Amethyst: Indications, Dosage, Precautions, Adverse Effects
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Amethyst – Product Information

Manufacture: Watson Pharmaceuticals Inc. (Allergan)
Country: United States
Condition: Birth Control (Contraception), Contraception (Birth Control)
Class: Contraceptives
Form: Tablets
Ingredients: levonorgestrel, microcrystalline cellulose, lactose monohydrate, magnesium stearate, croscarmellose sodium, and povidone

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

Description

Twenty-eight (28) white tablets each containing 90 mcg of levonorgestrel (17α)-(–)13-ethyl-17- hydroxy-18, 19-dinorpregn-4-en-20-yn-3-one, a totally synthetic progestogen, and 20 mcg of ethinyl estradiol, (17α)-19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol. The inactive ingredients present are microcrystalline cellulose, lactose monohydrate, magnesium stearate, croscarmellose sodium, and povidone.


Clinical pharmacology

Mode of Action

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 the endometrium (which reduce the likelihood of implantation).

Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel and ethinyl estradiol in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 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 between 38% and 48%.

A summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days 1 to 28.

Table 1: Mean (SD) Pharmacokinetic Parameters of Levonorgestrel and Ethinyl Estradiol Over a 28-Day Dosing Period

Levonorgestrel
Day Cmax (ng/mL) Tmax (h) t½ (h) AUC0 -24 (ng•h/mL)
12.4 (0.9)1.2 (0.4)-16 (8)
145.4 (2.1)1.7 (1.4)-68 (36)
285.7 (2.1)1.3 (0.8)36 (19)74 (41)
Ethinyl Estradiol
Day (pg/mL)(h)(h)(pg•h/mL)
147.7 (20.1)1.3 (0.5)-378 (140)
1472.7 (37.2)1.4 (0.5)-695 (361)
2874.4 (29.7)1.4 (0.5)21 (7)717 (351)

The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1.

Figure 1: Mean Plasma ± SD† Concentrations of Levonorgestrel and Ethinyl Estradiol Following Single (Day 1) and Multiple (Days 14 and 28) Oral Administrations of Levonorgestrel 90 mcg in Combination with Ethinyl Estradiol 20 mcg to Healthy Women


†SD = standard deviation

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of levonorgestrel and ethinyl estradiol has not been evaluated.

Distribution

Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.

Metabolism

Levonorgestrel: The most important metabolic pathways are reduction of the Δ4-3-oxo group and hydroxylation at positions 2α, 1β, and 16β, followed by conjugation. Most of the circulating metabolites are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17β-sulfate. 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.

Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2- hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation.

Excretion

The terminal elimination half-life for levonorgestrel in levonorgestrel and ethinyl estradiol is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in levonorgestrel and ethinyl estradiol is about 21 hours.

Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.

Special Populations

Race

No formal studies on the effect of race on the pharmacokinetic parameters of levonorgestrel and ethinyl estradiol were conducted.

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of levonorgestrel and ethinyl estradiol. However, steroid hormones may be poorly metabolized in patients with impaired liver function.

Renal Insufficiency

No formal studies have evaluated the effect of renal disease on the disposition of levonorgestrel and ethinyl estradiol.

Drug-Drug Interactions

See PRECAUTIONS section – Drug Interactions.

Indications and usage

Amethyst (levonorgestrel and ethinyl estradiol tablets USP) is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

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 implants, depend upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table 2: Percentage of Women Experiencing an Unintended Pregnancy During The First Year of Typical Use and The First Year of Perfect Use of Contraception and The Percentage Continuing Use at The End of the First Year. United States.

