Apri 28 Day

APRI 28 DAY- desogestrel and ethinyl estradiol
Teva Pharmaceuticals USA, Inc.

WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH SMOKING

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including Apri® , should not be used by women who are over 35 years of age and smoke.

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

DESCRIPTION

Apri® (desogestrel and ethinyl estradiol tablets USP) blister cards provide an oral contraceptive regimen of 21 rose-colored, round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-17-ol) and 0.03 mg ethinyl estradiol, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol). Inactive ingredients include colloidal silicon dioxide, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hydroxypropyl methylcellulose, lactose monohydrate, polyethylene glycol, polysorbate 80, povidone, pregelatinized corn starch, stearic acid, titanium dioxide, and vitamin E.

Apri blister cards also contain 7 white “inactive” tablets for oral administration, containing the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch.

Desogestrel

structural formula 1

C22 H30 O M.W. 310.48

Ethinyl Estradiol, USP

structural formula 2

C20 H24 O2 M.W. 296.40

The 21 rose-colored tablets meet USP Dissolution Test 2.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Combined 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 changes in the endometrium which reduce the likelihood of implantation.

Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, 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

Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-keto-desogestrel, is approximately 84%.

In the third cycle of use after a single dose of Apri, maximum concentrations of 3-keto-desogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC0-∞ ) is 33,858 ± 11,043 pg/mL • hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL • hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-keto-desogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormone-binding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).

The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3ß-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.

Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Apri, the relative bioavailability is approximately 83%.

In the third cycle of use after a single dose of Apri, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268 pg/mL • hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24 at steady state is 1,117 ± 302 pg/mL • hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.

The elimination half-life is 26 ± 6.8 hours at steady state. 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.

INDICATIONS AND USAGE

Apri® (desogestrel 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. Table 1 lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant System depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.

In a clinical trial with Apri (desogestrel and ethinyl estradiol tablets USP), 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.

Table 1: 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.
à
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 brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 4 yellow pills).
è
However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency of duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches 6 months of age.

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

% of Women Continuing Use at One Year *

Method

(1)

Typical Use

(2)

Perfect Use

(3)

(4)

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

2.0

1.5

81

Copper T380A

0.8

0.6

78

LNg 20

0.1

0.1

81

Depo-Provera

0.3

0.3

70

Norplant® and Norplant-2®

0.05

0.05

88

Female Sterilization

0.5

0.5

100

Male Sterilization

0.15

0.10

100

Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.à

Lactation Amenorrhea Method: LAM is a highly effective, temporary method of contraception.è

Source: Trussel 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.

Apri (desogestrel and ethinyl estradiol tablets USP) has not been studied for and is not indicated for use in emergency contraception.

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