CLINICAL PHARMACOLOGY
1. Mode of Action. Nora-BE progestin-only oral contraceptives prevent conception by suppressing ovulation in approximately half of users, thickening the cervical mucus to inhibit sperm penetration, lowering the mid-cycle LH and FSH peaks, slowing the movement of the ovum through the fallopian tubes, and altering the endometrium.
2. Pharmacokinetics.
Absorption: Norethindrone is rapidly absorbed with maximum plasma concentrations occurring within 1 to 2 hours after Nora-BE administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first pass metabolism resulting in an absolute bioavailability of approximately 65%.
Peak plasma concentrations occur approximately 1 hour after administration (mean Tmax 1.2 hours). The mean (SD) Cmax was 4816.8 (1532.6) pg/mL and generally occurred within 1 hour (mean) of tablet administration, ranging from 0.5 to 2 hours. The mean (SD) Cavg was 885 (250) pg/mL, however, the mean concentration at 24 hrs was 130 (47) pg/mL.
Table 1 provides summary statistics of the pharmacokinetic parameters associated with single dose Nora-BE administration.
Table 1: Mean ± SD Pharmacokinetic Parameters Following Single Dose Administration of Nora-BE in 12 Healthy Female Subjects Under Fasting Conditions Pharmacokinetic Parameter | Norethindrone 0.35 mg |
Tmax (hr) | 1.2 ± 0.5 |
Cmax (pg/mL) | 4817 ± 1533 |
AUC(0-48) (pg·h/mL) | 21233 ± 6002 |
t½ (h) | 7.7 ± 0.5 |
The food effect on the rate and extent of norethindrone absorption after Nora-BE administration has not been evaluated.
Distribution: Following oral administration, norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is approximately 4 L/kg.
Metabolism: Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20-40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfate, with glucuronides accounting for most of the urinary metabolites.
Excretion: Plasma clearance rate for norethindrone has been estimated to be approximately 600 L/day. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half-life of norethindrone following single dose administration of Nora-BE is approximately 8 hours.
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