% of Women Experiencing an Accidental Pregnancy within the First Year of Use% of Women Continuing Use at One Year3
Method (1) Typical Use1 (2) Perfect Use2 (3) (4)
Chance4 85 85
Spermicides 526 640
Periodic abstinence 25 63
Calendar 9
Ovulation method 3
Sympto-thermal 6 2
Post-ovulation 1
Cap7 2
Parous women 40 2642
Nulliparous women 20 956
Sponge
Parous women 40 2042
Nulliparous women 20 956
Diaphragm 720 656
Condom 8
Female (Reality®*)21 556
Male 14 361
Pill 5
Progestin only 0.5
Combined 0.1
IUD
Progesterone T 2.0 1.581
Copper T380A 0.8 0.678
Lng 200.1 0.181
Depo-Provera®*0.3 0.370
Norplant®* and Norplant®* II0.05 0.0588
Female sterilization 0.5 0.5100
Male sterilization 0.15 0.10100

Emergency Contraceptive Pills: The FDA has concluded that certain combined oral contraceptives containing ethinyl estradiol and norgestrel or levonorgestrel are safe and effective for use as postcoital emergency contraception. Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception. 10 Source: Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowel D, Guest F. Contraceptive Technology: Seventeenth Revised Edition.

New York NY: Irvington Publishers; 1998.

  1. Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
  2. Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
  3. Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
  4. The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
  5. Foams, creams, gels, vaginal suppositories, and vaginal film.
  6. Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
  7. With spermicidal cream or jelly. 8. Without spermicides.
  8. The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The FDA has declared the following dosage regimens of oral contraceptives to be safe and effective for emergency contraception: for tablets containing 50 mcg of ethinyl estradiol and 500 mcg of norgestrel 1 dose is 2 tablets; for tablets containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel 1 dose is 5 tablets; for tablets containing 30 mcg of ethinyl estradiol and 150 mcg of levonorgestrel 1 dose is 4 tablets.
  9. However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

Clinical Studies

The efficacy and safety of levonorgestrel and ethinyl estradiol tablets USP were studied in 2 one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (BMI), weight, or bleeding history.

The primary efficacy and safety study (313-NA) was a one-year open-label clinical trial that treated 2,134 subjects in North America. Of these subjects 1,213 (56.8%) discontinued prematurely, including 102 (4.8%) discontinued by the Sponsor for early study closure. The mean weight of subjects in this study was 70.38 kg. The efficacy of levonorgestrel and ethinyl estradiol tablets USP was assessed by the number of pregnancies that occurred after the onset of treatment and within 14 days of the last dose. Among subjects 35 years or less, there were 23 pregnancies (4 of these occurred during the interval 1 to 14 days after the last day of pill use) during 12,572 28-day pill packs of use. The resulting total Pearl Index was 2.38 (95% CI: 1.51, 3.57) and the one-year life table pregnancy rate was 2.39 (95% CI: 1.57, 3.62). Pill pack cycles during which subjects used back-up contraception or were not sexually active were not included in these calculations. Among women 35 years or less who took the pills completely as directed, there were 15 pregnancies (method failures) resulting in a Pearl Index of 1.55 (95% CI: 0.87, 2.56) and the one-year life table pregnancy rate was 1.59 (95% CI: 0.95 to 2.67).

In a second supportive study conducted in Europe (315-EU), 641 subjects were randomized to levonorgestrel and ethinyl estradiol tablets USP (n=323) or the cyclic comparator of 100 mcg levonorgestrel and 20 mcg ethinyl estradiol (n=318). The mean weight of subjects in this study was 63.86 kg. The efficacy analysis among women 35 years or less included 2,756 levonorgestrel and ethinyl estradiol tablets USP pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol tablets USP group that occurred within 14 days following the last dose. There were three pregnancies in the cyclic comparator group.

Inhibition of Menses (Bleeding Profile)

The bleeding profile for subjects in Study 313-NA also was assessed. Women with a history of unscheduled bleeding and/or spotting were not excluded from the study.

In those subjects who provided complete bleeding data, the percentage of patients who were amenorrheic in a given cycle and remained amenorrheic through cycle 13 (cumulative amenorrhea rate) was determined (Figure 2).

Figure 2: Percentage of Subjects with Cumulative Amenorrhea for Each Pill Pack through Pill Pack 13


The 779 subjects with complete data for 13 pill packs were used in this cumulative analysis. Subjects were to begin pill pack 1 on the first day of menses.

When prescribing Amethyst, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled bleeding and spotting (see WARNINGS, 11).

