Vol. VII, No. II
March/April 2004
Amy Decker,
Pharm.D. Candidate
Return to
Pharmacotherapy
Update Index
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Seasonale® (levonorgestrel 0.15 mg/ethinyl estradiol 0.03 mg)
Extended-Cycle Oral Contraception
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.
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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