SEASONALE- levonorgestrel / ethinyl estradiol
Duramed Pharmaceuticals, Inc.
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Seasonale® (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:
Levonorgestrel C21H28O2 MW: 312.4
Ethinyl Estradiol C20H24O2 MW: 296.4
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.
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and changes in the endometrium (which reduce the likelihood of implantation).
Absorption
No specific investigation of the absolute bioavailability of Seasonale 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%.
Analyte |
AUCt (mean ± SD) |
Cmax (mean ± SD) |
Tmax (mean ± SD) |
T1/2 (mean ± SD) |
Levonorgestrel | 60.8 ± 25.6 ng*hr/mL | 5.6 ± 1.5 ng/mL | 1.4 ± 0.3 hours | 29.8 ± 8.3 hours |
Ethinyl estradiol | 1307 ± 361 pg*hr/mL | 145 ± 45 pg/mL | 1.6 ± 0.5 hours | 15.4 ± 3.2 hours |
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Seasonale 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 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 was found to be about 15 hours.
No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Seasonale . However, steroid hormones may be poorly metabolized in patients with impaired liver function.
Seasonale 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 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.
Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York NY: Irvington Publishers, 1998. | |||
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% of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year * |
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Method (1) | Typical Use †
(2) | Perfect Use ‡
(3) |
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Chance § | 85 | 85 | |
Spermicides ¶ | 26 | 6 | 40 |
Periodic abstinence | 25 | 63 | |
Calendar | 9 | ||
Ovulation method | 3 | ||
Sympto-thermal # | 2 | ||
Post-ovulation | 1 | ||
Withdrawal | 19 | 4 | |
Cap Þ | |||
Parous women | 40 | 26 | 42 |
Nulliparous women | 20 | 9 | 56 |
Sponge | |||
Parous women | 40 | 20 | 42 |
Nulliparous women | 20 | 9 | 56 |
Diaphragm Þ | 20 | 6 | 56 |
Condom ß | |||
Female (Reality) | 21 | 5 | 56 |
Male | 14 | 3 | 61 |
Pill | 5 | 71 | |
Progestin only | 0.5 | ||
Combined | 0.1 | ||
IUD: | |||
Progesterone T | 2.0 | 1.5 | 81 |
Copper T 380A | 0.8 | 0.6 | 78 |
LNg 20 | 0.1 | 0.1 | 81 |
Depo Provera | 0.3 | 0.3 | 70 |
Norplant and Norplant-2 | 0.05 | 0.05 | 88 |
Female sterilization | 0.5 | 0.5 | 100 |
Male sterilization | 0.15 | 0.10 | 100 |
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%. à | |||
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. è |
Oral contraceptives should not be used in women who currently have the following conditions:
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.
Use of Seasonale provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (an additional 9 weeks per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with Seasonale have not suggested an increased risk of these disorders.
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). The severity and number of risk factors increase heart disease risk. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is less than that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's−but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
Adapted from H.W. Ory, Family Planning Perspectives, 15: 57-63, 1983. | ||||||
AGE | ||||||
Method of control and outcome |
15-19 |
20-24 |
25-29 |
30-34 |
35-39 |
40-44 |
No Fertility - control methods* | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
Oral contraceptives non-smokers† | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
Oral contraceptives smoker† | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
IUD† | 0.8 | 0.8 | 1.0 | 1.0 | 1.4 | 1.4 |
Condom* | 1.1 | 1.6 | 0.7 | 0.2 | 0.3 | 0.4 |
Diaphragm/ spermicide* | 1.9 | 1.2 | 1.2 | 1.3 | 2.2 | 2.8 |
Periodic abstinence* | 2.5 | 1.6 | 1.6 | 1.7 | 2.9 | 3.6 |
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. Although the risk of having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (RR=1.24), this excess risk decreases over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use and no consistent relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone sensitive tumor.
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.
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
Because women using Seasonale will likely have withdrawal bleeding only 4 times per year, pregnancy should be ruled out at the time of any missed menstrual period (see DOSAGE AND ADMINISTRATION 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 CONTRAINDICATIONS 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.
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
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 WARNINGS1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
Women with significant hypertension should not be started on hormonal contraceptive. An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c.)
When prescribing Seasonale , 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 (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 subjects, compared to subjects on the 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [Seasonale ] vs. 1.8% [28-day cycle regimen]).
Table 4 shows the percentages of women with ≥7 days and ≥20 days of intermenstrual spotting and/or bleeding in the Seasonale and the 28-day cycle treatment groups.