Contraindications

Combination oral contraceptives should not be used in women with any of the following conditions:

  • Thrombophlebitis or thromboembolic disorders
  • History of deep-vein thrombophlebitis or thromboembolic disorders
  • Cerebrovascular or coronary artery disease (current or past history)
  • Valvular heart disease with thrombogenic complications
  • Thrombogenic rhythm disorders
  • Hereditary or acquired thrombophilias
  • Major surgery with prolonged immobilization
  • Diabetes with vascular involvement
  • Headaches with focal neurological symptoms such as aura
  • Uncontrolled hypertension
  • Known or suspected carcinoma of the breast or personal history of breast cancer
  • Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
  • Undiagnosed abnormal genital bleeding
  • Cholestatic jaundice of pregnancy or jaundice with prior pill use
  • Hepatic adenomas or carcinomas, or active liver disease
  • Known or suspected pregnancy
  • Hypersensitivity to any of the components of Amethyst

Warnings

Cigarette smoking increases the risk of serious cardiovascular s ide effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a s ignificantly increased risk) 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 risks of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, stroke, and transient ischemic attack), hepatic neoplasia, gallbladder disease, and hypertension, although 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 or acquired thrombophilias, hypertension, hyperlipidemias, obesity, diabetes, and surgery or trauma with increased risk of thrombosis (see CONTRAINDICATIONS).

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 doses 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 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.

Thromboembolic Disorders and Other Vascular Problems

Amethyst is a non-cyclic oral contraceptive that provides a low daily dose of estrogen and progestin; however, Amethyst provide women with more hormonal exposure on a yearly basis (13 additional weeks of hormone intake per year) than conventional cyclic oral contraceptives containing the same strength of synthetic estrogens and similar strength of progestins.

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary-artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives.

Figure 3: Circulatory Disease Mortality Rates per 100,000 Woman Years by Age, Smoking Status and Oral Contraceptive Use


Adapted from P.M. Layde and V. Beral, Lancet, 1:541-546, 1981.

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). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Venous Thrombosis and Thromboembolism

An increased risk of venous thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. The risk of venous thrombotic and thromboembolic events is further increased in women with conditions predisposing for venous thrombosis and thromboembolism. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep-vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (< 0.05 mg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5 to 3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). The excess risk is highest during the first year a woman ever uses a combined oral contraceptive. Venous thromboembolism may be fatal. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and gradually disappears after pill use is stopped.

A two-to-four fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate post-partum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed, or after a midtrimester pregnancy termination.

c. Cerebrovascular Diseases

Oral contraceptives 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), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes. Transient ischemic attacks have also been associated with oral contraceptive use.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias. Women with migraine (particularly migraine/headaches with focal neurological symptoms such as aura) who take combination oral contraceptives may be at an increased risk of stroke. (See CONTRAINDICATIONS).

d. Dose-Related Risk of Vascular Disease from Oral Contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogen used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

e. Persistence of Risk of Vascular Disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least 9 years for women 40 to 49 years who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups.

In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 0.05 mg or higher of estrogens.

Estimates of Mortality from Contraceptive Use

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.

Table 3: Annual Number of Birth-Related or Method-Related Deaths Associated with Control of Fertility per 100,000 Nonsterile Women, by Fertility-Control Method and According to Age

Method of Control and Outcome AGE
15 to 1920 to 2425 to 2930 to 3435 to 3940 to 44
No fertility control methods*7.07.49.114.825.728.2
Oral contraceptives nonsmoker**0.30.50.91.913.831.6
Oral contraceptives smoker**2.23.46.613.551.1117.2
lUD**0.80.8111.41.4
Condom*1.11.60.70.20.30.4
Diaphragm/ spermicide*1.91.21.21.32.22.8
Periodic abstinence*2.51.61.61.72.93.6

* Deaths are birth-related

** Deaths are method-related

Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983.

Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiological studies have examined the association between the use of oral contraceptives and the incidence of breast and cervical cancer.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have reported a small increase in risk for women who first use combination oral contraceptives at a younger age. Most studies show a similar pattern of risk with combination oral contraceptive use regardless of a woman’s reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous oral contraceptive users tend to be less clinically advanced than in nonusers.

Women with known or suspected carcinoma of the breast or personal history of breast cancer should not use oral contraceptives because breast cancer is usually a hormonally 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 combination oral contraceptive use and breast and cervical cancers, a cause-and-effect relationship has not been established.

