Seasonale® (levonorgestrel
0.15 mg/ethinyl estradiol 0.03 mg)
Extended-Cycle Oral Contraception

Volume VII, Number 2 | September/October 2005
Amy Decker, Pharm.D. Candidate

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Introduction

Conventional oral contraceptives (OC) contain 21 days of active pills followed by 7 hormone-free days. The 28-day cycle OC were designed to mimic natural menstruation in hopes of gaining acceptance from physicians, the general population, and the church when oral contraception was still a novel idea. It is a common misconception that the 28-day cycle is necessary. The pill-induced menses does not occur by the same mechanism as natural menstruation. A woman's menstrual cycle begins with an increase in estrogen. Estrogen causes a build-up of the endometrium lining in the uterus, preparing the woman for pregnancy. Estrogen also stimulates luteinizing hormone which, along with follicle stimulating hormone, helps prepare and trigger the release of an egg from the ovary. Progesterone is produced from the released egg and continues to thicken the endometrium lining for pregnancy. If fertilization does not occur, progesterone production diminishes. The endometrium lining is then shed due to the decrease in progesterone. However, when a woman is taking OC, hormones are maintained at a constant level. Since there is no rise in hormones, there is little build-up of an endometrium lining. The menstruation that results with OC is simply a mechanism of hormone withdrawal and therefore not clinically needed. Based on this concept, Duramed Pharmaceuticals developed Seasonale®, an extended-cycle OC. Seasonale® contains 84 days of active pills followed by 7 hormone-free days. This differs from other "continuous-cycle" OC that modify a conventional 28-day OC by skipping the hormone-free pills and continuing with a new package of active pills. Both extended-cycle and continuous-cycle OC allow a woman to experience only four menstrual cycles per year versus the normal number, 12.

Many women are skeptical about altering their menstrual cycle without realizing that today's lifestyle already alters this cycle. At the turn of the century, monthly menses were suppressed by earlier and more frequent pregnancies, longer durations of breastfeeding, and earlier menopause. These women averaged 160 menses in their lifetime compared to today's average of approximately 450. Results from a number of studies verify that it is not necessary for menstruation to occur on a monthly basis, and in fact, it may be a health benefit to decrease the number of menses a woman has per year. Benefits include convenience, improvement in discomfort, risk reduction of cancer (e.g., breast and endometrial), prevention of complications that arise from other co-morbidities, and improvement in pain from endometriosis. Seasonale® is the first oral product on the market that can decrease the number of menses a woman experiences per year. Other products such as Depo-Provera® (injectable progestogen) and Norplant® (implantable levonorgestrel) may cause a decrease in menstruation but do not offer the convenience of an oral tablet.

Pharmacology

Seasonale® contains levonorgestrel 0.15 mg/ethinyl estradiol 0.03 and is similar to Levlen®, Levora®, Nordette®, and Portia®. It is a monophasic compound meaning that the dosage of hormones remains consistent throughout the entire cycle versus biphasic and triphasic OC in which the hormone dose changes based on each week of the monthly cycle. Seasonale® prevents pregnancy by suppressing the gonadotropin hormones, which results in an inhibition of ovulation. In addition, there is an increase in cervical mucus production and changes in the endometrium lining that decrease the ability of implantation.

Selected Clinical Trials

Continuous-Use OC: Loudon and colleagues conducted the first prospective study on the use of extended-cycle OC in 107 women between the ages of 18 and 45 years, using 2.5 mg lynoestrenol/0.05 mg ethinyloestradiol (Minilyn®, not available in the US). The tablet was taken daily for 84 days followed by a 6-day hormone-free interval to allow for withdrawal bleeding. Primary end points consisted of patient satisfaction, cycle control defined by number of bleeding days, and safety defined by adverse events. The difference between spotting and breakthrough bleeding was not defined. On the first 3-month cycle, 24% of women reported spotting and 3% reported breakthrough bleeding. On the second 3-month cycle, 16% of women reported spotting and 3% reported breakthrough bleeding. The third 3-month cycle reported 10% spotting and 1% breakthrough bleeding. The last 3-month cycle reported that 4% of women experienced spotting, with no reports of any breakthrough bleeding. Adverse events included weight gain (46%), headaches (11%), and breast discomfort (13%). Authors concluded that many women approved of using an OC that decreased the number of menstrual cycles. Cycle control was achieved almost completely by the fourth 3-month cycle of OC. Weight gain and breast tenderness were the major side effects.

