PIMTREA

PIMTREA — desogestrel/ethinyl estradiol and ethinyl estradiol
Northstar Rx LLC

Rx only

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

DESCRIPTION

PIMTREA™ (desogestrel/ethinyl estradiol and ethinyl estradiol tablets) provide an oral contraceptive regimen of 21 dark blue 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: titanium dioxide, macrogol/PEG 400 NF, hydroxypropyl-methylcellulose/hypromellose, FD&C Red #40, FD&C Yellow #6, FD&C Blue #1, lactose monohydrate, povidone, stearic acid and pregelatinized starch, followed by 2 white tablets with the following inactive ingredients: titanium dioxide, polydextrose, hypromellose, triacetin, macrogol/polyethylene glycol 8000, lactose, magnesium stearate and pregelatinized corn starch. PIMTREA™ also contains 5 green 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: titanium dioxide, macrogol/PEG 3000 NF, talc, polyvinyl alcohol, lecithin (soya), FD&C Red #40, FD&C Yellow #5, FD&C Blue #1, iron oxide yellow, iron oxide black, lactose monohydrate, magnesium stearate and pregelatinized starch. The molecular weights for desogestrel and ethinyl estradiol are 310.48 and 296.40 respectively. The structural formulas are as follows:

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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%. PIMTREA™ (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [dark blue] as well as 0.01 mg in the green tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of desogestrel/ethinyl estradiol combination tablet [dark blue], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [green] is 99%. The effect of food on the bioavailability of PIMTREA™ 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 I.

TABLE I : MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL/ETHINYL ESTRADIOL AND ETHINYL ESTRADIOL TABLETS OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=17).
Etonogestrel
Day Dose* Cm a x Tm a x t1 / 2 AUC0 - 2 4 CL/F
mg pg/mL h h pg/mL•hr 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)
*Desogestrel
Ethinyl Estradiol
Day Dose Cm a x Tm a x t1 / 2 AUC0 - 2 4 CL/F
mg pg/mL h h pg/mL•hr 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)
a n=16
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)
CL/F – apparent clearance

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