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Cyclessa

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Cyclessa

Cyclessa

CLINICAL PHARMACOLOGY

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 androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption

Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, based on the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.150 mg desogestrel/0.025 mg ethinyl estradiol, compared to solution, as measured by serum levels of etonogestrel, is approximately 100%. Ethinyl estradiol is rapidly and almost completely absorbed. When the lowest and highest tablet strengths, 0.100 mg desogestrel/0.025 mg ethinyl estradiol and 0.150 mg desogestrel/0.025 mg ethinyl estradiol, were compared to solution, the relative bioavailability of ethinyl estradiol was 92% and 98%, respectively. The effect of food on the bioavailability of Cyclessa® (desogestrel ethinyl estradiol tablets) tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Cyclessa® (desogestrel ethinyl estradiol tablets) tablets were determined during the third cycle in 21 subjects. After multiple dosing with Cyclessa® (desogestrel ethinyl estradiol tablets) , plasma concentrations of etonogestrel reached steady-state after four days of treatment during dosing Phases 1 and 3. During dosing Phase 2, steady-state was reached after five days of treatment. The dose-normalized AUC0-24 for etonogestrel was increased approximately 20% from Phase 1 to Phase 2 and approximately 10% from Phase 2 to Phase 3. SHBG concentrations were shown to be induced by the daily administration of ethinyl estradiol. Steady state for ethinyl estradiol was reached after four days of dosing in all dosing phases. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Cyclessa® (desogestrel ethinyl estradiol tablets) tablets are summarized in Table 1.

TABLE 1: MEAN (SD) PHARMACOKINETIC PARAMETERS OF Cyclessa® (desogestrel ethinyl estradiol tablets) OVER A 28-DAY DOSING
PERIOD IN THE THIRD CYCLE (n=21).


Etonogestrel
Phase
(days)
Dose†
mg
Cmax
pg/mL
tmax
hr
n-AUC0-24
pg•hr/mL/µg
CL/FL/
hr
1 (1-7) 0.100 2163.3 (856.4) 1.6 (0.7) 196.0 (75.4) 6.1 (2.3)
2 (8-14) 0.125 3241.5 (1296.5)a 1.1 (0.3)a 234.4 (85.0)a 5.1 (1.9)a
3 (15-21) 0.150 3855.7 (1273.1) 1.5 (0.8) 256.6 (104.0) 4.6 (1.6)
† Desogestrel

Ethinyl Estradiol


Phase
(days)
Dose
mg
Cmax
pg/mL
tmax
hr
n-AUC0-24
pg•hr/mL/µg
CL/FL/
hr
1 (1-7) 0.025 85.4 (51.7) 1.5 (0.8) 26.4 (11.5) 43.5 (15.0)
2 (8-14) 0.025 91.3 (52.2)a 1.2 (1.2)a 29.0 (15.5)a 41.7 (15.5)a
3 (15-21) 0.025 90.1 (48.2) 1.2 (0.7) 28.3 (13.2) 42.5 (18.7)
an=20
Cmax - maximum serum drug concentration
tmax - time at which maximum serum drug concentration occurs
n-AUC0-24 - area under the concentration- vs. time curve -0 to 24 hours normalized to 1 µg administered
CL/F - apparent clearance
Note: for information on t1/2 for Day 21, see the Excretion section.
Distribution

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 estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96-99).

Metabolism

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 -OH-desogestrel, 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.

Excretion

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. At steady state, on Day 21, the elimination half-lives of etonogestrel and ethinyl estradiol are 37.1 ± 14.8 hours and 28.2 ± 10.5 hours, respectively.

Special Populations

Race

There is no information to determine the effect of race on the pharmacokinetics of Cyclessa® (desogestrel ethinyl estradiol tablets) (desogestrel/ethinyl estradiol) Tablets.

Hepatic Insufficiency

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Cyclessa® (desogestrel ethinyl estradiol tablets) . However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Renal Insufficiency

No formal studies were conducted to evaluate the effect of renal disease on the disposition of Cyclessa® (desogestrel ethinyl estradiol tablets) .

Drug-Drug Interactions

Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with Cyclessa® (see PRECAUTIONS).

Non-Contraceptive Health Benefits

The following non-contraceptive health benefits related to the use of oral contraceptives are supported by epidemiologic studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg of mestranol (73-78).

REFERENCES

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: 9/25/2007
This monograph has been modified to include the generic and brand name in many instances.

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