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Days of intermenstrual bleeding and/or spotting | Percentage of Subjects * | |
Seasonale® | Cycle 1 (N=385) | Cycle 4 (N=261) |
≥ 7 days | 65% | 42% |
≥ 20 days | 35% | 15% |
28-day regimen | Cycles 1-4 (N=194) | Cycles 10-13 (N=158) |
≥ 7 days | 38% | 39% |
≥ 20 days | 6% | 4% |
Total days of bleeding and/or spotting (withdrawal plus intermenstrual) were similar over one year of treatment for Seasonale 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.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
A periodic history and physical examination are appropriate for all women, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In the case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
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 WARNINGS 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.
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related.
Contact-lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
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.
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
Small amounts of oral contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS 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:
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.
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
Although the occurrence of pregnancy is unlikely if Seasonale 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 should be discontinued if pregnancy is confirmed.
The dosage of Seasonale is one pink (active) tablet daily for 84 consecutive days, followed by 7 days of white (inert) tablets. To achieve maximum contraceptive effectiveness, Seasonale 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 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 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 “WHAT TO DO IF YOU MISS PILLS” section in the DETAILED PATIENT LABELING. 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 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 CONTRAINDICATIONS, WARNINGS and PRECAUTIONS 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 may be initiated immediately after a first-trimester abortion; if the patient starts Seasonale immediately, additional contraceptive measures are not needed.
Seasonale tablets (levonorgestrel / ethinyl estradiol tablets) 0.15 mg / 0.03 mg are available in Extended-Cycle Tablet Dispensers (NDC 51285-058-66), 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 S on one side and 62 on the other side. The inert tablets are white, round, biconvex, unscored tablet debossed with S on one side and 197 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.
TEVA WOMEN’S HEALTH, INC.
Subsidiary of TEVA PHARMACEUTICALS USA, INC.
Sellersville, PA 18960
Iss. 7/2011
This product (like all oral contraceptives) is intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
Oral contraceptives, also known as “birth control pills” or “the pill”, are taken to prevent pregnancy, and when taken correctly, have a failure rate of approximately 1.0% per year (1 pregnancy per 100 women per year of use). The typical failure rate of pill users is approximately 5% per year when women who miss pills are included.
For the majority of women, oral contraceptives can be taken safely. But for some women oral contraceptive use is associated with certain serious diseases that can be life-threatening or may cause temporary or permanent disability or death. The risks associated with taking oral contraceptives increase significantly if you:
You should not take the pill if you are pregnant.
Although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy, non-smoking women (even with the newer low-dose formulations), there are also greater potential health risks associated with pregnancy in older women.
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.
Most side effects of the pill are not serious. The most common are nausea, vomiting, bleeding or spotting between menstrual periods, weight gain, breast tenderness, and difficulty wearing contact lenses. Some of these side effects, especially nausea and vomiting, may subside within the first 3 months of use.
The serious side effects of the pill occur very infrequently, especially if you are in good health and do not smoke. However, you should know that the following medical conditions have been associated with or made worse by the pill:
The symptoms associated with these serious side effects are discussed in the detailed patient information leaflet. Notify your healthcare provider if you notice any unusual physical disturbances while taking the pill. In addition, drugs such as rifampin, as well as some anticonvulsants and some antibiotics, and herbal preparations containing St. John’s Wort (hypericum perforatum) may decrease oral contraceptive effectiveness.
Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This very small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It maybe that women taking the pill were examined more often, so that breast cancer was more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormone-sensitive tumor.
Some studies have found an increase in the incidence of cancer or precancerous lesions of the cervix in women who use the pill. However, this finding may be related to factors other than the use of the pill.
Be sure to discuss any medical condition you may have with your healthcare provider. Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is appropriate to postpone it. You should be reexamined at least once a year while taking oral contraceptives. The detailed patient information leaflet gives you further information which you should read and discuss with your healthcare provider.
What You Should Know About Your Menstrual Cycle When Taking Seasonale
When you take Seasonale , which has a 91-day treatment cycle, you should expect to have 4 menstrual periods per year (bleeding when you are taking the 7 white pills). However, you also should expect to have more bleeding or spotting between your menstrual periods than if you were taking an oral contraceptive with a 28-day treatment cycle. During the first Seasonale treatment cycle, about 1 in 3 women may have 20 or more days of unplanned bleeding or spotting (bleeding when you are taking pink pills). This bleeding or spotting tends to decrease during later cycles. Do not stop Seasonale because of the bleeding. If the spotting continues for more than 7 consecutive days or if the bleeding is heavy, call your healthcare provider.
