Azurette: Package Insert and Label Information

AZURETTE- desogestrel/ethinyl estradiol and ethinyl estradiol
Mayne Pharma Inc.

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

DESCRIPTION

Azurette® (desogestrel/ethinyl estradiol and ethinyl estradiol tablets USP) provides an oral contraceptive regimen of 21 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, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, and vitamin E, followed by 2 inert light-green, round tablets with the following inactive ingredients: FD&C blue no. 1 aluminum lake, FD&C yellow no. 6 aluminum lake, D&C yellow no. 10 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. Azurette also contains 5 light-blue, round tablets containing 0.01 mg ethinyl estradiol, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include colloidal silicon dioxide, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, hypromellose, lactose monohydrate, polydextrose, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, titanium dioxide, triacetin and vitamin E. The structural formulas are as follows:

DESOGESTREL

Desogestrel
(click image for full-size original)

C22 H30 O M.W. 310.48

ETHINYL ESTRADIOL, USP

Ethinyl Estradiol, USP

C20 H24 O2 M.W. 296.40

The 21 white 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%. Azurette (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the light-blue tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Azurette combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [light-blue] is 99%. The effect of food on the bioavailability of Azurette tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Azurette 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 Azurette tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF Azurette OVER A 28 DAY DOSING PERIOD IN THE THIRD CYCLE (n = 17).

Etonogestrel

Day

Dose

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)

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)

1.
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)

25.7 (9.1)

21

0.02

62.2 (25.9)

2 (0.8)

23.9 (25.5)

597 (127)

35.1 (8.2)

24

0.01

24.6 (10.8)

2.4 (1)

18.8 (10.3)

246 (65)

43.6 (12.2)

28

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

1.
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 to 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., 3a-OH-desogestrel, 3ß-OH-desogestrel, and 3a-OH-5a-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-blue], 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 Azurette.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Azurette.

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Azurette.

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

Azurette® (desogestrel/ethinyl estradiol and ethinyl estradiol tablets USP) is 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.

*
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
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.
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.
§
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.
Foams, creams, gels, vaginal suppositories, and vaginal film.
#
Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
Þ
With spermicidal cream or jelly.
ß
Without spermicides.

% of Women Experiencing an Unintended Pregnancy within the First Year of Use

% of Women

Continuing Use at

One Year * (4)

Method

(1)

Typical Use (2)

Perfect Use (3)

Chance §

85

85

Spermicides

26

6

40

Periodic Abstinence

25

63

Calendar

9

Ovulation Method

3

Sympto-Thermal #

2

Post-Ovulation

1

Withdrawal

19

4

Cap Þ

Parous Women

40

26

42

Nulliparous Women

20

9

56

Sponge

Parous Women

40

20

42

Nulliparous Women

20

9

56

Diaphragm Þ

20

6

56

Condom ß

Female (Reality)

21

5

56

Male

14

3

61

Pill

5

71

Progestin Only

0.5

Combined

0.1

IUD

Progesterone T

2

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.

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