Volnea

VOLNEA- desogestrel and ethinyl estradiol
Xiromed, LLC.

volneavolnea-day-stickervolnea-carton

Rx only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

DESCRIPTION

Volnea™ (desogestrel and ethinyl estradiol tablets, USP and ethinyl estradiol tablets, USP) provides an oral contraceptive regimen of 21 white round 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 alpha-tocopherol, colloidal silicon dioxide, aquarius cool vanilla (contains hypromellose 2910, polyethylene glycol and titanium dioxide), corn starch, lactose monohydrate, povidone, and stearic acid, followed by 2 inert green round tablets contain the following inactive ingredients: aquarius cottage green (contains FD&C blue no. 2 aluminum lake, hypromellose 2910, polysorbate 80, titanium dioxide, triacetin, and yellow iron oxide), colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate and povidone.

Volnea™ also contains 5 yellow round 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 lactose monohydrate, microcrystalline cellulose, magnesium stearate, and opadry yellow (contains lecithin, polyvinyl alcohol, talc, titanium dioxide, xanthan gum, and yellow iron oxide). The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40 respectively. The structural formulas are as follows:

structure formula
(click image for full-size original)

USP dissolution test 2 is used.

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 compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Desogestrel/ethinyl estradiol and ethinyl estradiol tablets 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/ethinyl estradiol and ethinyl estradiol combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [yellow] is 99%. The effect of food on the bioavailability of desogestrel/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 were 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 1.

TABLE 1: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL/ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=17).

Etonogestrel

Day

Dose*

mg

Cmax

pg/mL

Tmax

h

t1/2

h

AUC0–24

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)

*Desogestrel

Ethinyl Estradiol

Day

Dose

mg

Cmax

pg/mL

Tmax

h

t1/2

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)*

25.7 (9.1)

21

0.02

62.2 (25.9)

2

(0.8)

23.9 (25.5)

597 (127)*

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)

Cmax – measured peak concentration

Tmax – observed time of peak concentration

t1/2 – 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

*n=16

Distribution

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 to 99).

Metabolism

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.

Excretion

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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