Caziant Triphasic Regimen

CAZIANT TRIPHASIC REGIMEN- desogestrel and ethinyl estradiol
RPK Pharmaceuticals, Inc.

DESCRIPTION

Caziant® (desogestrel and ethinyl estradiol tablets USP) is a triphasic oral contraceptive containing two active components, desogestrel and ethinyl estradiol, USP. Each 28 day treatment cycle pack consists of three active dosing phases: 7 beige tablets containing 0.1 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and 0.025 mg ethinyl estradiol, USP (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); 7 orange tablets containing 0.125 mg desogestrel and 0.025 mg ethinyl estradiol, USP, and 7 pink tablets containing 0.15 mg desogestrel and 0.025 mg ethinyl estradiol, USP. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, polysorbate 80, povidone, pregelatinized corn starch, stearic acid, titanium dioxide and vitamin E. Beige tablets also contain iron oxide red and iron oxide yellow. Pink and orange tablets also contain FD&C Red No. 40 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. Caziant also contains 7 white tablets with the following inert ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. The structural formulas are as follows:

Structural Formulas-NEW
(click image for full-size original)

The 7 beige, 7 pink and 7 orange tablets meet Dissolution Test 2.

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 desogestrel and ethinyl estradiol tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel and ethinyl estradiol tablets were determined during the third cycle in 21 subjects. After multiple dosing with desogestrel and 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 to 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 desogestrel and ethinyl estradiol tablets are summarized in TABLE 1.

TABLE 1: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL AND ETHINYL ESTRADIOL TABLETS OVER A 28 DAY DOSING PERIOD IN THE THIRD CYCLE (n = 21).

Etonogestrel

Phase

Dose

Cmax

tmax

n-AUC0 to 24

CL/F

(days)

mg

pg/mL

hr

pg•hr/mL/mcg

L/hr

1 (1 to 7)

0.100

2163.3 (856.4)

1.6 (0.7)

196 (75.4)

6.1 (2.3)

2 (8 to 14)

0.125

3241.5 (1296.5)a

1.1 (0.3)a

234.4 (85)a

5.1 (1.9)a

3 (15 to 21)

0.150

3855.7 (1273.1)

1.5 (0.8)

256.6 (104)

4.6 (1.6)

Desogestrel

Ethinyl Estradiol

Phase

Dose

Cmax

tmax

n-AUC0 to 24

CL/F

(days)

mg

pg/mL

hr

pg•hr/mL/mcg

L/hr

1 (1 to 7)

0.025

85.4 (51.7)

1.5 (0.8)

26.4 (11.5)

43.5 (15)

2 (8 to 14)

0.025

91.3 (52.2)a

1.2 (1.2)a

29 (15.5)a

41.7 (15.5)a

3 (15 to 21)

0.025

90.1 (48.2)

1.2 (0.7)

28.3 (13.2)

42.5 (18.7)

a n = 20

Cmax – maximum serum drug concentration

tmax – time at which maximum serum drug concentration occurs

n-AUC0 to 24 – area under the concentration- vs. time curve -0 to 24 hours normalized to 1 mcg 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 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. 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.

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