocol population), prothrombin fragment 1 ? 2 levels (which are indicative of thrombin turnover) were increased from baseline (by 170, 158 and 592 pmol/L, respectively) after 6 months of treatment with SeasoniqueÒ, a standard 21/7-day regimen of levonorgestrel/ethinylestradiol 150/30 lg and 7 days’ placebo (21/7 levonorgestrel/ ethinylestradiol) or 21/7 desogestrel/ethinylestradiol [19]. The least squares mean change from baseline in prothrombin F1 ? 2 levels over 6 months’ treatment with SeasoniqueÒ was noninferior to that with 21/7 desogestrel/ ethinylestradiol [the lower limit of the 2-sided 95 % CI (-18.3 pmol/L) was greater than the predefined boundary of -130 pmol/L]. There was little difference in terms of the least squares mean change from baseline between SeasoniqueÒ and 21/7 levonorgestrel/ethinylestradiol; however, noninferiority was not achieved (lower limit of the 95 % CI was -440 pmol/L). The clinical relevance of these data is unclear [19]. COCs, including SeasoniqueÒ, are associated with metabolic disturbances such as glucose intolerance, increases in serum triglycerides and lipoprotein levels, and small increases in blood pressure [9].

3 Pharmacokinetic Properties Data discussed in this section are from a study in which 30 health women were administered oral levonorgestrel/ ethinylestradiol 150/30 lg for 84 days followed by ethinylestradiol 30 lg for 7 days [20]. Additional information was obtained from the EU summary of product characteristics (SPC) [9]. Pharmacokinetic data specific to the SeasoniqueÒ regimen (i.e. levonorgestrel/ethinylestradiol 150/30 lg for 84 days followed by ethinylestradiol 10 lg for 7 days) are not available. Levonorgestrel and ethinylestradiol are rapidly absorbed reaching maximum plasma concentrations within 2 h of administration of oral levonorgestrel/ethinylestradiol 150/30 lg tablets [20]. Orally administered levonorgestrel is not subject to appreciable first-pass metabolism and is completely absorbed (bioavailability almost 100 %) [9]. Conversely, ethinylestradiol undergoes first-pass metabolism in the gut and liver following oral administration, and has a bioavailability of &43 % [9]. Following multiple doses of levonorgestrel/ ethinylestradiol, the mean exposure of levonorgestrel or ethinylestradiol on day 84 (end of the extended-cycle regimen) was generally similar to that observed on day 21

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(the end of a typical 3-week contraceptive regimen) [9, 20]. There was no additional accumulation of ethinylestradiol during days 84-91 after administration of ethinylestradiol 0.03 mg alone [20]. Based on this finding, it is unlikely that accumulation would occur with SeasoniqueÒ (ethinylestradiol 0.01 mg) during the final 7 days [20]. Ethinylestradiol binds extensively (95–97 %) to serum albumin, but does not bind to sex hormone-binding globulin (SHBG) [9]. In serum, approximately 97.5–99 % of levonorgestrel is bound to proteins, primarily to SHBG and, to a lesser extent, serum albumin. However, ethinylestradiol induces SHBG synthesis, which decreases clearance of levonorgestrel. The apparent volume of distribution of levonorgestrel and ethinylestradiol is &1.8 and 4.3 L/kg, respectively [9]. Levonorgestrel is extensively metabolized in the liver to form sulphates and to a lesser extent, glucuronide conjugates; the primary metabolites in the plasma are conjugated and unconjugated 3a,5b-tetrahydrolevonorgestrel [9]. Ethinylestradiol is transformed into ethinylestradiol-3-sulfate in the gut wall and the remaining ethinylestradiol undergoes hydroxylation by cytochrome P-450 3A4 (CYP3A4) enzymes in the liver. The 2-hydroxy metabolite is further transformed by methylation and/or conjugation [9]. Levonorgestrel and it metabolites are excreted in the urine (&45 %) and faeces (&32 %; mostly as glucuronide conjugates) [9]. Ethinylestradiol undergoes enterohepatic recirculation and is excreted in the urine and faeces as sulphate and glucuronide conjugates [9]. Following a single dose of levonorgestrel/ethinylestradiol, the terminal elimination half-life for levonorgestrel and ethinylestradiol was about 34 and 18 h, respectively [9]. 3.1 Special Patient Populations and Potential Drug Interactions No formal studies have been conducted investigating the effect of age, race, renal impairment or hepatic impairment on the pharmacokinetic profile of SeasoniqueÒ [9]. In women with impaired liver function, steroid hormones may be poorly metabolized; as with all estrogen-progestin contraceptives, SeasoniqueÒ should be discontinued in women who experience acute or chronic liver function disturbances until liver function normalizes [9]. No formal drug-drug interactions studies have been conducted with SeasoniqueÒ [9]. However, concomitant administration of COCs and CYP3A4 inducers (e.g. barbiturates, phenytoin and rifampicin) may result in decreased plasma concentrations of COCs. Significant alterations (increases or decreases) in the plasma concentration of the estrogen and progestin have been observed

