AMETHIA- ethinyl estradiol and levonorgestrel
Mayne Pharma Inc
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AMETHIA tablets safely and effectively. See full prescribing information for AMETHIA tablets.
AMETHIA - Levonorgestrel/Ethinyl Estradiol tablets and Ethinyl Estradiol tablets for oral use.
Initial U.S. Approval: 1982
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
AMETHIA tablets are an estrogen/progestin COC indicated for use by women to prevent pregnancy. (1)
DOSAGE AND ADMINISTRATION
Take one tablet daily by mouth at the same time every day for 91 days. (2)
DOSAGE FORMS AND STRENGTHS
AMETHIA tablets consists of 84 white tablets containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets containing 0.01 mg ethinyl estradiol. (3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions (≥5%) in clinical trials for levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets are irregular and/or heavy uterine bleeding, weight gain, and acne. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma. at 1-844 -825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up method or alternative method of contraception when enzyme inducers are used with COCs. (7.1)
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
FULL PRESCRIBING INFORMATION: CONTENTS*
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See Contraindications (4).]
Take one tablet by mouth at the same time every day. The dosage of AMETHIA tablets is one white tablet containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one light blue ethinyl estradiol tablet for 7 days. To achieve maximum contraceptive effectiveness, AMETHIA tablets must be taken exactly as directed and at intervals not exceeding 24 hours.
Instruct the patient to begin taking AMETHIA tablets on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, the first white tablet is taken that day. One white tablet should be taken daily for 84 consecutive days, followed by one light blue tablet for 7 consecutive days. A non-hormonal back-up method of contraception (such as condoms or spermicide) should be used until a white tablet has been taken daily for 7 consecutive days. A scheduled period should occur during the 7 days that the light blue tablets are taken.
Begin the next and all subsequent 91-day cycles without interruption on the same day of the week (Sunday) on which the patient began her first dose of AMETHIA tablets, following the same schedule: 84 days taking a white tablet followed by 7 days taking a blue tablet. If the patient does not immediately start her next pill pack, she should protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a white tablet daily for 7 consecutive days.
If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider.
For patient instructions regarding missed pills, see FDA-Approved Patient Labeling.
For postpartum women who are not breastfeeding, start AMETHIA tablets no earlier than four to six weeks postpartum due to increased risk of thromboembolism. If the patient starts on AMETHIA tablets postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken a white tablet for 7 consecutive days.
AMETHIA tablets are available in Extended-Cycle Tablet Dispensers, each containing a 13-week supply of tablets: 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets each containing 0.01 mg of ethinyl estradiol. The white tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 268 on the other side. The light blue tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 270 on the other side.
AMETHIA tablets are contraindicated in females who are known to have or develop the following conditions:
Stop AMETHIA tablets if an arterial or deep venous thrombotic event occurs. Although the use of COCs increases the risk of venous thromboembolism, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs. The risk of venous thromboembolism in women using COCs is 3 to 9 per 10,000 woman-years. The excess risk is highest during the first year of use of a COC. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued.
Use of AMETHIA tablets provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year).
If feasible, stop AMETHIA tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.
Start AMETHIA tablets no earlier than 4 - 6 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
Stop AMETHIA tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately.
AMETHIA tablets are contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications (4)].
Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk. Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer. However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Postmarketing Experience (6.2)].
Discontinue AMETHIA tablets if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.
Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.
Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.
During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue AMETHIA tablets prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)]. AMETHIA tablets can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.
For women with well-controlled hypertension, monitor blood pressure and stop AMETHIA tablets if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.
An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.
Studies suggest a small increased relative risk of developing gallbladder disease among COC users.
Carefully monitor prediabetic and diabetic women who are taking AMETHIA tablets. COCs may decrease glucose tolerance in a dose-related fashion.
Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs.
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.
If a woman taking AMETHIA tablets develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Levonorgestrel/Ethinyl Estradiol tablets and Ethinyl Estradiol tablets if indicated.
An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.
Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If bleeding persists, check for causes such as pregnancy or malignancy.
If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.
When prescribing AMETHIA tablets, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased unscheduled bleeding and/or spotting. The primary clinical trial (PSE-301) that evaluated the efficacy of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets also assessed unscheduled bleeding. The participants in the 12-month clinical trial (N=1,006) completed the equivalent of 8,681 28-day cycles of exposure and were composed primarily of women who had used oral contraceptives previously (89%) as opposed to new users (11%). A total of 82 (8.2%) of the women discontinued levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets, at least in part, due to bleeding or spotting.
Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with an average of 3 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding in treatment cycles 1 and 4. Table 2 presents the number of days with unscheduled spotting in treatment cycles 1 and 4.
|91-Day Treatment Cycle||Days per 84-Day Interval||Days per 28-Day Interval|
|Q1=Quartile 1: 25% of women had this number of days of unscheduled bleeding
Median: 50% of women had ≤ this number of days of unscheduled bleeding
Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled bleeding
|91-Day Treatment Cycle||Days per 84-Day Interval||Days per 28-Day Interval|
|Q1=Quartile 1: 25% of women had ≤ this number of days of unscheduled spotting
Median: 50% of women had ≤ this number of days of unscheduled spotting
Q3=Quartile 3: 75% of women had ≤ this number of days of unscheduled spotting
Figure 1 shows the percentage of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets subjects participating in trial PSE-301 with ≥ 7 days or ≥ 20 days of unscheduled bleeding and/or spotting, or only unscheduled bleeding, during each 91-day treatment cycle.
Amenorrhea sometimes occurs in women who are using COCs. Pregnancy should be ruled out in the event of amenorrhea. Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.
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. Oral contraceptive use should be discontinued if pregnancy is confirmed.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].
Women with a history of depression should be carefully observed and AMETHIA tablets discontinued if depression recurs to a serious degree.
The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid binding globulin increase with use of COCs.
A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care.
In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
Adverse reactions commonly reported by COC users are:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The clinical trial that evaluated the safety and efficacy of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets was a 12-month, randomized, multicenter, open-label study, which enrolled women aged 18-40, of whom 1,006 took at least one dose of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets.
Adverse Reactions Leading to Study Discontinuation: 16.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions (≥ 1% of women) leading to discontinuation were irregular and/or heavy uterine bleeding (5.9%), weight gain (2.4%), mood changes (1.5%), and acne (1.0%).
Common Treatment-Emergent Adverse Reactions (≥ 5% of women): irregular and/or heavy uterine bleeding (17%), weight gain (5%), acne (5%).
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90–1.12 (Figure 2).
Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 2). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19–1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.
|RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.|
The following adverse reactions have been identified during post-approval use of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: abdominal distension, vomiting
General disorders and administration site conditions: chest pain, fatigue, malaise, edema peripheral, pain
Immune system disorders: hypersensitivity reaction
Investigations: blood pressure increased
Musculoskeletal and connective tissue disorders: muscle spasms, pain in extremity
Nervous system disorders: dizziness, loss of consciousness
Psychiatric disorders: insomnia
Reproductive and breast disorders: dysmenorrhea
Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary thrombosis
Skin and subcutaneous tissue disorders: alopecia
Vascular disorders: thrombosis
No drug-drug interaction studies were conducted with AMETHIA tablets.
If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Co-administration of atorvastatin and certain COCs 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. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.
Do not co-administer AMETHIA tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.4)].
COCs containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. COCs 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.
There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.
The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.
Women who do not breastfeed may start COCs no earlier than four to six weeks postpartum.
When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
Safety and efficacy of AMETHIA tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of AMETHIA tablets before menarche is not indicated.
AMETHIA tablets have not been studied in women who have reached menopause and is not indicated in this population.
No studies have been conducted to evaluate the effect of hepatic disease on the disposition of AMETHIA tablets. However, steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. [See Contraindications (4) and Warnings and Precautions (5.3)].
There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea.
AMETHIA tablets are an extended-cycle oral contraceptive consisting of 84 white tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 light blue tablets containing 0.01 mg of ethinyl estradiol.
The structural formulas for the active components are:
C21H28O2 MW: 312.4
Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-.
C20H24O2 MW: 296.4
Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-.
Each white tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate.
Each light blue tablet contains the following inactive ingredients: vitamin E, anhydrous lactose, povidone, FD&C Blue #1, colloidal silicon dioxide, corn starch and stearic acid.
COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.
Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after AMETHIA tablets administration. Levonorgestrel is completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first- pass metabolism. Ethinyl estradiol is 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 daily exposure to levonorgestrel and ethinyl estradiol on Day 21, corresponding to the end of a typical 3-week contraceptive regimen, and on Day 84, at the end of an extended cycle regimen, were similar. There was no additional accumulation of ethinyl estradiol after dosing a 0.03 mg ethinyl estradiol tablet during Days 84-91. The mean plasma pharmacokinetic parameters of AMETHIA tablets following a single dose of one levonorgestrel/ethinyl estradiol combination tablet, for 84 days, in normal healthy women are reported in Table 3.
|AUC 0-24 hr
(mean ± SD)
(mean ± SD)
(mean ± SD)
|Day 1||18.2 ± 6.1 ng∙hr/mL||3.0 ± 1.0 ng/mL||1.3 ± 0.4 hours|
|Day 21||64.4 ± 25.1 ng∙hr/mL||6.2 ± 1.6 ng/mL||1.3 ± 0.4 hours|
|Day 84||60.2 ± 24.6 ng∙hr/mL||5.5 ± 1.6 ng/mL||1.3 ± 0.3 hours|
|Day 1||509.3 ± 172.0 pg∙hr/mL||69.8 ± 26 pg/mL||1.5 ± 0.3 hours|
|Day 21||837.1 ± 271.2 pg∙hr/mL||99.6 ± 31 pg/mL||1.5 ± 0.3 hours|
|Day 84||791.5 ± 215.0 pg∙hr/mL||91.3 ± 32 pg/mL||1.6 ± 0.3 hours|
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of AMETHIA tablets has not been evaluated.
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 levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β- tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α- tetrahydrolevonorgestrel and 16β-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.
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 AMETHIA tablets was about 34 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 AMETHIA tablets was found to be about 18 hours.
In a 12-month, multicenter, randomized, open-label clinical trial, 1,006 women aged 18-40 were studied to assess the safety and efficacy of levonorgestrel/ethinyl estradiol tablets and ethinyl estradiol tablets, completing the equivalent of 8,681 28-day cycles of exposure. The racial demographic of those enrolled was: Caucasian (80%), African-American (11%), Hispanic (5%), Asian (2%), and Other (2%). There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 91 to 360 lbs., with a mean weight of 156 lbs. Among the women in the trial, 63% were current or recent hormonal contraceptive users, 26% were prior users (who had used hormonal contraceptives in the past but not in the 6 months prior to enrollment), and 11% were new starts. Of treated women, 14.8% were lost to follow-up, 16.3% discontinued due to an adverse event, and 12.9% discontinued by withdrawing their consent.
The pregnancy rate (Pearl Index [PI]) in women aged 18-35 years was 1.34 pregnancies per 100 women-years of use (95% confidence interval 0.54-2.75), based on 7 pregnancies that occurred after the onset of treatment and within 14 days after the last combination pill. Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes patients who did not take the drug correctly.
AMETHIA tablets, 0.15mg/0.03 mg and 0.01 mg are available in Extended-Cycle Tablet Dispensers (NDC 51862-047-01), each containing a 13-week supply of tablets: 84 white tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 light blue tablets each containing 0.01 mg of ethinyl estradiol. The white tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 268 on the other side. The light blue tablets are round, flat face beveled edge, unscored tablets with WATSON on one side and 270 on the other side.
Box of 2 Extended-Cycle Tablet Dispensers
Greenville, NC 27834
2100 Syntex Court
Mississauga, Ontario L5N 7K9 Canada
FDA-Approved Patient Labeling
Guide for Using
AMETHIA Levonorgestrel/Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets,
0.15 mg/0.03 mg and 0.01 mg
Revised August 2022
|WARNING TO WOMEN WHO SMOKE|
|Do not use AMETHIA tablets if you smoke cigarettes and are over 35. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.|
Birth control pills help to lower the chances of becoming pregnant. They do not protect against HIV infection (AIDS) and other sexually transmitted diseases.
What Are AMETHIA Tablets?
Levonorgestrel/Ethinyl Estradiol tablets and Ethinyl Estradiol tablets are a birth control pill. They contain two female hormones, an estrogen called ethinyl estradiol, and a progestin called levonorgestrel.
How Well Do AMETHIA Tablets Work?
Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The more carefully you follow the directions, the less chance you have of getting pregnant.
Based on the results of a single clinical study lasting 12 months, 1 to 3 women, out of 100 women, may get pregnant during the first year they use AMETHIA tablets.
The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant.
How Do I Take AMETHIA Tablets?
Before you start taking AMETHIA Tablets
When to Start AMETHIA Tablets
How to Take AMETHIA Tablets
If you MISS 1 white pill:
If you MISS 2 white pills in a row:
If you MISS 3 OR MORE white pills in a row:
If you MISS ANY of the 7 light blue pills:
Finally, if you are still not sure what to do about the pills you have missed
Who Should Not Take AMETHIA Tablets?
Your healthcare provider will not give you AMETHIA tablets if you have:
Also, do not take birth control pills if you:
Birth control pills may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy.
What Else Should I Know About Taking AMETHIA Tablets?
