Yaz Mechanism of Action

Pharmacotherapeutic group (ATC): 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.
In a 3-cycle ovulation inhibition study comparing Drospirenone + Ethinylestradiol (Yaz) with a COC containing drospirenone 3 mg/ethinylestradiol 0.020 mg in a conventional 21-day-regimen, the 24-day-regimen of Drospirenone + Ethinylestradiol (Yaz) was associated with greater suppression of follicular development. After intentionally introduced dosing errors during the third cycle of treatment, a greater proportion of women in the 21-day-regimen showed ovarian activity including escape ovulations compared to the women taking Drospirenone + Ethinylestradiol (Yaz).
A large prospective, comparative, non-interventional US cohort study in COC users identified a typical use Pearl Index for Drospirenone + Ethinylestradiol (Yaz) that was statistically significantly lower compared to the Pearl Index of all other COCs in this study. These results indicate that Drospirenone + Ethinylestradiol (Yaz) has higher contraceptive effectiveness under routine medical conditions compared to other COCs.
Post Authorization Safety Studies (PASS) have shown that the frequency of VTE diagnosis ranges between 7-10 per 10,000 woman years in low estrogen dose (<50 μg ethinylestradiol) COC users. The most recent data suggest that the frequency of VTE diagnosis is approximately 4 per 10,000 woman years in non-pregnant non-COC users, and ranges between 20 to 30 per 10,000 pregnant women or post partum.
The increased risk of VTE associated with COC use is attributed to the estrogen component. There remains a scientific debate regarding any modulating effect on the risk of VTE by the progestin component of COCs. Epidemiological studies that compared the risk of VTE associated with use of ethinylestradiol/drospirenone to the risk with use of COCs containing levonorgestrel reported differing results ranging from no difference in risk to a three-fold increase in risk. The majority of studies investigated Yasmin.
As well as protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warning under Precautions, Adverse Reactions), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency.
Drospirenone has beneficial properties in addition to contraception. Drospirenone has antimineralocorticoid activity that can prevent weight gain and other symptoms caused by fluid retention. It counteracts the estrogen-related sodium retention, providing for a very good tolerance and has positive effects on the premenstrual syndrome (PMS). Drospirenone + Ethinylestradiol (Yaz) with a shortened hormone free interval, was studied in PMDD. PMDD is a severe form of PMS. In two placebo controlled phase 3 studies including over 500 subjects, Drospirenone + Ethinylestradiol (Yaz) showed clinical superiority in relief of symptoms of PMDD. In combination with ethinylestradiol, drospirenone displays a favorable lipid profile with an increase in HDL. Drospirenone exerts antiandrogenic activity leading to a positive effect on the skin and to a reduction in acne lesions and sebum production. In addition, drospirenone does not counteract the ethinylestradiol‑related SHBG increase which is useful for binding and inactivating the endogenous androgens.
In two multicenter, double blind, randomized, placebo controlled studies on the efficacy and safety of Drospirenone + Ethinylestradiol (Yaz) as an acne therapy in women with moderate acne vulgaris, Drospirenone + Ethinylestradiol (Yaz) produced clinically and statistically significant anti-acne effects on all the primary efficacy variables (inflammatory lesion, non-inflammatory lesion, total lesion counts, and the number and percentage of subjects with a 'clear' or 'almost clear' rating on the Investigator's Stated Global Assessment (ISGA) scale) and on the majority of secondary efficacy variables.
In two Japanese multicenter studies, the efficacy and safety of Drospirenone + Ethinylestradiol (Yaz) [drospirenone 3 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate)] was demonstrated in women suffering from dysmenorrhea: In a double-blind, randomized, placebo-controlled comparative study Drospirenone + Ethinylestradiol (Yaz) was demonstrated to have the optimal dose as compared with preparations containing drospirenone 2 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate), drospirenone 1 mg/ethinylestradiol 20 μg (as β-cyclodextrin clathrate) and placebo.
A single-blind, randomized study, investigated the efficacy of ethinylestradiol for intracyclic bleeding profile during 24 weeks (6 cycles) with Drospirenone + Ethinylestradiol (Yaz) and a preparation containing drospirenone 3 mg/ethinylestradiol 30 μg in patients with dysmenorrhea. This study also investigated the long term safety of Drospirenone + Ethinylestradiol (Yaz) administered for 52 weeks (13 cycles).
Drospirenone is devoid of any androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity. This, in combination with the antimineralocorticoid and antiandrogenic properties, gives drospirenone a biochemical and pharmacological profile closely resembling the natural hormone progesterone. Apart from this, there is evidence of a reduced risk of endometrial cancer and ovarian cancer. Furthermore, the higher dosed COCs (0.05 mg ethinylestradiol) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Whether this also applies to lower-dosed COCs remains to be confirmed.
Pharmacokinetics: Drospirenone: Absorption: Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the drug in serum of about 35 ng/mL are reached at about 1-2 h after single ingestion. Bioavailability is 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 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-dihydro-drospirenone-3-sulfate formed by reduction and subsequent sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.
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 feces is 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 CLcr, 50-80 mL/min) were comparable to those of women with normal renal function (CLcr, >80 mL/min). The serum drospirenone levels were on average 37% higher in women with moderate renal impairment (CLcr, 30-50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was well tolerated by all groups. Drospirenone treatment did not show 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 Cmax 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 seen in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed 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 observed. 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 studied after single and repeated daily oral administration to young, healthy Caucasian and Japanese women. The results showed 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 absorbed rapidly and completely. Peak serum concentrations of about 33 pg/mL are reached within 1-2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%. Concomitant intake of food reduced 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 was determined.
Metabolism: Ethinylestradiol is subject to significant gut and hepatic first-pass metabolism Ethinylestradiol and its oxidative metabolites are primarily conjugates with glucuronides or 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 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 data: Preclinical data reveal 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.