If You Miss Your Menstrual Period When Taking Seasonale
You should consider the possibility that you are pregnant if you miss your menstrual period (no bleeding on the days that you are taking white tablets). Since scheduled menstrual periods are less frequent when you are taking Seasonale , notify your healthcare provider that you have missed your period and are taking Seasonale . Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider evaluates you to determine if you are pregnant. Stop taking Seasonale if it is determined that you are pregnant.
HOW TO TAKE SEASONALE
IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING SEASONALE
BEFORE YOU START TAKING SEASONALE
WHEN TO START SEASONALE
HOW TO TAKE SEASONALE
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 pink “active” pill:
If you MISS 2 pink “active” pills in a row:
If you MISS 3 OR MORE pink “active” pills in a row:
If you MISS ANY of the 7 white inactive pills.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED
This product (like all oral contraceptives) is intended to prevent pregnancy. Oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.
INTRODUCTION
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 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® and during your revisits. You should also follow your healthcare provider's advice with regard to regular check-ups while you are on Seasonale.
EFFECTIVENESS OF ORAL CONTRACEPTIVES
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%
WHO SHOULD NOT TAKE ORAL CONTRACEPTIVES
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the amount of smoking (15 or more cigarettes per day has been associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should not smoke.
Some women should not use the pill. You should not use the pill if you have any of the following conditions:
Tell your healthcare provider if you have any of the above conditions. Your healthcare provider can recommend a safer method of birth control.
OTHER CONSIDERATIONS BEFORE TAKING ORAL CONTRACEPTIVES
Tell your healthcare provider if you or any family member has ever had:
Women with any of these conditions should be checked often by their healthcare provider if they choose to use oral contraceptives. Also, be sure to inform your healthcare provider if you smoke or are on any medications.
RISKS OF TAKING ORAL CONTRACEPTIVES
If you use Seasonale you will receive more exposure to hormones on a yearly basis than if you used a conventional 28-day cycle oral contraceptives containing a similar amount of estrogen and progestin (an additional 9 weeks exposure per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with Seasonale® have not suggested an increased risk of these disorders.
ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY
All methods of birth control and pregnancy are associated with a risk of developing certain diseases which may lead to disability or death. An estimate of the number of deaths associated with different methods of birth control and pregnancy has been calculated and is shown in the following table.
AGE | ||||||
Method of Control and outcome |
15-19 |
20-24 |
25-29 |
30-34 |
35-39 |
40-44 |
No fertility - control methods* | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
Oral contraceptives non-smoker† | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
Oral contraceptives smoker† | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
IUD† | 0.8 | 0.8 | 1.0 | 1.0 | 1.4 | 1.4 |
Condom* | 1.1 | 1.6 | 0.7 | 0.2 | 0.3 | 0.4 |
Diaphragm/ spermicide* | 1.9 | 1.2 | 1.2 | 1.3 | 2.2 | 2.8 |
Periodic abstinence* | 2.5 | 1.6 | 1.6 | 1.7 | 2.9 | 3.6 |
In the above table, the risk of death from any birth control method is less than the risk of childbirth, except for oral contraceptive users over the age of 35 who smoke and pill users over the age of 40 even if they do not smoke. It can be seen in the table that for women aged 15 to 39, the risk of death was highest with pregnancy (7 to 26 deaths per 100,000 women, depending on age). Among pill users who do not smoke, the risk of death was always lower than that associated with pregnancy for any age group, although over the age of 40, the risk increases to 32 deaths per 100,000 women, compared to 28 associated with pregnancy at that age. However, for pill users who smoke and are over the age of 35, the estimated number of deaths exceeds those for other methods of birth control. If a woman is over the age of 40 and smokes, her estimated risk of death is four times higher (117/100,000 women) than the estimated risk associated with pregnancy (28/100,000 women) in that age group.
The suggestion that women over 40 who don't smoke should not take oral contraceptives is based on information from older high-dose pills. An Advisory Committee of the FDA discussed this issue in 1989 and recommended that the benefits of oral contraceptive use by healthy, nonsmoking women over 40 years of age may outweigh the possible risks. Older women, as all women who take oral contraceptives, should take an oral contraceptive that contains the least amount of estrogen and progestin that is compatible with the individual patient needs.
