Source: Web Search Revision Year: 2020 Publisher: Gedeon Richter Plc., Gyömrői út 19-21, 1103 Budapest, Hungary
Pharmacotherapeutic group: Hormonal contraceptives for systemic use; Progestogens and estrogens, fixed combinations;
ATC code: G03AA07
The contraceptive effect of Rigevidon is based on the interaction of various factors. The most important of these factors are the inhibition of ovulation and changes in the cervical mucus.
Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.
Clinical trials have been performed in 2498 women aged 18 to 40 years. The overall Pearl Index calculated from these trials was 0.69 (95% confidence interval 0.30-1.36) based on 15,026 treatment cycles.
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.
Levonorgestrel is to a large extent bound to albumin and SHBG (Sex Hormon Binding Globulin) in plasma.
Metabolism is mainly by reduction of the 4-3-oxo group and hydroxylation at the positions 2, 1 and 16, followed by conjugation. The majority of the metabolites circulating in the blood are sulphates of 3,5-tetrahydro-levonorgestrel, while excretion mainly takes place as glucuronides. Some of the original levonorgestrel is also circulating as 17-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.
Levonorgestrel is eliminated with a mean T½ 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 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 Cmax may over time be expected to increase slightly.
Ethinylestradiol is to 98.8% bound to plasma proteins, almost entirely to albumin.
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-OHEthinylestradiol is further metabolised to chemically reactive metabolites.
Ethinylestradiol disappears from plasma with a T½ 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).
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 SPC.
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