Miller and colleagues conducted a randomized, controlled trial in 53 women between the ages of 18 and 45 years to compare a conventional 28-day cycle OC (0.3 mg norgestrel/0.03 mg ethinyl estradiol) and an extended 49-day cycle OC in terms of bleeding patterns, symptoms, and method satisfaction. Spotting was defined as any bloody vaginal discharge that did not require sanitary protection. There were significantly fewer bleeding days between the 28-day cycle and 49-day cycle groups, 53.5 days and 27.3 days, respectively (p<0.001). There was no significant difference between the two groups in number of spotting days. Adverse events were similar between the two groups with the exception of a significant decrease in headaches and tiredness in the 49-day cycle group. Authors concluded that the 49-day cycle OC resulted in fewer bleeding days and no increase in spotting days. At the conclusion of the study, 52.4% of women in the extended-cycle OC group approved of the continuation of this regimen.

Miller and colleagues conducted a randomized, parallel trial in 79 women between the ages of 18 and 45 years to determine if amenorrhea was possible with a low-dose monophasic OC. Women were randomized to take either 0.1mg levonorgestrel/0.02 mg ethinyl estradiol (Alesse®) daily for 336 days or daily for 21 days followed by 7 days of placebo for 12 cycles. Bleeding events were defined using Suvisaari and colleagues adaptation of the World Health Organization's bleeding pattern analysis. During cycles 1 through 3, 68% of patients on continuous-cycle OC reported amenorrhea or infrequent bleeding. This number increased to 88% during cycles 10 through 12. The number of days of breakthrough bleeding/spotting increased initially in the continuous OC group but decreased after the first 21 days. Adverse events including changes in blood pressure, hemoglobin, and weight were similar in the two groups. Authors concluded that continuous OC is effective in producing amenorrhea without any significant adverse events.

Seasonale®: Anderson and colleagues conducted a randomized, parallel, multicenter trial in 682 women between the ages of 18 and 40 years to assess the safety and efficacy of Seasonale®, compared to Nordette-28®, a conventional 28-day cycle OC. Both OC contain 0.15 mg levonorgestrel/0.03 mg ethinyl estradiol. Safety was assessed by reports of adverse events while efficacy was measured by failure in preventing pregnancy. Bleeding was defined as vaginal blood loss that required the use of sanitary protection. Spotting was defined as vaginal blood loss that did not require the use of sanitary protection. Pregnancy prevention was assessed by the cumulative rate of pregnancy at 52 weeks using 4-week intervals for the conventional-cycle OC and 91-day intervals for the extended-cycle OC. Patients received either 13 cycles of 28-day Nordette® or four 91-day cycles of Seasonale®. Adverse events were similar between the two groups.

Women taking Seasonale® reported less incidence of headache (21% vs. 28%) but more breakthrough bleeding/spotting events (21% vs. 3%) than those women on Nordette-28®. Breakthrough bleeding/spotting events were comparable to the conventional OC by the fourth 3-month cycle. Three pregnancies were considered method failure, one in the extended-cycle group and two in the conventional-cycle group. The cumulative rates of pregnancy between the two groups were 0.55 per 100 women for Seasonale® versus 1.45 per 100 women for Nordette-28®. The authors concluded that Seasonale® is a safe and effective option for those women considering OC.

Based on these studies, it can be concluded that a continuous-cycle OC allows for significantly less days of bleeding than a conventional-cycle OC. The continuous-cycle OC is similar to conventional-cycle OC in regards to prevention of pregnancy and adverse events. The biggest complaint with continuous-cycle OC was an initial increase in breakthrough bleeding during the first few months. In each of these studies, breakthrough bleeding on extended-cycle OC decreased and was comparable to conventional-cycle OC by the fourth 3-month cycle.

Contraindications/Warnings/Precautions

Seasonale® is contraindicated in women with a known or suspected pregnancy, a history of thromboembolic disorders, valvular heart disease with thrombogenic complications, cerebrovascular or coronary artery disease, uncontrolled hypertension, diabetes with vascular involvement, abnormal vaginal bleeding, history of carcinoma of the endometrium, breast, or liver, suspected estrogen-dependent neoplasia, headaches with focal neurological symptoms, jaundice with pregnancy or prior pill use, smokers (>15 cigarettes/day) >35 years old, and hypersensitivity to any component of this product.

This product, along with all other OC, does not protect against HIV infections or other sexually-transmitted diseases. Caution should be used in patients with conditions that may be aggravated by migraines, depression, or fluid retention. These contraindications are similar between all OC.