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C. B. Burness

following co-administration of COCs and HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors [9]. The use of other birth control methods (e.g. condoms or spermicide) is recommended with the concomitant administration of SeasoniqueÒ and any other medication which may reduce the plasma concentration of levonorgestrel or ethinylestradiol [9]. Concurrent treatment with ethinylestradiol and lamotrigine may significantly reduce plasma lamotrigine concentrations, probably due to induction of lamotrigine glucuronidation, which may result in a reduction in seizure control [9]. Thus, lamotrigine dosage adjustments may be required when these drugs are coadministered [9].

Table 1 Efficacy of SeasoniqueÒ for the prevention of pregnancy in adult women in a 1-year, noncomparative, multicentre, phase III trial [9, 22] Patient number for Pearl index calculation: 18–35 years of age

621

18–40 years of age

NR

Exposure (total no. of 91-day cycles)

1578

No. of pregnancies

3

Pearl index (pregnancies per 100 women-years of use): overall (18–35 years of age) overall (18–40 years of age)

0.76 0.67

method failure (‘‘compliant use’’)

0.26

NR not reported

4 Therapeutic Efficacy Ò

The efficacy of Seasonique was assessed in a 1-year, noncomparative, multicentre, phase III trial in healthy adult women (n = 1006) aged 18–40 years who were at risk of pregnancy [21]. Women aged [35 years who were smokers were excluded [21]. Results discussed in this section focus on data from the EU SPC [9] and the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) assessment report for SeasoniqueÒ [22]. Treatment with SeasoniqueÒ was initiated on the first Sunday after the beginning of their menstrual period or withdrawal bleeding from their prior oral contraceptive cycle [21]. Women were encouraged to take their tablet at approximately the same time each day [21]. Daily electronic diaries were used to evaluate pill taking, bleeding patterns and hormone-related symptoms [21]. Compliance was assessed using the electronic diaries and pill counts. A noncompliant cycle was defined as a cycle with any one of the following: missing two or more consecutive pills; overall compliance with study medication \80 %; used other forms of contraception; or used prohibited concomitant medications [21]. At screening, the mean age was 27.4 years (30 % of women were aged [35 years), women had a mean body mass index of 26.0 kg/m2, 21 % of women were current smokers and 89 % had previously used oral contraceptives [21]. Efficacy was assessed using the pregnancy rate in the subgroup of women aged 18–35 years who completed C1 full cycle of treatment (n = 621), using the Pearl index [calculated by dividing the number of on-treatment pregnancies by the total number of complete cycles of exposure (91 days)] [9, 22]. In this 1-year trial, SeasoniqueÒ demonstrated acceptable efficacy for the prevention of pregnancy in terms of the Pearl index for the overall (typical use) and method-

