Gveza Mechanism of Action

Pharmacology: Pharmacodynamics: Estrogen-prosgestin combinations produce a contraceptive effect mainly by suppressing the hypothalamic-pituitary system resulting in prevention of ovulation. The estrogen acts mainly by suppressing secretion of follicle-stimulating hormone (FSH), resulting in prevention of follicular development and the rise of plasma estradiol concentration which is thought to be the stimulus for release of luteinizing hormone (LH). In combination products, the progestin appears to act mainly by inhibiting the preovulatory rise of LH. Long-term administration of these combination products results inhibition of both FSH and LH secretion. It has been suggested that oral contraceptives may also produce a direct effect on ovarian steroidogenesis or the response of the ovary to gonadotropins. In addition, changes in the cervical mucus may prevent sperm penetration; however, further studies are required to determine the precise effects of estrogen-progestin combinations on sperm activity.
Endometrial changes depend on the type of oral contraceptive administered. Conventional-cycle combination products are usually associated with a shortened period of endometrial proliferation followed by an early but brief and limited secretory activity in the epithelium of endometrial glands. After several oral contraceptive cycles, thinning or regression of the endometrium may occur, resulting in reduced menstrual flow or possible amenorrhea.
Pharmacokinetics: Estrogens: Ethinyl estradiol is rapidly absorbed with peak concentrations attained within 2 hours. It undergoes considerable first-pass elimination. Mestranol is demethylated to ethinyl estradiol. Ethinyl estradiol is 97% to 98% bound to plasma albumin. Half-life varies from 6 to 20 hours. It is excreted in bile and urine as conjugates and undergoes some enterohepatic recirculation. Estradiol valerate peak concentrations are attained within approximately 6 hours with 60% bound to plasma albumin. Estradiol undergoes extensive first-pass effect and metabolites are mainly excreted in the urine. The terminal half-life is approximately 14 hours.
Drospirenone: Absorption: Oral contraceptive steroids are generally well absorbed from GI tract.
Absolute bioavailability: 76%.
Mean peak serum concentration: 36.9 ng/mL at about 1.7 hours.
Peak serum concentrations: 1 to 3 hours after administration.
Steady state: mean peak drospirenone concentration of 78.7-87.5 ng/mL in about 1.6-1.8 hours after a dose.
Distribution: Contraceptive steroids are widely distributed into body tissue and fluids. The apparent volume of distribution for contraceptive steroid reportly ranges from 1.5-4.3 L/kg.
Protein bound: 97% with albumin. It does not appear to bind to sex hormone binding globulin (SHBG).
Metabolism: Drospirenone is metabolized to 2 major inactive metabolites, which according to one study are formed independently of the cytochrome P-450 enzyme system. The manufacturers state that drospirenone is metabolized only to a minor extent in vitro, mainly by CYP3A4. At least 20 metabolites have been detected in urine or feces.
Elimination: Terminal half-life: 30 hours.
Toxicology: Preclinical safety data: Mutagenicity and carcinogenicity: Chromosomal abnormalities determined in peripheral lymphocytes have been increased in woman receiving oral contraceptives compared with non users.
Prolonged continuous administration of natural or synthetic estrogen in certain animal species increases the frequency of certain benign or malignant tumors including those of the breast, cervix, uterus, vagina, ovary, pituitary and liver. Drospirenone has increased the frequency of benign and total (benign plus malignant) adrenal gland pheochromocytomas in rats and the frequency of carcinoma of the harderian gland in mice.
Fertility: Studies have found a slight delay in return to fertility but no absolute impairment of fertility following discontinuance of fixed-combination conventional-cycle oral contraceptives. A survey of pregnant women attending antenatal clinics in England reported that the time to conception following discontinuance of long-term (i.e., longer than 2 years) use of fixed-combination oral contraceptives (8.2 months) was two fold longer than time to conception following condom use (4.2 months).