Tri-Sprintec

TRI-SPRINTEC- norgestimate and ethinyl estradiol
Proficient Rx LP

9018

Rx only

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

DESCRIPTION

Tri-Sprintec^® (norgestimate and ethinyl estradiol tablets USP) is a combination oral contraceptive containing the progestational compound norgestimate, USP and the estrogenic compound ethinyl estradiol, USP.

Each gray 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), and the inactive ingredients include anhydrous lactose, lactose monohydrate, lake blend black LB 636 (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, FD&C red no. 40, FD&C yellow no. 6, sodium bicarbonate and sodium carbonate), magnesium stearate, and pregelatinized corn starch.

Each light blue tablet contains 0.215 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), and the inactive ingredients include anhydrous lactose, FD&C blue no. 2 aluminum lake (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, sodium bicarbonate and sodium carbonate), lactose monohydrate, magnesium stearate, and pregelatinized corn 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), and the inactive ingredients include anhydrous lactose, FD&C blue no. 2 aluminum lake (ingredients include aluminum sulfate solution, aluminum-chloride solution, FD&C blue no. 2, sodium bicarbonate and sodium carbonate), lactose monohydrate, magnesium stearate, and pregelatinized corn starch.

Each white tablet contains only inert ingredients as follows: anhydrous lactose, hypromellose, magnesium stearate, and microcrystalline cellulose.

The structural formulas are as follows:

Norgestimate

C23H31NO3 M.W. 369.50

C23H31NO3 M.W. 369.50

Ethinyl Estradiol

C20H24O2 M.W. 296.40

C20H24O2 M.W. 296.40

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 Tri-Sprintec . Accumulation following multiple dosing of the 250 mcg NGM / 35 mcg 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 mcg to 250 mcg. 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 Tri-Sprintec During a Three Cycle Study
Analyte	Cycle	Day	Cmax	tmax (h)	AUC0-24h	t1/2 (h)
NGMN	3	7	1.80 (0.46)	1.42 (0.73)	15 (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 (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)

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 Tri-Sprintec has not been studied.