Pharmacokinetics and Drug-Drug Interactions

Levonorgestrel is a major substrate of cytochrome P450 (CYP) 3A4. Ethinyl estradiol is a major substrate of CYP 3A4 and weakly inhibits CYP enzymes 1A2, 2B6, 2C19, and 3A4. Antibiotics (e.g., tetracycline and ampicillin), anticonvulsants, aminoglutethimide (Cytadren®), griseofulvin (Grifulvin®), nevirapine (Viramune®), and rifampin may decrease the effectiveness of hormonal contraceptives. An increase or decrease in plasma levels of estrogen and progestin may be observed with anti-coagulants and some anti-HIV protease inhibitors. St. John's wort may decrease contraceptive steroid concentrations through an interaction with CYP 3A4. Patients should avoid concomitant use of black cohosh, dong quai, red clover, saw palmetto, and ginseng, all of which have proposed estrogen activity. Co-administration with acetaminophen, itraconazole (Sporanox®), ketoconazole (Nizoral®), atorvastatin (Lipitor®), and ascorbic acid may increase plasma hormone levels of ethinyl estradiol. Ethinyl estradiol may inhibit the metabolism of theophylline, prednisolone, selegiline (Eldepryl®), tricyclic antidepressants (e.g., amitriptyline [Elavil®], imipramine [Tofranil®], and nortriptyline [Pamelor®]), and cyclosporine (Neoral® and Sandimmune®) while increasing the clearance of temazepam (Restoril®), morphine, clofibric acid, and salicylic acid.

Adverse Reactions

The most serious adverse effects associated with Seasonale® include increased risk of thrombophlebitis, pulmonary embolism, arterial thromboembolism, cerebral thrombosis, cerebral hemorrhage, myocardial infarction, hypertension, hepatic adenomas, and gallbladder disease. Common side effects include breakthrough bleeding and spotting, headache, nausea, and breast tenderness.

Pregnancy/Lactation

All OC are classified as pregnancy-risk category X. Studies have demonstrated fetal malformation in mothers using OC, as well as the risk of fetal malformation outweighs any benefit of medication use. Decreased milk production, shortened duration of lactation, decreased infant weight gain, and decreased composition of nitrogen and protein content of milk has been associated with OC. Estrogens and progestins both cross into breast milk but there are few reports of any adverse events. The American Academy of Pediatrics states that combination OC are compatible with breastfeeding.

Dosing

Seasonale® should be started on the Sunday after the onset of menses. One pink active tablet is taken at a consistent time interval for 84 consecutive days, followed by one white placebo tablet daily for 7 days. Back-up birth control should be used during the first 7 days after initiation of Seasonale®. If one pink pill is missed, it should be taken as soon as it is remembered and then the regular schedule is to be resumed. If two pink pills are missed, two pills should be taken on the day remembered and two pills should be taken on the following day, then resume the regular schedule. Alternative protection against pregnancy must be used in the 7 days after missing the two pills. If three or more pink pills are missed, the missed pills should be thrown away and the regular schedule should be resumed. There will be no protection from pregnancy during this time. Alternative protection must be used during any of the days a pill was missed and for 7 days after. If any of the white inactive pills are missed, throw away missed pills and resume regular schedule. Alternative protection is not needed during this time.

Cost

The cost of Seasonale® versus conventional 28-day OC is described in Table 1.

Table 1: Cost Comparison

*Contains 0.03 mg ethinyl estradiol/levonorgestrel 0.15 mg
† Contains progestogen
‡ Generic product
Cost adapted from www.drugstore.com. Accessed: 1/15/2004.

Summary

Continuous-cycle OC is not a new concept. The first trial comparing a longer hormonal cycle to the conventional 28-day cycle was completed in 1977. Following this study, women were asked to comment on their impression of the continuous-cycle OC. The most common reservations included concern of pregnancy with no menstruation, fear that menstruation would not resume after discontinuation of the OC, fear of possible increased cancer risk, and genuine worry that they were interfering with the natural process of menstruation. With the increased acceptance of OC today, studies are again focusing on continuous-cycle OC. It is now clearly understood that there is no need for a 28-day menstrual cycle. Most women returned to a normal menstruation cycle within a year after discontinuing continuous-cycle OC. With Seasonale®, only one out of 456 women got pregnant due to method failure while on extended-cycle OC. Seasonale® has many advantages including convenience, less visits to the pharmacy, less money spent on sanitary protection, and improvement in quality of life. Seasonale® provides an increased benefit in special patient populations such as military personnel, athletes, and the mentally handicapped. It is of note that no long-term results (over one year) are available in regards to adverse events and safety. There are also no definitive results available on the effects that extended-cycle OC have on cancer risk or the prevention/alleviation of symptoms related to premenstual syndrome. These questions will be answered as the use of extended-cycle OC increases. Seasonale® is only the first step in improving quality of life in regards to the menstruation cycle.

There are no extended-cycle OC, including Seasonale®, on the Cleveland Clinic Foundation Formulary of Accepted Drugs. The Cleveland Clinic currently has two OC on the Formulary, Demulen® and Ovral®, therefore they are the only OC stocked in the Inpatient Hospital Pharmacy.

References Available Upon Request

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