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Ortho Tri-Cyclen

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Ortho Tri-Cyclen / Ortho-Cyclen

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 firstpass (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 ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. Accumulation following multiple dosing of the 250 g NGM / 35 g 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 g to 250 g. 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 I : Summary of norelgestromin, norgestrel and ethinyl estradiol pharmacokinetic parameters.

Mean (SD) Pharmacokinetic Parameters of ORTHO TRI-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0-24h t½ (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 ORTHO-CYCLEN During a Three Cycle Study
Analyte Cycle Day Cmax tmax (h) AUC0-24h t½ (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)
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, t1/2 = elimination half-life, NC = not calculated.
NGMN and NG: Cmax= ng/mL, AUC0-24h=h•ng/mL
EE: Cmax=pg/mL, AUC0-24h=h•pg/mL

The effect of food on the pharmacokinetics of ORTHO-CYCLEN or ORTHO TRI-CYCLEN has not been studied.

Distribution

Norelgestromin and norgestrel 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 and induces an increase in the serum concentrations of SHBG.

Metabolism

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.

Excretion

The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways. Following administration of 14C-norgestimate, 47% (45-49%) and 37% (16-49%) of the administered radioactivity was eliminated in the urine and feces, respectively. Unchanged norgestimate was not detected in the urine. In addition to 17-deacetyl norgestimate, a number of metabolites of norgestimate have been identified in human urine following administration of radiolabeled norgestimate. These include 18, 19-Dinor-17-pregn-4-en-20-yn-3-one,17-hydroxy-13-ethyl,(17α)-(-);18,19-Dinor-5β-17-pregnan-20-yn,3α,17β-dihydroxy-13-ethyl,(17α), various hydroxylated metabolites and conjugates of these metabolites.

Special Populations

The effects of body weight, body surface area or age on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied. However, steroid hormones may be poorly metabolized in women with impaired liver function (see PRECAUTIONS).

Renal Impairment

The effects of renal impairment on the pharmacokinetics of ORTHO-CYCLEN® or ORTHO TRI-CYCLEN® have not been studied.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with ORTHO-CYCLEN® or ORTHO TRI-CYCLEN®. Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS).

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).

REFERENCES

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.

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.

Last reviewed on RxList: 12/15/2010
This monograph has been modified to include the generic and brand name in many instances.

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