Esteretta^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Haupt Pharma Munster, GmbH (Germany)

Or

Gedeon Richter, Plc. (Hungary)

Packaging and Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

G03AA18 (Drospirenone and estetrol)

Active Substances

Drospirenone (Rec.INN registered by WHO)

Estetrol (Rec.INN registered by WHO)

Dosage Form

Esteretta®

Film-coated tablets, two types: 28 pcs. in a blister, 1 or 3 blisters in a pack, incl.: light pink tablets, 3 mg+15 mg: 24 pcs. in a blister; placebo tablets: 4 pcs. in a blister

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex, with an engraving in the shape of a (droplet) on one side (24 pcs. in a blister).

Excipients: lactose monohydrate, sodium starch glycolate, type A, corn starch, povidone K30, magnesium stearate (E470b).

Film coating composition AquaPolish^® Pink 044.08 MS (AquaPolish^® Pink 044.08 MS) (hypromellose (E464), hydroxypropyl cellulose (E463), talc (E553b), hydrogenated cottonseed oil, titanium dioxide (E171), red iron oxide dye (E172)).

Placebo tablets

Film-coated tablets white or almost white, round, biconvex, with an engraving in the shape of a (droplet) on one side (4 pcs. in a blister).

Excipients: StarLac^® (StarLac^®) (lactose monohydrate and corn starch), magnesium stearate (E470b).

Film coating composition AquaPolish^® White 014.17 MS (AquaPolish^® White 014.17 MS) (hypromellose (E464), hydroxypropyl cellulose (E463), talc (E553b), hydrogenated cottonseed oil, titanium dioxide (E171)).

28 pcs. – blisters (1) with 1 sticker indicating the days of the week and a case for storing the blister – cardboard packs.
28 pcs. – blisters (3) with 3 stickers indicating the days of the week and a case for storing the blister – cardboard packs.

Clinical-Pharmacological Group

Combined hormonal contraceptive (estrogen + progestogen)

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system. Progestogens and estrogens, fixed combinations

Pharmacological Action

Mechanism of action

The drug Esteretta^® is a combined oral contraceptive (COC). The estrogen component is estetrol, a synthetic analogue of a naturally occurring estrogen produced by the fetal human liver during pregnancy. The progestogenic component in the drug Esteretta^® is drospirenone, which is included in the same dose in combination with ethinylestradiol in other COCs.

During pregnancy, estetrol is found in the mother’s and fetus’s bodies. By the end of pregnancy, the concentration of estetrol in the woman’s plasma is 1 ng/ml, and in the fetal plasma it is more than 10 times higher. Estetrol differs from ethinylestradiol, which is part of other COCs, by the absence of an ethinyl group at the 17-alpha position. Unlike estradiol valerate, estetrol is a terminal metabolite of sex hormones and cannot be converted back to estrone, estrone sulfate, estradiol, or estriol. Estetrol has high selectivity for estrogen receptors (ER) and binds predominantly to ER, with its affinity being approximately 5% compared to the affinity of ethinylestradiol and estradiol. Estetrol has a dose-dependent effect on estrogen receptors. In humans, estetrol suppresses the secretion of gonadotropic hormones, leading to a dose-dependent decrease in the concentration of FSH and LH in plasma.

Drospirenone is a progestogen structurally related to spironolactone (an aldosterone antagonist). It has affinity for the human progesterone receptor similar to natural progesterone, and has antigonadotropic, antiandrogenic, and moderate antimineralocorticoid effects. It does not possess estrogenic, glucocorticoid, or antiglucocorticoid activity. Drospirenone has a pharmacological profile similar to that of natural progesterone.

The contraceptive effect of the drug Esteretta^® is based on the interaction of various factors, the most important of which is the suppression of ovulation.

Clinical efficacy and safety

More than 3400 women received the drug Esteretta^® for 13 consecutive cycles (according to the 24/4 regimen) during 2 randomized open-label studies evaluating efficacy and safety.

Within the framework of the clinical study of the drug Esteretta^® conducted in the European Union and the Russian Federation, the following Pearl Index values were calculated for the age group 18-35 years: method failure: 0.26 (upper limit of 95% CI 0.77); method failure and patient error: 0.44 (upper limit of 95% CI 1.03); the protection percentage in this age group is 99.55% over one year of use.

Pearl Index values in the age group 18-50 years were: method failure: 0.23 (upper limit of 95% CI 0.67); method failure and patient error: 0.38 (upper limit of 95% CI 0.89); the protection percentage in this age group is 99.61% over one year of use.

Suppression of ovarian function was assessed during a randomized open-label study using the drug Esteretta^® and a comparator drug from the COC group containing 20 mcg ethinylestradiol and 3 mg drospirenone, which were prescribed for 3 consecutive cycles. In the Esteretta^® group (N=40), ovulation was not observed. In 97% of women in the Esteretta^® group, ovulation resumed by the end of the 1st menstrual cycle after discontinuation of treatment.