Endometrial biopsies performed in a subset of subjects (Study 1; n = 93) ages 18 to 49 years, after 6 to 12 months of use of levonorgestrel and ethinyl estradiol tablets USP, did not reveal any hyperplasias or malignancies. Endometrial malignancy is rare in this age group, so change in the risk is unlikely to be detected with a study of this size.

Hepatic Neoplasia

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of these benign tumors 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 rare, benign, 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 user. 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.

Ocular Lesions

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.

Oral Contraceptive Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in infants born to women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly insofar 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.

The possibility of pregnancy should be considered in any patient who may be experiencing symptoms of pregnancy, especially if she has not adhered to the prescribed schedule. Oral contraceptive use must be discontinued if pregnancy is confirmed.

Gallbladder Disease

Combination oral contraceptives may worsen existing gallbladder disease and may accelerate the development of this disease in previously asymptomatic women. 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.

Carbohydrate and Lipid Metabolic Effects

Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 0.075 mg 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 WARNINGS, 1a. and 1d.; PRECAUTIONS, 3.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

Elevated Blood Pressure

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 quantities 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.

Headache

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. and CONTRAINDICATIONS).

Bleeding Irregularities

When prescribing Amethyst, the convenience of having no scheduled menstrual bleeding should be weighed against the inconvenience of unscheduled breakthrough bleeding and spotting. In Study 313- NA, 385/2,134 (18%) of women discontinued prematurely due to bleeding that was reported either as an adverse event or where bleeding was given as one of the reasons for discontinuation (see INDICATIONS AND USAGE, Clinical Studies).

Figure 4 shows the percentage of levonorgestrel and ethinyl estradiol tablets USP subjects in study 313-NA by pill pack who experienced unscheduled bleeding or spotting only (Defined as “No sanitary protection required”).

Figure 4: Percentage of Subjects Reporting Bleeding or Spotting Only per Pill Pack


*: The N for each pill pack is the number of subjects with 28 days of data.

Bleeding required sanitary protection; spotting only did not require sanitary protection.

Figure 5 shows the percentage of levonorgestrel and ethinyl estradiol tablets USP subjects with complete bleeding data in Study 313-NA who had 4 or more and 7 or more days of bleeding and/or spotting during each pill pack cycle. During pill pack 2, 67% of subjects experienced 4 or more days of bleeding and/or spotting and 54% of these subjects experienced 7 or more days of bleeding and/or spotting. During the final cycle of use of levonorgestrel and ethinyl estradiol tablets USP (pill pack 13), these percentages were 31% and 20%, respectively.

Figure 5: Percentage of Subjects Reporting Greater than or Equal to 4 or 7 Days of Bleeding and/or Spotting per Pill Pack (Study 313-NA)


*: The N for each pill pack is the number of subjects with 28 days of data.

As in any case of bleeding irregularities, nonhormonal causes should be considered and adequate diagnostic measures may be indicated to rule out pregnancy, infection, malignancy, or other conditions.

Some women may encounter post-pill amenorrhea or oligomenorrhea (possibly with anovulation), especially when such a condition was preexistent.

Ectopic Pregnancy

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

General

Patients should be counseled that oral contraceptives do not protect against transmission of HIV (AIDS) and other sexually transmitted diseases (STDs) such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis.

Scheduled withdrawal bleeding does not occur with the use of levonorgestrel and ethinyl estradiol, therefore, the absence of withdrawal bleeding cannot be used as a sign of an unexpected pregnancy and as such, unexpected pregnancy may be difficult to recognize. Although pregnancy is unlikely if levonorgestrel and ethinyl estradiol is taken as directed, if for any reason, pregnancy is suspected in a woman using levonorgestrel and ethinyl estradiol, a pregnancy test should be performed.

Physical Examination and Follow-Up

A periodic personal and family medical history and complete 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 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.

Lipid Disorders

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, 1a., 1d., and 8.)

A small proportion of women will have adverse lipid changes while taking oral contraceptives. Nonhormonal contraception should be considered in women with uncontrolled dyslipidemias. Persistent hypertriglyceridemia may occur in a small population of combination oral contraceptive users. Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Liver Function

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.

