Seasonale Information
Seasonale (Ethinyl)
Seasonale (Ethinyl) Description
Seasonale (Ethinyl) (levonorgestrel/ethinyl estradiol tablets) is an extended-cycle oral contraceptive consisting of 84 pink active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 white inert tablets (without hormones).
The chemical formula of levonorgestrel USP is 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. The structural formulas are as follows:
Each pink active tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP. Each white inert tablet contains the following inactive ingredients: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.
Seasonale (Ethinyl) Clinical Pharmacology
Absorption
No specific investigation of the absolute bioavailability of Seasonale (Ethinyl) in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Seasonale (Ethinyl) has not been evaluated.
Distribution
The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.
Metabolism
Following absorption, levonorgestrel is conjugated at the 17ß-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5ß-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16ß-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall , followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
Excretion
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Seasonale (Ethinyl) was about 30 hours.
Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Seasonale (Ethinyl) was found to be about 15 hours.
Seasonale (Ethinyl) Special Populations
See PRECAUTIONS section – Drug Interactions.
Seasonale (Ethinyl) Indications And Usage
Seasonale (Ethinyl) tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Seasonale (Ethinyl) during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) pregnancy rate of 1.98 per 100 women-years of use.
Oral contraceptives are highly effective for pregnancy prevention. Table 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and Norplant Implant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
Seasonale (Ethinyl) Contraindications
Oral contraceptives should not be used in women who currently have the following conditions:
Seasonale (Ethinyl) Warnings
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension. The risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower doses of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors. In spite of many studies of the relationship between oral contraceptive use and breast cancer and cervical cancers, a cause-and-effect relationship has not been established.
Benign hepatic adenomas are associated with oral contraceptive use, although their occurrence is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.
Because women using Seasonale (Ethinyl) will likely have withdrawal bleeding only 4 times per year, pregnancy should be ruled out at the time of any missed menstrual period (see section). Oral contraceptive use should be discontinued if pregnancy is confirmed.
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy (see section).
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
When prescribing Seasonale (Ethinyl) , the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased intermenstrual bleeding and/or spotting.
The clinical trial (SEA 301) that compared the efficacy of Seasonale (Ethinyl) (91-day cycles) to an equivalent dosage 28-day cycle regimen also assessed intermenstrual bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥10 consecutive days on oral contraceptives were excluded from the study. More Seasonale (Ethinyl) subjects, compared to subjects on the 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [Seasonale (Ethinyl) ] vs. 1.8% [28-day cycle regimen]).
Table 4
Total days of bleeding and/or spotting (withdrawal plus intermenstrual) were similar over one year of treatment for Seasonale (Ethinyl) subjects and subjects on the 28-day cycle regimen.
As in any case of bleeding irregularities, nonhormonal causes should always be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy.
In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.
Seasonale (Ethinyl) Precautions
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult. (See 1d.)
In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.
Changes in contraceptive effectiveness associated with co-administration of other products
Increase in plasma levels of estradiol associated with co-administered drugs
Co-administration of atorvastatin and certain combination oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.
Changes in plasma levels of co-administered drugs
Combination oral contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of combination oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation have been noted when these drugs were administered with combination oral contraceptives. Combination OCs have been shown to significantly decrease plasma concentrations of lamotrigine likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
Pregnancy Category X.
Seasonale (Ethinyl) Information For The Patient
See Patient Labeling Printed Below.
Seasonale (Ethinyl) Adverse Reactions
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see section):
There is evidence of an association between the following conditions and the use of oral contraceptives:
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related:
The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:
Seasonale (Ethinyl) Overdosage
Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.
Seasonale (Ethinyl) Noncontraceptive Health Benefits
The following noncontraceptive health benefits related to the use of oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol.
Effects on menses:
Effects related to inhibition of ovulation:
Effects from long-term use:
May decrease incidence of ovarian cancer
Seasonale (Ethinyl) Dosage And Administration:
Although the occurrence of pregnancy is unlikely if Seasonale (Ethinyl) is taken according to directions, if withdrawal bleeding does not occur while taking white (inactive) tablets, the possibility of pregnancy must be considered. Appropriate diagnostic measures to rule out pregnancy should be taken at the time of any missed menstrual period. Seasonale (Ethinyl) should be discontinued if pregnancy is confirmed.
The dosage of Seasonale (Ethinyl) is one pink (active) tablet daily for 84 consecutive days, followed by 7 days of white (inert) tablets. To achieve maximum contraceptive effectiveness, Seasonale (Ethinyl) must be taken exactly as directed and at intervals not exceeding 24 hours. Ideally, the tablets should be taken at the same time of the day on each day of active treatment. The tablets should not be removed from the protective blister packaging and outer plastic dispenser to avoid damage to the product. The plastic dispenser should be kept in the foil pouch until dispensed to the patient.
