DESOGESTREL AND ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL: Package Insert and Label Information

DESOGESTREL AND ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL-
Mylan Pharmaceuticals Inc.

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP provide an oral contraceptive regimen of 21 white to off-white round tablets each containing 0.15 mg desogestrel (13-ethyl-11- methylene-18,19-dinor-17 alpha-pregn- 4-en- 20-yn-17-ol), 0.02 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include anhydrous lactose, colloidal silicon dioxide, polyvinyl pyrrolidone, potato starch, stearic acid, and vitamin E, followed by 2 inert green round tablets with the following inactive ingredients: FD&C Blue No. 1 Aluminum Lake, ferric oxide yellow, lactose monohydrate, magnesium stearate and polacrilin potassium. Desogestrel and Ethinyl Estradiol Tablets, USP and Ethinyl Estradiol Tablets, USP, 0.15 mg/0.02 mg and 0.01 mg also contain 5 light peach round tablets containing 0.01 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20- yne-3,17-diol) and inactive ingredients which include anhydrous lactose, dl -alpha-tocopherol, FD&C Y ellow No. 6 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polacrilin potassium and povidone K-25. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40 respectively. The structural formulas are as follows:

Structure
(click image for full-size original)

Desogestrel and ethinyl estradiol tablets meet USP dissolution test 2

CLINICAL PHARMACOLOGY

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).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91, 92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. and ethinyl estradiol tablets and ethinyl estradiol tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white to off-white] as well as 0.01 mg in the light peach tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Desogestrel and Ethinyl Estradiol Tablets and Ethinyl Estradiol Tablets combination tablet [white to off-white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [light peach] is 99%. The effect of food on the bioavailability of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets were determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by Day 21. The AUC(0–24) for etonogestrel at steady-state on Day 21 was approximately 2.2 times higher than AUC(0–24) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL AND ETHINYL ESTRADIOL TABLETS AND ETHINYL ESTRADIOL TABLETS OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=17).

Etonogestrel

Day

Dosea mg

Cmax pg/mL

Tmax h

t1/2 h

AUC0–24 pg/mL•hr

CL/F L/h

1

0.15

2503.6 (987.6)

2.4 (1.0)

29.8 (16.3)

17,832 (5674)

5.4 (2.5)

21

0.15

4091.2 (1186.2)

1.6 (0.7)

27.8 (7.2)

39,391 (12,134)

4.4 (1.4)

a Desogestrel

Ethinyl Estradiol

Day

Dose mg

Cmax pg/mL

Tmax h

t1/2 h

AUC0–24 pg/mL•hr

CL/F L/h

1

0.02

51.9 (15.4)

2.9 (1.2)

16.5 (4.8)

566 (173)a

25.7 (9.1)

21

0.02

62.2 (25.9)

2.0 (0.8)

23.9 (25.5)

597 (127)a

35.1 (8.2)

24

0.01

24.6 (10.8)

2.4 (1.0)

18.8 (10.3)

246 (65)

43.6 (12.2)

24

0.01

35.3 (27.5)

2.1 (1.3)

18.9 (8.3)

312 (62)

33.2 (6.6)

Cmax measured peak concentration

Tmax observed time of peak concentration

t1/2 elimination half-life, calculated by 0.693/Kelim

AUC0–24 area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours)

CL/F apparent clearance

a)
n=16

Distribution

Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99).

Metabolism

Desogestrel:

Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3α-OH-desogestrel, 3ß-OH-desogestrel, and 3α-OH-5α-H-desogestrel) with no pharmacologic actions also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl estradiol:

Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol escaping gut wall conjugation undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion

Etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. For the 0.01 mg ethinyl estradiol tablet [light peach], the elimination half-life at steady state, Day 28, is 18.9±8.3 hours.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets.

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS section).

INDICATIONS AND USAGE

Desogestrel and ethinyl estradiol tablets and ethinyl estradiol tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

Oral contraceptives are highly effective. Table II lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

TABLE II: 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 Unintended Pregnancy within the First Year of Use

% of Women Continuing Use at One Yeara

Method (1)

Typical Useb (2)

Perfect Usec (3)

(4)

Chanced

85

85

Spermicidese

26

6

40

Periodic abstinence

25

63

Calendar

9

Ovulation Method

3

Sympto-Thermalf

2

Post-Ovulation

1

Withdrawal

19

4

Capg

Parous Women

40

26

42

Nulliparous Women

20

9

56

Sponge

Parous Women

40

20

42

Nulliparous Women

20

9

56

Diaphragmg

20

6

56

Condomh

Female (Reality)

21

5

56

Male

14

3

61

Pill

5

71

Progestin Only

0.5

Combined

0.1

IUD

Progesterone T

2.0

1.5

81

Copper T 380A

0.8

0.6

78

LNg 20

0.1

0.1

81

Depo-Provera

0.3

0.3

70

Norplant and Norplant-2

0.05

0.05

88

Female sterilization

0.5

0.5

100

Male sterilization

0.15

0.10

100

Adapted from Hatcher et al., 1998, ref # 1.

a)
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.

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