Fluid Retention

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.

Emotional Disorders

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. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

Contact Lenses

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

Gastrointestinal

Diarrhea and/or vomiting may reduce hormone absorption resulting in decreased serum concentrations.

Drug Interactions

Changes in Contraceptive Effectiveness Associated with Coadministration of Other Products:

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or unscheduled bleeding. Examples include rifampin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin, and modafinil. In such cases a nonhormonal back-up method of birth control should be considered.

Several cases of contraceptive failure and unscheduled bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and other penicillins, and tetracyclines. However, clinical pharmacology studies investigating drug interactions between combined oral contraceptives and these antibiotics have reported inconsistent results. Enterohepatic recirculation of estrogens may also be decreased by substances that reduce gut transit time.

Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with coadministration of anti-HIV protease inhibitors. Health care professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John’s Wort (Hypericum perforatum) may induce hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in unscheduled bleeding.

Increase in Plasma Levels Associated with Coadministered Drugs:

Coadministration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increases AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen increase the bioavailability of ethinyl estradiol since these drugs act as competitive inhibitors for sulfation of ethinyl estradiol in the gastrointestinal wall, a known pathway of elimination for ethinyl estradiol. CYP 3A4 inhibitors such as indinavir, itraconazole, ketoconazole, fluconazole, and troleandomycin may increase plasma hormone levels. Troleandomycin may also increase the risk of intrahepatic cholestasis during coadministration with combination oral contraceptives.

Changes in Plasma Levels of Coadministered Drugs:

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporine, prednisolone and other corticosteroids, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and lamotrigine, and increased clearance of temazepam, salicylic acid, morphine, and clofibric acid, due to induction of conjugation (particularly glucuronidation), have been noted when these drugs were administered with oral contraceptives.

The prescribing information of concomitant medications should be consulted to identify potential interactions.

Interaction with Laboratory Tests

Certain endocrine- and liver-function tests and blood components may be affected by oral contraceptives:

a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

b. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4concentration is unaltered.

c. Other binding proteins may be elevated in serum i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulins (SHBG) leading to increased levels of total circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged.

d. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.

e. Glucose tolerance may be decreased.

f. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

Carcinogenesis

See WARNINGS section.

Pregnancy

Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.

Nursing Mothers

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, combination 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 combination oral contraceptives, but to use other forms of contraception until she has completely weaned her child.

Pediatric Use

Safety and efficacy of levonorgestrel and ethinyl estradiol 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 16 and for users 16 years and older. Use of this product before menarche is not indicated.

Geriatric Use

This product has not been studied in women over 65 years of age and is not indicated in this population.

Information for Patients

See DETAILED PATIENT LABELING printed below.

Adverse reactions

An increased risk of the following serious adverse reactions (see WARNINGS section for additional information) has been associated with the use of oral contraceptives:

  • Thromboembolic and thrombotic disorders and other vascular problems (including thrombophlebitis and venous thrombosis with or without pulmonary embolism, mesenteric thrombosis, arterial thromboembolism, myocardial infarction, cerebral hemorrhage, cerebral thrombosis, transient ischemic attack)
  • Carcinoma of the reproductive organs and breasts
  • Hepatic neoplasia/liver disease (including hepatic adenomas or benign liver tumors)
  • Ocular lesions (including retinal vascular thrombosis)
  • Gallbladder disease
  • Carbohydrate and lipid effects
  • Elevated blood pressure
  • Headache including migraine

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related (alphabetically listed):

  • Acne
  • Amenorrhea
  • Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms
  • Breast changes: tenderness, pain, enlargement, secretion
  • Budd-Chiari syndrome
  • Cervical erosion and secretion, change in
  • Cholestatic jaundice
  • Chorea, exacerbation of
  • Colitis
  • Contact lenses, intolerance to
  • Corneal curvature (steepening), change in
  • Dizziness
  • Edema/fluid retention
  • Erythema multiforme
  • Erythema nodosum
  • Focal nodular hyperplasia
  • Gastrointestinal symptoms (such as abdominal pain, cramps, and bloating)
  • Hirsutism
  • Infertility after discontinuation of treatment, temporary
  • Lactation, diminution in, when given immediately postpartum
  • Libido, change in
  • Melasma/chloasma which may persist
  • Menstrual flow, change in
  • Mood changes, including depression
  • Nausea
  • Nervousness
  • Pancreatitis
  • Porphyria, exacerbation of
  • Rash (allergic)
  • Scalp hair, loss of
  • Serum folate levels, decrease in
  • Spotting
  • Systemic lupus erythematosus, exacerbation of
  • Unscheduled bleeding
  • Vaginitis, including candidiasis
  • Varicose veins, aggravation of
  • Vomiting
  • Weight or appetite (increase or decrease), change in

