Amethyst

Amethyst is a prescription birth control medication used to prevent pregnancy. Amethyst contains two hormones, levonorgestrel and ethinyl estradiol, which belong to a group of drugs called hormonal contraceptives. These hormones prevent pregnancy by stopping ovulation and by altering cervical mucus and the lining of the uterus.

This medication comes in tablet form and is taken once daily, with or without food. 

Common side effects of Amethyst include nausea, breast tenderness, and vaginal bleeding between menstrual periods. 

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: uncontrolled high blood pressure, heart disease, a blood-clotting disorder, circulation problems, diabetic problems with your eyes or kidneys, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, if you smoke and are over 35, or if you have ever had breast or uterine cancer, jaundice caused by birth control pills, a heart attack, a stroke, or a blood clot.

Taking this medicine can increase your risk of blood clots, stroke, or heart attack, especially if you have certain other conditions, or if you are overweight.

Smoking can greatly increase your risk of blood clots, stroke, or heart attack. You should not take this medicine if you smoke and are over 35 years old.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You will take your first pill on the first day of your period or on the first Sunday after your period begins. You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.

Take one pill every day, no more than 24 hours apart. When the pills run out, start a new pack the following day. You may get pregnant if you do not take one pill daily. Get your prescription refilled before you run out of pills completely.

Some birth control packs contain seven "reminder" pills to keep you on your regular cycle. Your period will usually begin while you are using these reminder pills.

You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

Use a back-up birth control if you are sick with severe vomiting or diarrhea.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medicine for a short time. Any doctor or surgeon who treats you should know that you are using birth control pills.

While taking birth control pills, you will need to visit your doctor regularly.

Store this medicine at room temperature away from moisture and heat.

Do not smoke while taking birth control pills, especially if you are older than 35 years of age.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Follow how to use as you have been told by the doctor or read the package insert.
• Take Amethyst at the same time of day.
• Take with or without food. Take with food if it causes an upset stomach.
• Do not skip doses, even if you do not have sex very often.
• If you throw up or have diarrhea, this medicine may not work as well to prevent pregnancy. Use an extra form of birth control, like condoms, until you check with your doctor.
• If your monthly cycle is 28 days and you miss 2 periods in a row, take a pregnancy test before starting a new dosing cycle.
• If you have a cycle longer than 91 days and you miss one period, take a pregnancy test before starting a new dosing cycle.

What do I do if I miss a dose?

• If a dose is missed, check the package insert or call the doctor to find out what to do. If using Amethyst to prevent pregnancy, another form of birth control may need to be used for some time to prevent pregnancy.

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.

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 ∆4-3-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.

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.

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.

: 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.
   
9. 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.
   
10. 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 were studied in 2 one-year clinical trials of subjects age 18 to 49. There were no exclusions for body mass index (), 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 . 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 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 (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 pill packs and 2,886 cyclic comparator pill packs. There was one pregnancy in the levonorgestrel and ethinyl estradiol tablets 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).

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

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.

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