Rigevidon Mechanism of Action

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC code: G03AA07.
Pharmacology: Pharmacodynamics: Combined, estrogen-progestogen mini-pill.
Pearl index: 0.1 per cent women years.
The contraceptive efficacy of Rigevidon arises from 3 complementary actions: at the hypothalamic-pituitary axis by means of inhibition of ovulation; at the cervical mucus which becomes impermeable to migration of spermatozoids; at the endometrium, which becomes inappropriate for implantation.
Pharmacokinetics: Levonorgestrel: Absorption: Levonorgestrel is rapidly and completely absorbed after oral administration of Rigevidon. The bioavailability is approximately 100% and levonorgestrel is not subject to first-pass metabolism.
Distribution: Levonorgestrel is to a large extent bound to albumin and SHBG (Sex Hormon Binding Globulin) in plasma.
Biotransformation: Metabolism is mainly by reduction of the △4-3-oxo group and hydroxylation at the positions 2α, 1β and 16β, followed by conjugation. The majority of the metabolites circulating in the blood are sulphates of 3α, 5β-tetrahydro-levonorgestrel, while excretion mainly takes place as glucuronides. Some of the original levonorgestrel is also circulating as 17β-sulphate. Metabolic clearance is subject to marked inter-individual variation which may partly explain the wide variation in the concentrations of levonorgestrel observed among patients.
Elimination: Levonorgestrel is eliminated with a mean T_½ of approximately 36 hours at steady state. Levonorgestrel and its metabolites are primarily excreted in the urine (40%-68%) and approximately 16%-48% is excreted in the faeces.
Ethinylestradiol: Absorption: Ethinylestradiol is rapidly and completely absorbed, and peak plasma levels are reached after 1.5 hours. Following presystemic conjugation and first-pass metabolism, the absolute bioavailability is 60%. The area under curve and C_max may over time be expected to increase slightly.
Distribution: Ethinylestradiol is to 98.8% bound to plasma proteins, almost entirely to albumin.
Biotransformation: Ethinylestradiol undergoes presystemic conjugation both in the small intestinal mucosa and in the liver. Hydrolysis of the direct conjugates of ethinylestradiol by the intestinal flora gives ethinylestradiol, which can be re-absorbed, thereby creating an enterohepatic circulation. The primary route of metabolism of ethinylestradiol is cytochrome P-450-mediated hydroxylation, where the primary metabolites are 2-OH-ethinylestradiol and 2-methoxy-ethinylestradiol. 2-OH-ethinylestradiol is further metabolised to chemically reactive metabolites.
Elimination: Ethinylestradiol disappears from plasma with a T_½ of approximately 29 hours (26-33 hours), plasma clearance varies from 10-30 l/hour. The excretion of conjugates of ethinylestradiol and its metabolites takes place via urine and faeces (ratio 1:1).
Toxicology: Preclinical safety data: Acute toxicity of ethinylestradiol and levonorgestrel is low. Because of marked species differences preclinical results possess a limited predictive value for the application of estrogens in humans.
In experimental animals estrogens displayed an embryolethal effect already at relatively low doses; malformations of the urogenital tract and feminisation of male fetuses were observed. Levonorgestrel displayed a virilising effect in female fetuses. Reproduction toxicology studies in rats, mice and rabbits revealed no hint for teratogenicity beyond the effect on sexual differentiation.
Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risks beyond those discussed in other sections of the CCDS.