The following adverse reactions have been reported in users of oral contraceptives:

  • Cataracts
  • Cystitis-like syndrome
  • Dysmenorrhea
  • Hemolytic uremic syndrome
  • Hemorrhagic eruption
  • Optic neuritis, which may lead to partial or complete loss of vision
  • Premenstrual syndrome
  • Renal function, impaired

Overdosage

Symptoms of oral contraceptive overdosage in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur in females. There is no specific antidote and further treatment of overdose, if necessary, is directed to the symptoms.

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:

May decrease blood loss and may decrease the incidence of iron-deficiency anemia May decrease incidence of dysmenorrhea

Effects related to inhibition of ovulation:

May decrease incidence of functional ovarian cysts

May decrease incidence of ectopic pregnancies

Effects from long-term use:

May decrease incidence of fibroadenomas and fibrocystic disease of the breast

May decrease incidence of acute pelvic inflammatory disease

May decrease incidence of endometrial cancer

May decrease incidence of ovarian cancer

Dosage and administration

To achieve maximum contraceptive effectiveness, Amethyst must be taken exactly as directed and at intervals not exceeding 24 hours. The possibility of ovulation and conception prior to initiation of medication should be considered. Women who do not wish to become pregnant after discontinuation should be advised to immediately use another method of birth control. The dosage of Amethyst is one white tablet daily without any tablet-free interval.

It is recommended that Amethyst be taken at the same time each day.

Initiation of Therapy

Instructions for beginning Amethyst are provided in Table 4 below.

Table 4

Current contraceptive therapy Levonorgestrel and ethinyl estradiol tablets USP start day Nonhormonal back-up method of birth control needed when correctly starting levonorgestrel and ethinyl estradiol tablets USP?
None Day 1 of patient’s menstrual cycle (during the first 24 hours of her period) No
21-day COC regimen OR 28- day COC regimen Day 1 of patient’s withdrawal bleed, at the latest 7 days after her last active tablet No
Progestin-only pill Day after taking a progestin-only pill Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablets USP tablet-taking
Implant Day of implant removal Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablets USP tablet-taking
Injection Day the next injection is due Yes, for the first 7 days of levonorgestrel and ethinyl estradiol tablets USP tablet-taking

If spotting or unscheduled bleeding occurs, the patient is instructed to continue on the same regimen. This type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient is advised to consult her health care professional. The possibility of ovulation increases with each successive day that scheduled white tablets are missed. If the patient has not adhered to the prescribed schedule (missed one or more tablets or started taking them on a day later than she should have), the probability of pregnancy should be considered. Hormonal contraception must be discontinued if pregnancy is confirmed.

The risk of pregnancy increases with each tablet missed. For additional patient instructions regarding missed tablets, see the WHAT TO DO IF YOU MISS PILLS section in the DETAILED PATIENT LABELING below.Levonorgestrel and ethinyl estradiol tablets USP may be initiated no earlier than day 28 postpartum in the nonlactating mother or after a second-trimester abortion due to the increased risk for thromboembolism (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, pregnancy should be excluded before the start of combined oral contraceptive use or the patient must wait for her first menstrual period.

In the case of first-trimester abortion, if the patient starts Amethyst immediately, additional contraceptive measures are not needed.

How supplied

Amethyst (levonorgestrel and ethinyl estradiol tablets USP 90 mcg/20 mcg) is available in a 28 tablet dispenser, arranged in 4 rows of 7 active tablets as follows:

28 round, white, flat face, beveled edge, uncoated tablets debossed with 295 on one side and WATSON on the other side (NDC 52544-295-28).

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].