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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 andro-genicity (91,92). 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 compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Kariva™ (desogestrel and ethinyl estradiol and ethinyl estradiol) (deso-gestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradi-ol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the light-blue tablet. Ethinyl estra-diol is rapidly and almost completely absorbed. After a single dose of desogestrel/ethinyl estradiol combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [light-blue] is 99%. The effect of food on the bioavailability of Kariva™ (desogestrel and ethinyl estradiol and ethinyl estradiol) Tablets following oral administration has not been evaluated.
The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets was determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by Day 21. The AUC(0-24) for etonogestrel at steady-state on Day 21 was approximately 2.2 times higher than AUC(0-24) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel/ethinyl estradiol and ethinyl estradiol tablets are summarized in Table I.
TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL/ETHINYL
ESTRA-DIOL AND ETHINYL ESTRADIOLOVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE
|Day||Dose† mg||Cmax pg/mL||Tmax h||t½ h||AUC0-24 pg/mL •hr||CL/F L/h|
|1||0.15||2503.6 (987.6)||2.4 (1.0)||29.8 (16.3)||17832 (5674)||5.4 (2.5)|
|21||0.15||4091.2 (1186.2)||1.6 (0.7)||27.8 (7.2)||39391 (12134)||4.4 (1.4)|
|Day||Dose mg||Cmax pg/mL||Tmax h||t½ h||AUC0-24 pg/mL•hr||CL/F L/h|
|1||0.02||51.9 (15.4)||2.9 (1.2)||16.5 (4.8)||566 (173)a||25.7 (9.1)|
|21||0.02||62.2 (25.9)||2.0 (0.8)||23.9 (25.5)||597 (127)a||35.1 (8.2)|
|24||0.01||24.6 (10.8)||2.4 (1.0)||18.8 (10.3)||246 (65)||43.6 (12.2)|
|28||0.01||35.3 (27.5)||2.1 (1.3)||18.9 (8.3)||312 (62)||33.2 (6.6)|
Cmax - measured peak concentration
Tmax - observed time of peak concentration
t½ - elimination half-life, calculated by 0.693/Kelim
AUC0-24 - area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours)
CL/F - apparent clearance
Etonogestrel, the active metabolite of desogestrel was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96-99).
Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel) with no pharmacologic actions 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 excreted in urine, bile and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. For the 0.01 mg ethinyl estradiol tablet [light-blue], the elimination half-life at steady state, Day 28, is 18.9±8.3 hours.
There is no information to determine the effect of race on the pharmacokinetics of Kariva™ (desogestrel and ethinyl estradiol and ethinyl estradiol) .
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Kariva™ (desogestrel and ethinyl estradiol and ethinyl estradiol) .
No formal studies were conducted to evaluate the effect of renal disease on the disposition of Kariva™ (desogestrel and ethinyl estradiol and ethinyl estradiol) .
Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS section).
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(I),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 globu-lin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol, 1984; 64:517-23.
Last reviewed on RxList: 8/5/2008
This monograph has been modified to include the generic and brand name in many instances.
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