WARNING SIGNALS
If any of these adverse effects occur while you are taking oral contraceptives, call your healthcare provider immediately:
SIDE EFFECTS OF ORAL CONTRACEPTIVES
In addition to the risks and more serious side effects discussed above (see RISKS OF TAKING ORAL CONTRACEPTIVES, ESTIMATED RISK OF DEATH FROM A BIRTH CONTROL METHOD OR PREGNANCY and WARNING SIGNALS sections), the following may also occur:
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Number of days of intermenstrual bleeding and/or spotting | Percentage of subjects with intermenstrual bleeding or spotting* | |
Seasonale ® | Cycle 1 | Cycle 4 |
7 or more days | 65% | 42% |
20 or more days | 35% | 15% |
28-day cycle pill | Cycles 1-4 | Cycles 10-13 |
7 or more | 38% | 39% |
20 or more days | 6% | 4% |
Total days of bleeding and/or spotting (withdrawal plus intermenstrual) were similar over one year of treatment for Seasonale subjects and subjects on the 28-day cycle regimen.
Other side effects may include nausea and vomiting, change in appetite, breast tenderness, headache, nervousness, depression, dizziness, loss of scalp hair, rash, vaginal infections, and allergic reactions.
If any of these side effects bother you, call your healthcare provider.
GENERAL PRECAUTIONS
What You Should Know About Your Menstrual Cycle When Taking Seasonale
When you take Seasonale , which has a 91-day treatment cycle, you should expect to have 4 menstrual periods per year (bleeding when you are taking the 7 white pills). However, you also should expect to have more bleeding or spotting between your menstrual periods than if you were taking an oral contraceptive with a 28-day treatment cycle. During the first Seasonale treatment cycle, about 1 in 3 women may have 20 or more days of unplanned bleeding or spotting (bleeding when you are taking pink pills). This bleeding or spotting tends to decrease during later cycles. Do not stop Seasonale because of the bleeding. If the spotting continues for more than 7 consecutive days or if the bleeding is heavy, call your healthcare provider.
HOW TO TAKE SEASONALE
IMPORTANT POINTS TO REMEMBER BEFORE YOU START TAKING SEASONALE
BEFORE YOU START TAKING SEASONALE
WHEN TO START SEASONALE
HOW TO TAKE SEASONALE
WHAT TO DO IF YOU MISS PILLS
If you MISS 1 pink “active” pill:
If you MISS 2 pink “active” pills in a row:
If you MISS 3 OR MORE pink “active” pills in a row:
If you MISS ANY of the 7 white inactive pills.
FINALLY, IF YOU ARE STILL NOT SURE WHAT TO DO ABOUT THE PILLS YOU HAVE MISSED
PREGNANCY DUE TO PILL FAILURE
If taken every day as directed, the incidence of pill failure resulting in pregnancy is approximately 1 % (ie, one pregnancy per 100 women per year), but more typical failure rates are about 5%. If failure does occur, the risk to the fetus is minimal.
PREGNANCY AFTER STOPPING THE PILL
There may be some delay in becoming pregnant after you stop using oral contraceptives, especially if you had irregular menstrual cycles before you used oral contraceptives. It may be advisable to postpone conception until you begin menstruating regularly once you have stopped taking the pill and desire pregnancy.
There does not appear to be any increase in birth defects in newborn babies when pregnancy occurs soon after stopping the pill.
OVERDOSAGE
Serious ill effects have not been reported following ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding in females. In case of overdosage, contact your healthcare provider or pharmacist.
OTHER INFORMATION
Your healthcare provider will take a medical and family history before prescribing oral contraceptives and will examine you. The physical examination may be delayed to another time if you request it and the healthcare provider believes that it is appropriate to postpone it. You should be reexamined at least once a year. Be sure to inform your healthcare provider if there is a family history of any of the conditions listed previously in this leaflet. Be sure to keep all appointments with your healthcare provider, because this is a time to determine if there are early signs of side effects of oral contraceptive use.
Do not use the drug for any condition other than the one for which it was prescribed. This drug has been prescribed specifically for you; do not give it to others who may want birth control pills.
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:
If you want more information about birth control pills, ask your doctor or pharmacist. They have a more technical leaflet called the Professional Labeling which you may wish to read.
TEVA WOMEN’S HEALTH, INC.
Subsidiary of TEVA PHARMACEUTICALS USA, INC.
Sellersville, PA 18960
Iss. 7/2011
SEASONALE
levonorgestrel / ethinyl estradiol kit |
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Labeler - Duramed Pharmaceuticals, Inc. (017038951) |