failure (compliant use) rates (Table 1) [9, 22]. Of the three women who became pregnant during treatment with SeasoniqueÒ, one became pregnant while receiving 84-day levonorgestrel/ethinylestradiol treatment [21]. The overall treatment compliance for all treated patients was C97 % [22]. In an open-label extension study in women who received SeasoniqueÒ for up to 3 additional consecutive years, six (1.9 %) women became pregnant [23]; this study included women who had completed the 1-year, phase III efficacy [21] and the 1-year endometrial safety [14] trials (n = 320). Of the pregnant women, four were considered noncompliant with treatment and two became pregnant C14 days after completing study medication [23]. The overall treatment compliance for all treated patients was C98 % [22]. In a retrospective study, using real-world data from the i3Invision Data MartTM database in women aged 15–40 years, extended-cycle OC regimens appeared to be more effective than 28-day OC regimens for the prevention of pregnancy [24]. This study included two distinct analyses: one comparing pregnancy rates post-initiation on a 84/7 [SeasoniqueÒ or 84 days of levonorgestrel/ ethinylestradiol plus placebo for 7 days (84/7 levonorgestrel/ethinylestradiol)] OC regimen versus 21/7 regimen (n = 52,664) and the other comparing pregnancy postinitiation on a 84/7 regimen versus 24/4 regimen (n = 50,694) [24]. One-year pregnancy rates were significantly lower in women receiving 84/7 regimens than with 21/7 (4.4 vs. 7.3 %; p \ 0.0001) regimens or 24/4 (4.4 vs. 6.9 %; p \ 0.0001) regimens [24]. Moreover, pregnancy rates were significantly (p \ 0.0001) lower in women receiving 84/7 COC regimens compared with the 21/7 and 24/4 regimens after 2 and 3 years’ treatment [24]. In another retrospective analysis using data from the US i3 InVisionTM database (available as an abstract), pregnancy rates during the first year of treatment were lower in

Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol: A Review

patients receiving SeasoniqueÒ compared with those receiving the 84/7 levonorgestrel/ethinylestradiol regimen (3.0 vs. 4.5 %; p = 0.02) [25].

5 Tolerability 5.1 Shorter-Term Tolerability SeasoniqueÒ was generally well tolerated in clinical trials in healthy adult women, with an acceptable tolerability profile in line with that expected for a COC [14, 21]. Of note, adverse events commonly reported in women receiving COCs include irregular and/or heavy uterine bleeding, weight gain and acne [8]. The most frequently reported treatment-emergent adverse events with SeasoniqueÒ during the 1-year, phase III efficacy trial were intermenstrual bleeding (11.5 % of women), nasopharyngitis (7.2 %), sinusitis (6.5 %) and menorrhagia (5.8 %) [21]. Four women (0.4 %) reported serious treatment-related adverse events [migraine (n = 1), cholelithiasis (n = 1), cholelithiasis with pancreatitis (n = 1), or cholecystitis (n = 1)] [21]. Adverse events led to treatment discontinuation in 16 % of women the 1-year, phase III efficacy trial; the most frequent of these were irregular and/or heavy uterine bleeding, weight gain, mood swings and acne [21]. In the 1-year endometrial safety study, 7.4 % of patients receiving SeasoniqueÒ discontinued because of bleeding/spotting adverse events, compared with 1.1 % of patients receiving a standard 21/7-day regimen of levonorgestrel/ ethinylestradiol 150/30 lg plus placebo [22]. Extended-cycle COCs may expose women to an increased cumulative amount of estrogen compared with a standard 21/7 regimen, thus making risk of VTE of particular concern [17]. No thromboembolic events were reported during treatment with SeasoniqueÒ during the 1-year clinical trials [14, 21]. No adverse fetal effects were reported in any of the five pregnancies following maternal exposure to SeasoniqueÒ [21]. Three women delivered healthy full-term infants, one woman was lost to follow-up and the remaining woman elected to have a surgical abortion [21]. No clinically remarkable changes in laboratory or vital signs were noted, apart from an increase in the median platelet count by 14.0 9 103/lL at study end [21]. Median weight gain over 1 year of treatment was 0.9 kg (2.0 lbs) [21]. 5.2 Longer-Term Tolerability The long-term tolerability profile (up to 4 years’ treatment in 320 women) of SeasoniqueÒ appeared to be consistent

