BEKYREE — desogestrel and ethinyl estradiol and ethinyl estradiol
Lupin Pharmaceuticals, Inc.
Patients should be counseled that this product does not protect against HIV infection (aids) and other sexually transmitted diseases.
Bekyree™ (desogestrel and ethinyl estradiol tablets USP and ethinyl estradiol tablets USP) provide an oral contraceptive regimen of 21 white round biconvex tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol), 0.02 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, stearic acid, talc, vitamin E and opadry white, a film coating made of hypromellose, polyethylene glycol, and titanium dioxide, followed by 2 inert green round biconvex tablets with the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, and opadry green, a film coating made of D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, hypromellose, polyethylene glycol, and titanium dioxide. Bekyree also contains 5 yellow round biconvex tablets containing 0.01 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, povidone, stearic acid, talc, vitamin E and opadry yellow, a film coating made of FD&C Yellow No. 5 Aluminum Lake, hypromellose, iron oxide yellow, polyethylene glycol, and titanium dioxide. The molecular weights for desogestrel and ethinyl estradiol are 310.5 and 296.40 respectively. The structural formulas are as follows:
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.
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%. Bekyree provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the yellow tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of desogestrel and ethinyl estradiol combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg ethinyl estradiol tablet [yellow] is 99%. The effect of food on the bioavailability of Bekyree following oral administration has not been evaluated.
The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Bekyree 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 Bekyree are summarized in Table I.
|Day||Dose * mg||Cm a x pg / mL||Tm a x h||t1 / 2 h||AUC0 – 2 4 pg / mL . hr||CL / F L / h|
|1||0.15||2503.6 (987.6)||2.4 (1)||29.8 (16.3)||17,832 (5674)||5.4 (2.5)|
|21||0.15||4091.2 (1186.2)||1.6 (0.7)||27.8 (7.2)||39,391 (12,134)||4.4 (1.4)|
Cm a x –measured peak concentration
Tm a x — observed time of peak concentration
t1 / 2 — elimination half-life, calculated by 0.693/Ke l i m
AUC0 – 2 4 -area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours
|Day||Dose mg||Cm a x pg / mL||Tm a x h||t1 / 2 h||AUC0 – 2 4 pg / mL . hr||CL / F L / h|
|1||0.02||51.9 (15.4)||2.9 (1.2)||16.5 (4.8)||566 (173)1||25.7 (9.1)|
|21||0.02||62.2 (25.9)||2 (0.8)||23.9 (25.5)||597 (127)1||35.1 (8.2)|
|24||0.01||24.6 (10.8)||2.4 (1)||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)|
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 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 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 [yellow], the elimination half-life at steady state, Day 28, is 18.9±8.3 hours.
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