During the first cycle of medication, the patient is instructed to begin taking Seasonale (Ethinyl) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first tablet (pink) is taken that day. One pink tablet should be taken daily for 84 consecutive days, followed by 7 days on which a white (inert) tablet is taken. Withdrawal bleeding should occur during the 7 days following discontinuation of pink active tablets. During the first cycle, contraceptive reliance should not be placed on Seasonale (Ethinyl) until a pink (active) tablet has been taken daily for 7 consecutive days and a non-hormonal back-up method of birth control (such as condoms or spermicide) should be used during those 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered.
The patient begins her next and all subsequent 91-day courses of tablets without interruption on the same day of the week (Sunday) on which she began her first course, following the same schedule: 84 days on which pink tablets are taken followed by 7 days on which white tablets are taken. If in any cycle the patient starts tablets later than the proper day, she should protect herself against pregnancy by using a non-hormonal back-up method of birth control until she has taken a pink tablet daily for 7 consecutive days.
If spotting or breakthrough bleeding occurs , the patient is instructed to continue on the same regimen. This type of bleeding may be transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her healthcare provider.
For patient instructions regarding missed pills, see the “ section in the . Any time the patient misses two or more pink tablets, she should also use another method of non-hormonal back-up contraception until she has taken a pink tablet daily for seven consecutive days. If the patient misses one or more white tablets, she is still protected against pregnancy provided she begins taking pink tablets again on the proper day. The possibility of ovulation increases with each successive day that scheduled pink tablets are missed. The risk of pregnancy increases with each active (pink) tablet missed.
In the nonlactating mother, Seasonale (Ethinyl) may be initiated no earlier than day 28 postpartum, for contraception due to the increased risk for thromboembolism. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (See , and concerning thromboembolic disease). The patient should be advised to use a nonhormonal back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, the possibility of ovulation and conception prior to initiation of medication should be considered. Seasonale (Ethinyl) may be initiated immediately after a first-trimester abortion; if the patient starts Seasonale (Ethinyl) immediately, additional contraceptive measures are not needed.
Seasonale (Ethinyl) How Supplied:
Seasonale (Ethinyl) tablets (levonorgestrel / ethinyl estradiol tablets) 0.15 mg / 0.03 mg are available in Extended-Cycle Tablet Dispensers (), each containing a 13-week supply of tablets: 84 pink tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 white inert tablets. The active pink tablets are round, film-coated, biconvex, unscored tablets with a debossed on one side and on the other side. The inert tablets are white, round, biconvex, unscored tablet debossed with on one side and on the other side.
Store at controlled room temperature 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature].
References available upon request.
Seasonale (Ethinyl)
Seasonale (Ethinyl) Arraydetailed Patient Labeling
Any woman who considers using oral contraceptives (“the birth control pill” or “the pill”) should understand the benefits and risks of using this form of birth control. Although oral contraceptives have important advantages over other methods of contraception, they have certain risks that no other method has, and some of these risks may continue after you have stopped using the oral contraceptive. This leaflet will give you much of the information you will need to make this decision and will also help you determine if you are at risk of developing any of the serious side effects of the pill. It will tell you how to use Seasonale (Ethinyl) properly so that it will be as effective as possible. However, this leaflet is not a replacement for a careful discussion between you and your healthcare provider. You should discuss the information provided in this leaflet with your healthcare provider, both when you first start taking Seasonale (Ethinyl) and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on Seasonale (Ethinyl) .
Oral contraceptives or “the birth control pill” or “the pill”are used to prevent pregnancy and are more effective than most other nonsurgical methods of birth control. The chance of becoming pregnant is approximately 1.0% per year (1 pregnancy per 100 women per year of use) when the pills are used correctly, and no pills are missed. Typical failure rates are approximately 5.0% per year when women who miss pills are included. The chance of becoming pregnant increases with each missed pill during the menstrual cycle.
In comparison, typical failure rates for other methods of birth control during the first year of use are as follows:
No methods: 85%Vaginal sponge: 20 to 40%Cervical cap: 20 to 40%Spermicides alone: 26%Periodic abstinence: 25%Condom (female): 21%Diaphragm with spermicides: 20%Withdrawal: 19%Condom (male): 14%Female sterilization: 0.5%IUD: 0.1 to 2.0%Injectable progestogen: 0.3%Male sterilization: 0.15%Norplant system: 0.05%
Seasonale (Ethinyl) Principal Display Panel
Rx only
Contains 3 Extended-Cycle Tablet Dispensers, each containing 91 tablets: Eighty-four pink tablets, each containing 0.15 mg levonorgestrel with 0.03 mg ethinyl estradiol, and seven white inert tablets.
Store at controlled room temperature 20°-25° C (68°-77° F) [See USP].
