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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
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. Mean pharmacokinetic parameters for NGMN, NG and EE during three cycles of administration of ORTHO TRI-CYCLEN® Lo are summarized in Table 1. These results indicate that: (1) Peak serum concentrations of NGMN and EE were generally reached by 2 hours after dosing; (2) Accumulation following multiple dosing of the 180 µg NGM / 25 µg dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for EE compared with single dose administration, in agreement with that predicted based on linear kinetics of NGMN and EE; (3) The kinetics of NGMN are dose proportional following NGM doses of 180 to 250 µg; (4) Steady-state conditions for NGMN following each NGM dose and for EE were achieved during the three cycle study; (5) Non-linear accumulation (4.5-14.5 fold) of norgestrel was observed as a result of high affinity binding to SHBG, which limits its biological activity.100 The effect of food on the pharmacokinetics of ORTHO TRI-CYCLEN® Lo has not been studied. Table 1 provides a summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.
Table 1: Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN® Lo During a Three Cycle Study
|Analyte1||Cycle||Day||Cmax||tmax (h)||AUC0-24h||t½ (h)|
|NGMN(2-4)||1||1||0.91 (0.27)||1.8 (1.0)||5.86 (1.54)||NC|
|3||7||1.42 (0.43)||1.8 (0.7)||11.3 (3.2)||NC|
|14||1.57 (0.39)||1.8 (0.7)||13.9 (3.7)||NC|
|21||1.82 (0.54)||1.5 (0.7)||16.1 (4.8)||28.1 (10.6)|
|NG(2-4)||1||1||0.32 (0.14)||2.0 (1.1)||2.44 (2.04)||NC|
|3||7||1.64 (0.89)||1.9 (0.9)||27.9 (18.1)||NC|
|14||2.11 (1.13)||4.0 (6.3)||40.7 (24.8)||NC|
|21||2.79 (1.42)||1.7 (1.2)||49.9 (27.6)||36.4 (10.2)|
|EE(2,3,5)||1||1||55.6 (18.1)||1.7 (0.5)||421 (118)||NC|
|3||7||91.1 (36.7)||1.3 (0.3)||782 (329)||NC|
|14||96.9 (38.5)||1.3 (0.3)||796 (273)||NC|
|21||95.9 (38.9)||1.3 (0.6)||771 (303)||17.7 (4.4)|
| 1 NGMN = Norelgestromin,
NG = norgestrel, EE = ethinyl estradiol
2 Cmax = peak serum concentration, tmax = time to reach peak serum concentration, AUC0-24h = area under serum concentration vs time curve from 0 to 24 hours, t½ = elimination half-life.
3 units for all analytes; h = hours
4 units for NGMN and NG - Cmax = ng/mL, AUC0-24h = h.ng/mL
5 units for EE only - Cmax = pg/mL, AUC0-24h = h.pg/mL NC = not calculated
Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound (> 97%) to serum albumin.
Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Following 3 cycles of administration of ORTHO TRI-CYCLEN® Lo, the mean (± SD) elimination half-life values, at steady-state, for norelgestromin, norgestrel and ethinyl estradiol were 28.1 (± 10.6) hours, 36.4 (±10.2) hours and 17.7 (± 4.4) hours, respectively (Table 1). The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways.
Effects of Body Weight, Body Surface Area, and Age
The effects of body weight, body surface area, age and race on the pharmacokinetics of norelgestromin, norgestrel and ethinyl estradiol were evaluated in 79 healthy women using pooled data following single dose administration of NGM 180 or 250 µg / EE 25 µg tablets in four pharmacokinetic studies. Increasing body weight and body surface area were each associated with decreases in Cmax and AUC0-24h values for norelgestromin and ethinyl estradiol and increases in CL/F (oral clearance) for ethinyl estradiol. Increasing body weight by 10 kg is predicted to reduce the following parameters: NGMN Cmax by 9% and AUC0-24h by 19%, norgestrel Cmax by 12% and AUC0-24h by 46%, EE Cmax by 13% and AUC0-24h by 12%. These changes were statistically significant. Increasing age was associated with slight decreases (6% with increasing age by 5 years) in Cmax and AUC0-24h for norelgestromin and were statistically significant, but there was no significant effect for norgestrel or ethinyl estradiol. Only a small to moderate fraction (5-40%) of the overall variability in the pharmacokinetics of norelgestromin and ethinyl estradiol following ORTHO TRI-CYCLEN® Lo Tablets may be explained by any or all of the above demographic parameters.
In clinical studies involving 1673 subjects with a mean weight of 141 pounds, there was no association between pregnancy and weight.
Renal and Hepatic Impairment
No studies with ORTHO TRI-CYCLEN® Lo have been conducted in women with renal or hepatic impairment.
Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki). Interactions between oral contraceptives and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with ORTHO TRI-CYCLEN® Lo (see PRECAUTIONS).
90. Anderson FD, Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand 1992; 156 (Supplement):15-21. 91. Chapdelaine A, Desmaris J-L, Derman RJ. Clinical evidence of minimal androgenic activity of norgestimate. Int J Fertil 1989; 34(51):347-352. 92. Phillips A, Demarest K, Hahn DW, Wong F, McGuire JL. Progestational and androgenic receptor binding affinities and in vivo activities of norgestimate and other progestins. Contraception 1989; 41(4):399-409. 93. Phillips A, Hahn DW, Klimek S, McGuire JL. A comparison of the potencies and activities of progestogens used in contraceptives. Contraception 1987; 36(2):181-192. 94. Janaud A, Rouffy J, Upmalis D, Dain M-P. A comparison study of lipid and androgen metabolism with triphasic oral contraceptive formulations containing norgestimate or levonorgestrel. Acta Obstet Gynecol Scand 1992; 156 (Supplement):34-38. 95. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet 1996; 347:1713-1727. 96. Palmer JR, Rosenberg L, Kaufman DW, Warshauer ME, Stolley P, Shapiro S. Oral Contraceptive Use and Liver Cancer. Am J Epidemiol 1989;130:878-882. 97. Lewis M, Spitzer WO, Heinemann LAJ, MacRae KD, Bruppacher R, Thorogood M on behalf of Transnational Research Group on Oral Contraceptives and Health of Young Women. Third generation oral contraceptives and risk of myocardial infarction: an international case-control study. Br Med J, 1996;312:88-90. 98. Improving access to quality care in family planning: Medical eligibility criteria for contraceptive use. Geneva, WHO, Family and Reproductive Health, 1996. 99. Hampton RM, Short M, Bieber E, et al. Comparison of a novel norgestimate/ethinyl estradiol oral contraceptive (Ortho Tri-Cyclen Lo) with the oral contraceptive Loestrin Fe 1/20. Contraception 2001;63:289-295. 100. Sitteri PK, Murai J T, Hammond GL, Nisker JA, Raymoure WJ, Huhn RW. The serum transport of steroid hormones. Rec Prog Horm Res 1982;38:457-510.
Last reviewed on RxList: 6/27/2007
This monograph has been modified to include the generic and brand name in many instances.
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