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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, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity91,92. The relevance of this latter finding in humans is unknown.
Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of etonogestrel, is approximately 84%. In the third cycle of use after a single dose of DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP), maximum concentrations of etonogestrel of 2805 ± 1203 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 5840 ± 1667 pg/mL are reached at 1.4±0.9 hours. The minimum plasma levels of etonogestrel at steady state are 1400 ± 560 pg/mL. The AUC0–24 at steady state is 52,299 ± 17,878 pg/mL•hr. The mean AUC0–∞ for etonogestrel at single dose is significantly lower than the mean AUC0–24 at steady state. This indicates that the kinetics of etonogestrel are non-linear due to an increase in binding of etonogestrel to SHBG in the cycle, attributed to increased SHBG levels which are induced by the daily administration of ethinyl estradiol. SHBG levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of DESOGEN®, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of DESOGEN®, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5±0.8 hours. The AUC0–∞ is 1471 ± 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 1117 ± 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.
Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogeninduced increase in SHBG, resulting in lower serum levels of free testosterone96–99.
Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6β-hydroxy, etonogestrel and 6β- 13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OHdesogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.
Ethinyl estradiol: 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.
Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. The elimination half-life of etonogestrel is approximately 38±20 hours at steady state. The elimination half-life of ethinyl estradiol is 26±6.8 hours at steady state.
There is no information to determine the effect of race on the pharmacokinetics of DESOGEN® Tablets (desogestrel and ethinyl estradiol tablets USP).
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of DESOGEN®. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).
No formal studies were conducted to evaluate the effect of renal disease on the disposition of DESOGEN®.
Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with DESOGEN® (see PRECAUTIONS).
91. Kloosterboer, HJ et al. Selectivity in progesterone and
androgen receptor binding of progestogens used in oral contraception.
Contraception, 1988; 38:325–32.
92. Van der Vies, J and de Visser, J. Endocrinological studies with desogestrel. Arzneim. Forsch./Drug Res., 1983; 33(l),2:231–6.
96. Cullberg, G et al. Effects of a low-dose desogestrel-ethinyl estradiol combination on hirsutism, androgens and sex hormone binding globulin in women with a polycystic ovary syndrome. Acta Obstet Gynecol Scand, 1985; 64:195–202.
97. Jung-Hoffmann, C and Kuhl, H. Divergent effects of two low-dose oral contraceptives on sex hormone-binding globulin and free testosterone. AJOG, 1987; 156:199–203.
98. Hammond, G et al. Serum steroid binding protein concentrations, distribution of progestogens, and bioavailability of testosterone during treatment with contraceptives containing desogestrel or levonorgestrel. Fertil. Steril., 1984; 42:44–51.
99. Palatsi, R et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol, 1984; 64:517–23.
Last reviewed on RxList: 12/14/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Desogen Information
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