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with that observed during the 1-year studies [23]. The most frequently reported treatment-related adverse events were headache (9.4 % of women), metrorrhagia (9.1 %), increased weight (6.9 %), dysmenorrhea (4.4 %), vulvovaginal mycotic infection (4.0 %), bacterial vaginitis (2.8 %), fungal infection (2.2 %) and acne (2.2 %). Overall, 9.7 % of women discontinued treatment because of adverse events. Mean weight gain over 4 years was 4.7 kg (10.4 lbs) [23]. Twelve women (\4 %) reported serious adverse events during treatment with SeasoniqueÒ for up to 4 years [23]. Of these, three women experienced events that were considered possibly related to treatment (spontaneous abortion, non-thrombotic coronary artery spasm and acute cholecystitis). There were no reports of VTE events [23]. 5.3 Bleeding Pattern Scheduled withdrawal bleeding is expected during the 7-day ethinylestradiol monotherapy period of SeasoniqueÒ treatment due to progestin withdrawal [21]. The pattern of scheduled bleeding and/or spotting days was stable throughout the 1-year, phase III efficacy [21] and in the 3-year extension trial [23], with women generally reporting a median of 3 days of bleeding and/or spotting during most 91-day cycles (median of 2 days of bleeding only). Any bleeding and/or spotting during any day of levonorgestrel/ethinylestradiol administration was considered to be unscheduled [21]. The number of days of unscheduled bleeding and/or spotting, and bleeding alone were highest during the first 91-day cycle of SeasoniqueÒ in the 1-year, phase III efficacy trial and subsequently declined in further cycles (Fig. 1) [21]. For example, median unscheduled bleeding days decreased from 4 (1.0 days/woman-month) in the first cycle to 1 (0.3 days/woman-month) in cycles 2–4 [21]. In the 3-year extension trial, median rates of unscheduled bleeding or spotting decreased from 4 days during the first 91-day cycle to 1 day during the last 91-day cycle (cycle 11) [23]. The bleeding pattern of SeasoniqueÒ was compared with a 21/7-day regimen of levonorgestrel/ethinylestradiol 150/30 lg plus placebo [22]. Over a year, the mean total number of days with bleeding/spotting, depending on the extrapolation rule, was 61–62 days in the SeasoniqueÒ group compared with 55–56 days in the 21/7-day regimen group [22]. As expected, the total number of scheduled bleeding/spotting was three times lower in the SeasoniqueÒ group compared with standard 21/7-day regimen group (mean 11 vs. 33 days) [22]. In contrast, the total number of unscheduled bleeding/spotting days was 2-fold higher in the SeasoniqueÒ group than the 21/7-day regimen (mean 53 vs. 24 days) [22]. The intensity of unscheduled bleeding

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A

C. B. Burness 12

11

Bleeding only

Median number of days per 91-day cycle

10

Bleeding and/or spotting

8 6

5

5

4

4

4 2

1

1

1

3

4

0 1

2

Cycle number (91-day cycles)

B

bleeding episodes was 3 days with SeasoniqueÒ and 4 days with the 84/7 levonorgestrel/ethinylestradiol regimen [26]. Unscheduled bleeding and/or spotting decreased earlier with SeasoniqueÒ compared with the 84/7 levonorgestrel/ ethinylestradiol regimen [26]. During the first 91-day cycle, 65 % of women in both treatment groups reported [7 days of unscheduled bleeding during cycle 1. By the third 91-day cycle, significantly fewer women receiving SeasoniqueÒ experienced unscheduled bleeding and/or spotting than those receiving the 84/7 levonorgestrel/ ethinylestradiol regimen (37 vs. 50 %; p \ 0.001). There was no significant between-group difference in the proportion of women with unscheduled bleeding and/or spotting during the fourth 91-day cycle [26].

4

6 Dosage and Administration Median number of days per patient-month

Bleeding only 3

2.8

Bleeding and/or spotting

2

1.3 1

1

1

0.3

0.3

0.3

2

3

4

1

0 1

Cycle number (91-day cycles) Fig. 1 Median unscheduled bleeding and/or spotting and bleeding alone days per 91-day cycle (a) and per patient-month (b) during treatment with SeasoniqueÒ in adult women (n = 1006) in a 1-year, noncomparative, multicentre, phase III trial [21]

was generally similar between the SeasoniqueÒ and 21/7 day regimen groups with bleeding reported as light (80.0 vs. 78.4 %), moderate (52.5 vs. 47.7 %) or heavy (17.5 vs. 14.8 %) [22]. In a retrospective, cross-study analysis of three clinical trials of SeasoniqueÒ (n = 1006 [21] and 95 [14]) and 84/7 levonorgestrel/ethinylestradiol plus placebo regimen (n = 456 [7]), SeasoniqueÒ appeared to have a better bleeding profile compared with the 84/7 levonorgestrel/ethinylestradiol regimen [26]. For example, the proportion of women reporting scheduled withdrawal bleeding and/or spotting during days 85–91 was significantly (p \ 0.05) lower in SeasoniqueÒ group than in the 84/7 levonorgestrel/ethinylestradiol group during all cycles [26]. The median duration of the scheduled

