Teva Pharmaceuticals USA, Inc.
KARIVA- desogestrel/ethinyl estradiol and ethinyl estradiol
Teva Pharmaceuticals USA, Inc.
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs, including Kariva® , are contraindicated in women who are over 35 years of age and smoke (see CONTRAINDICATIONS and WARNINGS).
DESCRIPTION
Kariva® (desogestrel/ethinyl estradiol 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, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, and vitamin E, followed by 2 inert light-green, round tablets with the following inactive ingredients: FD&C blue no. 1 aluminum lake, FD&C yellow no. 6 aluminum lake, D&C yellow no. 10 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch. Kariva® also contains 5 light-blue, round tablets containing 0.01 mg ethinyl estradiol, USP (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include colloidal silicon dioxide, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, hypromellose, lactose monohydrate, polydextrose, polyethylene glycol, povidone, pregelatinized corn starch, stearic acid, titanium dioxide, triacetin and vitamin E. The structural formulas are as follows:
DESOGESTREL
(click image for full-size original)
C22 H30 O M.W. 310.48
ETHINYL ESTRADIOL, USP
C20 H24 O2 M.W. 296.40
The 21 white tablets meet USP 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.
Pharmaco*kinetics
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%. Kariva® (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 light-blue tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Kariva® 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® tablets following oral administration has not been evaluated.
The pharmaco*kinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Kariva® 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 pharmaco*kinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Kariva® tablets are summarized in Table I.
| Etonogestrel | ||||||
| Day | Dosea 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 (1.0) | 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) |
a) 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)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 | ||||||
| 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 | ||||||
a) n=16
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https://medlibrary.org/lib/rx/meds/kariva-1/