Birth control pills do not protect you against any sexually transmitted disease, including HIV, the virus that causes AIDS.
Do not skip any pills, even if you do not have sex often.
Birth control pills should not be taken during pregnancy. However, birth control pills taken by accident during pregnancy are not known to cause birth defects.
If you are breastfeeding, consider another birth control method until you are ready to stop breastfeeding. Birth control pills that contain estrogen, like AMETHIA tablets, may decrease the amount of milk you make. A small amount of the pill's hormones pass into breast milk.
Tell your healthcare provider about all medicines and herbal products that you take. Some medicines and herbal products may make birth control pills less effective, including:
Consider using another birth control method when you take medicines that may make birth control pills less effective.
Birth control pills may interact with lamotrigine, an anticonvulsant used for epilepsy. This may increase the risk of seizures, so your physician may need to adjust the dose of lamotrigine.
If you have vomiting or diarrhea, your birth control pills may not work as well. Use another birth control method, like condoms or a spermicide, until you check with your healthcare provider.
What Are The Most Serious Risks Of Taking Birth Control Pills?
Like pregnancy, birth control pills increase the risk of serious blood clots, especially in women who have other risk factors, such as smoking, obesity, or age > 35. It is possible to die from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious blood clots are blood clots in the:
Women who take birth control pills may get:
All of these events are uncommon in healthy women.
Call your healthcare provider right away if you have:
What Are Common Side Effects Of Birth Control Pills?
The most common side effects of birth control pills are:
These side effects are usually mild and usually disappear with time.
Less common side effects are:
This is not a complete list of possible side effects. Talk to your healthcare provider if you develop any side effects that concern you. You may report side effects to the FDA at 1-800-FDA-1088.
No serious problems have been reported from a birth control pill overdose, even when accidentally taken by children.
Do Birth Control Pills Cause Cancer?
It is not known if hormonal birth control pills cause breast cancer. Some studies, but not all, suggest that there could be a slight increase in the risk of breast cancer among current users with longer duration of use.
If you have breast cancer now, or have had it in the past, do not use hormonal birth control because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners.
What Should I Know About My Period When Taking AMETHIA tablets?
When you take AMETHIA tablets, which have a 91-day extended dosing cycle, you should expect to have 4 scheduled periods per year (bleeding when you are taking the 7 light blue pills). Each period is likely to last about 3 days. However, you will probably have more bleeding or spotting between your scheduled periods than if you were using a birth control pill with a 28-day dosing cycle. During the first AMETHIA tablets 91-day treatment cycle, about 3 in 10 women may have 20 or more days of unplanned bleeding or spotting. This bleeding or spotting tends to decrease with time. Do not stop taking AMETHIA tablets because of this bleeding or spotting. If the spotting continues for more than 7 consecutive days or if the bleeding is heavy, call your healthcare provider.
What If I Miss My Scheduled Period When Taking AMETHIA tablets?
You should consider the possibility that you are pregnant if you miss your scheduled period (no bleeding on the days that you are taking light blue tablets). Since scheduled periods are less frequent when you are taking AMETHIA tablets, notify your healthcare provider that you have missed your period and that you are taking AMETHIA tablets. 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 AMETHIA tablets if it is determined that you are pregnant.
What If I Want To Become Pregnant?
You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill.
General Advice About AMETHIA tablets
Your healthcare provider prescribed AMETHIA tablets for you. Do not share AMETHIA tablets with anyone else. Keep AMETHIA tablets out of the reach of children.
If you have concerns or questions, ask your healthcare provider. You may also ask your healthcare providers for a more detailed label written for medical professionals.
Greenville, NC 27834
2100 Syntex Court
Mississauga, Ontario L5N 7K9
Revised: August 2022
(Levonorgestrel/Ethinyl Estradiol Tablets
and Ethinyl Estradiol Tablets,
0.15 mg/0.03 mg and 0.01 mg)
Contains 2 Extended-Cycle Tablet Dispensers, each containing 91 tablets: 84 white tablets,
each containing 0.15 mg levonorgestrel with 0.03 mg ethinyl estradiol, and 7 light blue
tablets, each containing 0.01 mg ethinyl estradiol.
2 Extended-Cycle Tablet Dispensers, 91 Tablets Each
ethinyl estradiol and levonorgestrel kit
|Labeler - Mayne Pharma Inc (867220261)|
|Patheon Inc.||240769596||MANUFACTURE(51862-047) , PACK(51862-047) , LABEL(51862-047)|
|Patheon Pharmaceuticals Inc.||005286822||ANALYSIS(51862-047)|