Ermina Mechanism of Action

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations. ATC code: G03AA12.
Pharmacology: Pharmacodynamics: The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone has been reported to be rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 35 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is reported to be between 76 and 85%. The intake of food had no influence on the bioavailability of drospirenone as compared to drug intake on an empty stomach.
Distribution: After oral administration, serum drospirenone levels decrease in two phases which are characterized by half-lives of 1.6±0.7 h and 27.0±7.5 h, respectively. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3-5% of the total serum drug concentrations are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is reported to be 3.7±1.2 l/kg.
Metabolism: Drospirenone is extensively metabolized after oral administration. The major metabolites in the plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydrodrospirenone-3-sulfate, both of which are formed without involvement of the P450 system. Drospirenone is metabolized to a minor extent by cytochrome P450 3A4 and has demonstrated a capacity to inhibit this enzyme and cytochrome P450 1A1, cytochrome P450 2C9 and cytochrome P450 2C19 in vitro.
Elimination: The metabolic clearance rate of drospirenone in serum is 1.5±0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the feces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces reported to be about 40 h.
Steady-State Conditions: During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 60 ng/ml are reached between day 7 and day 14 of treatment. Serum drospirenone levels accumulated by a factor of about 2 to 3 as a consequence of the ratio of terminal half-life and dosing interval. Further accumulation of drospirenone levels beyond treatment cycles was observed between cycles 1 and 6 but thereafter, no further accumulation was observed.
Special Populations: Effect of renal impairment: Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance Cr_CL 50-80 ml/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (Cr_CL 30-50 ml/min) compared to those in women with normal renal function. Drospirenone treatment was well reported to be tolerated by all groups. Drospirenone treatment did not report any clinically significant effect on serum potassium concentration.
Effect of hepatic impairment: In women with moderate hepatic function, (Child-Pugh B) mean serum drospirenone concentration-time profiles were comparable to those of women with normal hepatic function during the absorption/distribution phases with similar C_max values. The mean terminal half-life of drospirenone for volunteers with moderate hepatic impairment was 1.8 times greater than for volunteers with normal hepatic function.
An about 50% decrease in apparent oral clearance (CL/F) was reported in volunteers with moderate hepatic impairment as compared to those with normal liver function. The reported decline in drospirenone clearance in volunteers with moderate hepatic impairment compared to normal volunteers did not translate into any apparent difference in terms of serum potassium concentrations between the two groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not reported. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).
Ethnic groups: The impact of ethnic factors on the pharmacokinetics of drospirenone and ethinylestradiol was reported after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results reported that ethnic differences between Japanese and Caucasian women had no clinically relevant influence on the pharmacokinetics of drospirenone and ethinylestradiol.
Ethinylestradiol: Absorption: Orally administered ethinylestradiol is reported to be absorbed rapidly and completely. Peak serum concentrations of about 33 ng/ml are reached within 1-2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism to be absorbed approximately 60%. Concomitant intake of food has been reported to reduce the bioavailability of ethinylestradiol in about 25% of the investigated subjects while no change was observed in the others.
Distribution: Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 l/kg has been reported.
Metabolism: Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.
Elimination: Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is reported to be about 1 day.
Steady-state conditions: Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of about 1.4 to 2.1.
Toxicology: Preclinical Safety: Preclinical data reported no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.