Norgestimate and Ethinyl Estradiol

NORGESTIMATE AND ETHINYL ESTRADIOL-
Glenmark Generics Inc., USA

WARNINGS: 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 Norgestimate and Ethinyl Estradiol Tablets 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

Each of the following products is a combination oral contraceptive containing the progestational compound norgestimate USP and the estrogenic compound ethinyl estradiol USP.

Norgestimate and Ethinyl Estradiol Tablets USP, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg

Each white to off white tablet contains 0.18 mg of the progestational compound, norgestimate USP (18,19-Dinor-17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.

Each light blue tablet contains 0.215 mg of the progestational compound norgestimate USP (18,19-Dinor17-pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2, lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.

Each blue tablet contains 0.25 mg of the progestational compound norgestimate USP (18,19-Dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include FD & C Blue No. 2, lactose monohydrate, povidone, magnesium stearate, colloidal silicon dioxide, talc and pregelatinized starch.

Each light green tablet contains only inert ingredients, as follows: D&C Yellow No. 10, FD&C Blue No. 2, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc.

Norgestimate and Ethinyl Estradiol Tablets USP, 0.25 mg/0.035 mg

Each blue tablet contains 0.25 mg of the progestational compound, norgestimate USP (18,19-Dinor-17- pregn-4-en-20-yn-3-one,17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-) and 0.035 mg of the estrogenic compound, ethinyl estradiol USP (19-nor-17α-pregna,1,3,5(10)-trien-20-yne-3,17-diol). Inactive ingredients include lactose monohydrate, povidone, FD&C Blue No. 2, colloidal silicon dioxide, talc, magnesium stearate, and pregelatinized starch.

Each light green tablet contains only inert ingredients, as follows: D&C Yellow No. 10, FD&C Blue No. 2, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch and talc.

Structural Formulas for Norgestimate and EE
(click image for full-size original)

CLINICAL PHARMACOLOGY

Oral Contraception

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 and humans, have shown that norgestimate and 17-deacetyl norgestimate, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity (90-93). Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone (90,91,94).

Acne

Acne is a skin condition with a multifactorial etiology, including androgen stimulation of sebum production. While the combination of ethinyl estradiol and norgestimate increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established.

Pharmacokinetics

Absorption

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following oral administration. Norgestimate is rapidly and completely metabolized by first pass (intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel (NG), which are the major active metabolites of norgestimate.

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg or norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg.

Accumulation following multiple dosing of the 250 μg NGM / 35 μg dose is approximately 2-fold for NGMN and EE compared with single dose administration. The pharmacokinetics of NGMN is dose proportional following NGM doses of 180 μg to 250 μg. Steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21. Non-linear accumulation (approximately 8 fold) of norgestrel is observed as a result of high affinity binding to SHBG (sex hormone-binding globulin), which limits its biological activity.

Table 1. Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.

Mean (SD) Pharmacokinetic Parameters of Norgestimate and Ethinyl Estradiol Tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg and 0.25 mg/0.035 mg during a Three Cycle Study

Analyte

Cycle

Day

Cmax

tmax (h)

AUC 0-24h

t 1/2 (h)

NGMN

3

7

1.80 (0.46)

1.42 (0.73)

15.0 (3.88)

NC

14

2.12 (0.56)

1.21 (0.26)

16.1 (4.97)

NC

21

2.66 (0.47)

1.29 (0.26)

21.4 (3.46)

22.3 (6.54)

NG

3

7

1.94 (0.82)

3.15 (4.05)

34.8 (16.5)

NC

14

3.00 (1.04)

2.21 (2.03)

55.2 (23.5)

NC

21

3.66 (1.15)

2.58 (2.97)

69.3 (23.8)

40.2 (15.4)

EE

3

7

124 (39.5)

1.27 (0.26)

1130 (420)

NC

14

128 (38.4)

1.32 (0.25)

1130 (324)

NC

21

126 (34.7)

1.31 (0.56)

1090 (359)

15.9 (4.39)

Mean (SD) Pharmacokinetic Parameters of Norgestimate and Ethinyl Estradiol Tablets, 0.25 mg/0.035 mg during a Three Cycle Study

Analyte

Cycle

Day

Cmax

tmax (h)

AUC 0-24h

t 1/2 (h)

NGMN

1

1

1.78 (0.397)

1.19 (0.250)

9.90 (3.25)

18.4 (5.91)

3

21

2.19 (0.655)

1.43 (0.680)

18.1 (5.53)

24.9 (9.04)

NG

1

1

0.649 (0.49)

1.42 (0.69)

6.22 (2.46)

37.8 (14.0)

3

21

2.65 (1.11)

1.67 (1.32)

48.2 (20.5)

45.0 (20.4)

EE

1

1

92.2 (24.5)

1.2 (0.26)

629 (138)

10.1 (1.90)

3

21

147 (41.5)

1.13 (0.23)

1210 (294)

15.0 (2.36)

C max = peak serum concentration, t max = time to reach peak serum concentration,

AUC 0-24h = area under serum concentration vs time curve from 0 to 24 hours, t 1/2 = elimination half-life, NC = not calculated.

NGMN and NG: C max = ng/mL, AUC 0-24h =h•ng/mL

EE: C max =pg/mL, AUC 0-24h =h•pg/mL

The effect of food on the pharmacokinetics of norgestimate and ethinyl estradiol tablets, 0.25 mg/0.035 mg or norgestimate and ethinyl estradiol tablets, 0.18 mg/0.035 mg, 0.215 mg/0.035 mg, 0.25 mg/0.035 mg has not been studied.

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