Qlaira Mechanism of Action

ATC code: G03A.
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.
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.
One post approval commitment study has been completed specifically for Estradiol valerate + Dienogest (Qlaira). In this prospective active surveillance study, the incidence of VTE in women with or without other risk factors for VTE who used Estradiol valerate + Dienogest (Qlaira) is in the same range as that for users of levonorgestrel-containing COCs. As well as protection against pregnancy, COCs have several positive properties, which next to the negative properties (see 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. 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 estradiol valerate containing COCs remains to be confirmed.
Estradiol valerate + Dienogest (Qlaira) has beneficial properties (delivers estradiol, which has a limited proliferative effect on the endometrium, contains a progestogen with a pronounced endometrial effect and is dosed using an estrogen step-down and a progestogen step-up regimen) that can be used to treat heavy and/or prolonged menstrual bleeding in the absence of an organic pathology, symptoms sometimes referred to as dysfunctional uterine bleeding.
Two double-blinded, placebo-controlled clinical studies were conducted to demonstrate the efficacy and safety of Estradiol valerate + Dienogest (Qlaira) for treating symptoms of dysfunctional uterine bleeding. Both studies had identical designs and analysis plans and randomized a total of 269 patients on Estradiol valerate + Dienogest (Qlaira) and 152 patients on placebo. In both studies, Estradiol valerate + Dienogest (Qlaira) was effective in treating the symptoms of dysfunctional uterine bleeding with a point estimate of the proportion of subjects with complete symptom relief of 29% in the Estradiol valerate + Dienogest (Qlaira) group compared to 2% in the placebo group (difference 27%; CI of the difference 21%-33%; p<0.0001). After 6 months of treatment the median menstrual blood loss (MBL) was decreased by 88% (from 142 mL to 17 mL) in the Estradiol valerate + Dienogest (Qlaira) group compared to 24% (from 154 mL to 117 mL) in the placebo group. The decrease in MBL achieved with Estradiol valerate + Dienogest (Qlaira) is rapid (already in Cycle 2 the median MBL was 41 mL compared to 140 mL in the placebo group) and sustained with no loss of the effect over the duration of dosing (in Cycle 7, the MBL in the Estradiol valerate + Dienogest (Qlaira) group was 17 mL compared to 117 mL in the placebo group). The median decrease of number of bleeding days per 90-days reference period was significantly higher in the Estradiol valerate + Dienogest (Qlaira) group compared to Placebo (4 days compared to 2 days). This was accompanied by a statistically significant improvement in iron metabolism parameters (hemoglobin, hematocrit and ferritin) and a decrease in use of sanitary protection items.
The estrogen in Estradiol valerate + Dienogest (Qlaira) is estradiol valerate, a prodrug of the natural human 17 β-estradiol (1 mg estradiol valerate corresponds to 0.76 mg 17 β-estradiol). The estrogenic component used in this COC is therefore different from the estrogens usually used in COCs which are the synthetic estrogens ethinylestradiol or its prodrug mestranol both containing an ethinyl group in 17alpha position. This group is responsible for the high metabolic stability but also for the stronger hepatic effects.
Estradiol valerate + Dienogest (Qlaira) leads to lower hepatic effects when compared to a triphasic EE/LNG-containing COC. The impact on SHBG levels and hemostasis parameters was shown to be lower. In combination with dienogest, estradiol valerate displays an increase in HDL, while LDL-cholesterol levels are slightly decreased.
Dienogest is an orally and parenterally potent progestogen which has additional antiandrogenic partial effects. Its estrogenic, antiestrogenic and androgenic properties are negligible. As a result of the special chemical structure a pharmacological spectrum of action is obtained which combines the most important advantages of the 19-norprogestogens and of the progesterone derivatives. Endometrial histology was investigated in a small subgroup of women in one clinical study after 20 cycles of treatment. There were no abnormal results. Findings were in accordance with the typical endometrial changes described for EE containing COCs.
Pharmacokinetics: Dienogest: Absorption: Orally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5 ng/ml are reached at about 1 hour after oral administration of the Estradiol valerate + Dienogest (Qlaira) tablet containing 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91%. The pharmacokinetics of dienogest are dose proportional within the dose range of 1-8 mg. Concomitant food intake has no clinically relevant effect on the rate and extent of dienogest absorption.
Distribution: A relatively high fraction of 10% of circulating dienogest is present in the free form, with approx. 90% being bound non-specifically to albumin. Dienogest does not bind to the specific transport proteins SHBG and CBG. There is therefore no possibility of testosterone being displaced from its SHBG-binding or cortisol from its CBG-binding. Any influence on physiological transport processes for endogenous steroids is consequently unlikely. The volume of distribution at steady state (Vd, ss) of dienogest is 46 l after the intravenous administration of 85 μg ³H-dienogest.
Metabolism: Dienogest is nearly completely metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), with the formation of endocrinologically mostly inactive metabolites. The metabolites are excreted very quickly so that in plasma unchanged dienogest is the dominating fraction.
The total clearance following the intravenous administration of 3H-dienogest was calculated as 5.1 l/h.
Elimination: The plasma half-life of dienogest is approximately 11 hours. Dienogest is excreted in the form of metabolites which are excreted at a urinary to fecal ratio of about 3:1 after oral administration of 0.1 mg/kg. Following oral administration, 42% of the dose is eliminated within the first 24 h and 63% within 6 days by renal excretion. A combined 86% of the dose is excreted by urine and feces after 6 days.
Steady-State Conditions: Pharmacokinetics of dienogest are not influenced by SHBG levels. Steady state is reached after 3 days of the same dosage of 3 mg dienogest in combination with 2 mg estradiol valerate. Trough, maximum and average dienogest serum concentrations at steady state are 11.8 ng/ml, 82.9 ng/ml and 33.7 ng/ml, respectively. The mean accumulation ratio for AUC (0-24h) was determined to be 1.24.
Estradiol valerate: Absorption: After oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites estrone and estriol. Maximal serum estradiol concentrations of 70.6 pg/ml are reached between 1.5 and 12 hours after single ingestion of the tablet containing 3 mg estradiol valerate on Day 1. Concomitant food intake has no clinically relevant effect on the rate and extent of estradiol valerate absorption.
Metabolism: The valeric acid undergoes very fast metabolism. After oral administration, approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95% of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.
Distribution: In serum 38% of estradiol is bound to SHBG, 60% to albumin and 2-3% circulate in free form. Estradiol can slightly induce the serum concentrations of SHBG in a dose-dependent manner. On day 21 of the treatment cycle, SHBG was approximately 148% of the baseline, and decreased to about 141% of the baseline by day 28 (end of placebo phase). An apparent volume of distribution of approximately 1.2 l/kg was determined after iv. administration.
Elimination: The plasma half-life of circulating estradiol is about 90 min. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the terminal half-life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h.
Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the stool.
Steady-state conditions: Pharmacokinetics of estradiol are influenced by SHBG levels. In young women, the measured estradiol plasma levels are a composite of the endogenous estradiol and the estradiol generated from Estradiol valerate + Dienogest (Qlaira). During the treatment phase of 2 mg estradiol valerate + 3 mg dienogest, maximum and average estradiol serum concentrations at steady state are 66.0 pg/ml, and 51.6 pg/ml, respectively. Throughout the 28 day cycle, stable minimum estradiol concentrations were maintained and ranged from 28.7 pg/ml to 64.7 pg/ml.
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.