Prescription Drug Information: Amethyst

AMETHYST- levonorgestrel and ethinyl estradiol tablet
Actavis Pharma, Inc.

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.

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.
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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 Amethyst 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 Amethyst Over a 28-Day Dosing Period
Levonorgestrel
Day C max (ng/mL) T max (h) t 1/2 (h) AUC 0-24 (ng•h/mL)
1 2.4 (0.9) 1.2 (0.4) 16 (8)
14 5.4 (2.1) 1.7 (1.4) 68 (36)
28 5.7 (2.1) 1.3 (0.8) 36 (19) 74 (41)
Ethinyl Estradiol
Day (pg/mL) (h) (h) (pg•h/mL)
1 47.7 (20.1) 1.3 (0.5) 378 (140)
14 72.7 (37.2) 1.4 (0.5) 695 (361)
28 74.4 (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

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
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SD = standard deviation

The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Amethyst 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 Amethyst 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 Amethyst 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 Amethyst were conducted.

Hepatic Insufficiency

No formal studies have evaluated the effect of hepatic disease on the disposition of Amethyst. 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 Amethyst.

Drug-Drug Interactions

See PRECAUTIONS section – Drug Interactions.

INDICATIONS AND USAGE

Amethyst™ (levonorgestrel and ethinyl estradiol tablets) 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 anUnintended Pregnancywithin the First Year of Use % of Women Continuing Useat One Year 3
Method(1) Typical Use 1 (2) Perfect Use 2 (3) (4)
Chance 4 85 85
Spermicides 5 26 6 40
Periodic abstinence 25 63
Calendar 9
Ovulation method 3
Sympto-thermal 6 2
Post-ovulation 1
Cap 7
Parous women 40 26 42
Nulliparous women 20 9 56
Sponge
Parous women 40 20 42
Nulliparous women 20 9 56
Diaphragm 7 20 6 56
Withdrawal 19 4
Condom 8
Female (Reality®) 21 5 56
Male 14 3 61
Pill 5 71
Progestin only 0.5
Combined 0.1
IUD
Progesterone T 2.0 1.5 81
Copper T380A 0.8 0.6 78
LNg 20 0.1 0.1 81
Depo-Provera® 0.3 0.3 70
Levonorgestrel Implants (Norplant®) 0.05 0.05 88
Female sterilization 0.5 0.5 100
Male sterilization 0.15 0.10 100

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.
  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.

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