SeasoniqueÒ is indicated as an oral contraceptive in women and is available in 91-day packs, with each pack contains 84 active tablets, each containing 150 lg of levonorgestrel and 30 lg of ethinylestradiol, and seven ethinylestradiol 10 lg tablets [9]. In the EU, SeasoniqueÒ should be initiated on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding) in those who have not used contraceptives in the prior month, and the day after the last active tablet in those who have switched from another COC. Tablets should be taken orally around the same time on each consecutive day [9]. The EU SPC includes a warning for an increased risk of VTE among COC users compared with nonusers (the excess risk of VTE is highest during the first year of COC use). The presence of one serious risk factor or multiple risk factors for VTE or arterial thrombosis is a contraindication for the use of SeasoniqueÒ [9]. The local manufacturer’s prescribing information should be consulted for full details on contraindications, warnings, precautions, use in special patient populations, drug-drug interactions and recommendations for additional contraceptive measures and management of missed tablets.

7 Extended-Cycle Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol (SeasoniqueÒ): Current Status Extended-cycle OCs have increased in popularity as they offer the option of fewer overall scheduled withdrawal bleeding episodes [4]. In some women, withdrawal bleeding is associated with numerous medical conditions, such as premenstrual syndrome, menstrual migraines,

Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol: A Review

endometriosis, iron deficiency and anaemia, and in others, monthly bleeding is an inconvenience that interferes with quality of life and productivity [3, 5]. Additionally, it has been postulated that an extended-cycle OC may help to avoid missing first pills, which is a cause of pill failure and unintended pregnancy [27]. In a 1-year, noncomparative trial of healthy, sexually active women, SeasoniqueÒ was found to have acceptable efficacy for the prevention of pregnancy in terms of the Pearl index for the overall (typical use) and method-failure (compliant use) pregnancy rates (Sect. 4). It is difficult to compare the efficacy and tolerability of different contraceptive products as there is no single accepted and uniformly used design for clinical trials [27]. Moreover, regulatory agencies have differing requirements for the calculation of the Pearl index [27]. For example, the US FDA calculated the Pearl index for SeasoniqueÒ as 1.77, based on 7 pregnancies that occurred on-treatment over 5125.25 28-day equivalent patient months (1577 91-day cycles) using the same clinical trial data [8]. SeasoniqueÒ was generally well tolerated for up to 4 years, with a tolerability profile in line with that expected for a COC (Sect. 5). The most frequently reported adverse events were were irregular and/or heavy uterine bleeding, weight gain and acne. Intermenstrual or unscheduled bleeding is unanticipated by the patient and is the most bothersome type of bleeding and may contribute to an increased discontinuation rate with the necessity of changing the contraceptive method [26, 28]. Cycle control was generally acceptable, with short (two days bleeding and one day spotting) quarterly scheduled bleeding. The incidence of unscheduled bleeding was highest during the first few cycles of SeasoniqueÒ and decreased thereafter (Sect. 5.3). The total number of unscheduled bleeding/spotting days was 2-fold higher in the SeasoniqueÒ group than with a conventional 21/7 day cycle OC. Nevertheless, compliance was high (C98 %) and, compared to a conventional 21/7 day cycle OC, compliance was not affected, anaemia was not evident and there were no clinically important changes in laboratory results. The CHMP committee concluded that the bleeding pattern did not represent a safety issue for women nor impaired the contraceptive efficacy [22]. Counselling about expected bleeding patterns during treatment with an extended-cycle contraceptive may decrease the likelihood of discontinuation [26]. Thus, SeasoniqueÒ extends the contraceptive options currently available to women, particularly in those who desire fewer withdrawal bleeding episodes per year. Further well-designed comparative studies to fully establish

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the relative efficacy and tolerability of SeasoniqueÒ compared with other OC regimens would be of interest. Data selection sources: Relevant medical literature (including published and unpublished data) on ethinylestradiol/levonorgestrel (SeasoniqueÒ) was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) (searches last updated 27 April 2015), bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Ethinyl?estradiol, levonorgestrel, Seasonique, prevent* pregnan*, contracepti*. Study selection: Studies in women who received ethinylestradiol/levonorgestrel (SeasoniqueÒ) for the prevention of pregnancy. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Celeste Burness is a salaried employee of Adis, Springer.

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