The effect on bleeding patterns (cycle control) of the drug Esteretta^® was assessed during a dose-finding study using estradiol valerate/dienogest combination as a comparator for 6 cycles. Cycle control during administration of the drug Esteretta^® was optimal.

The effect on hemostasis parameters, endocrine function, and metabolism was assessed during a randomized open-label study involving 98 women. 38 women received the drug Esteretta^®, 29 women received the combination ethinylestradiol (30 mcg)/levonorgestrel (150 mcg) and 31 women received the combination ethinylestradiol (20 mcg)/Drospirenone (3 mg) for 6 cycles.

The use of the drug Esteretta^® was accompanied by smaller deviations from baseline values in the activity of procoagulant factors compared to the use of the ethinylestradiol/levonorgestrel combination.

The effect of both the drug Esteretta^® and the ethinylestradiol/levonorgestrel combination on anticoagulant factors was minimal. Changes in the fibrinolytic activity indicator D-dimer were also minimal both with the use of the drug Esteretta^® (4%) and the ethinylestradiol/levonorgestrel combination (7%).

Overall, the ethinylestradiol/Drospirenone combination had a greater impact on hemostasis parameters compared to the drug Esteretta^® and the ethinylestradiol/levonorgestrel combination.

The use of the drug Esteretta^® and the ethinylestradiol/levonorgestrel combination was accompanied by a significantly lower degree of increase in the concentration of sex hormone-binding globulin (SHBG) compared to the use of the ethinylestradiol/Drospirenone combination: 55% compared to 74% and 251%, respectively.

The use of the drug Esteretta^® and the ethinylestradiol/Drospirenone combination was accompanied by an increase in aldosterone concentration, which is due to the antimineralocorticoid activity of drospirenone. The use of the ethinylestradiol/levonorgestrel and ethinylestradiol/Drospirenone combinations was accompanied by a more pronounced increase in cortisol concentration compared to the use of the drug Esteretta^®.

When using the drug Esteretta^®, a less pronounced increase in the concentration of angiotensinogen and corticosteroid-binding globulin (CBG) relative to baseline values was observed, compared to the use of the ethinylestradiol/levonorgestrel and ethinylestradiol/Drospirenone combinations, as well as a less pronounced increase in the content of SHBG and thyroxine-binding globulin (TBG) relative to baseline values, compared to the ethinylestradiol/Drospirenone combination.

The drug Esteretta^® did not affect the lipid profile, as confirmed by the absence of changes in the concentration of total cholesterol, HDL cholesterol and LDL cholesterol after 6 cycles of drug use, compared to baseline values. When using the ethinylestradiol/levonorgestrel combination, a significant decrease in HDL cholesterol concentration was observed after 6 cycles compared to baseline values. The use of the ethinylestradiol/Drospirenone combination was accompanied by a pronounced increase in total cholesterol concentration by cycle 6 compared to baseline values (mainly due to an increase in HDL cholesterol concentration).

During the administration of the drug Esteretta^® and the ethinylestradiol/levonorgestrel combination, a moderate increase in triglyceride levels was noted, while the administration of the ethinylestradiol/Drospirenone combination was accompanied by a more pronounced increase in triglyceride concentration.

None of the three listed drugs affected carbohydrate metabolism parameters.

Within the framework of phase III clinical trials, an additional study was conducted in a subgroup of 108 women who underwent endometrial biopsy. The identified changes in the endometrium corresponded to the expected effects caused by the use of combined hormonal contraceptives.

Pharmacokinetics

Estetrol

Absorption

After oral administration, estetrol is rapidly absorbed. After a single oral dose of the drug Esteretta^®, the mean C_max in plasma is 17.9 ng/ml and is achieved within 0.5-2 hours.

The rate of absorption when the drug is taken after a meal is somewhat lower than when taken on an empty stomach; the C_max achieved in this case is approximately 50% lower. Nevertheless, the overall exposure of estetrol is comparable regardless of food intake. After the first absorption phase, less pronounced concentration peaks are observed, associated with reabsorption due to enterohepatic circulation.

Distribution

Estetrol does not bind to SHBG. In a study of protein binding using equilibrium dialysis, it was shown that estetrol moderately binds to human plasma proteins (45.5%-50.4%), to albumin (58.6%), and binds insignificantly to α-glycoprotein (11.2%). The distribution of estetrol in erythrocytes is insignificant.

Metabolism

After oral administration, estetrol undergoes significant 2-phase metabolism with the formation of glucuronides and sulfate conjugates. The 2 main metabolites of estetrol (estetrol-3-glucuronide and estetrol-16-glucuronide) have insignificant estrogenic activity. The main UGT isoenzyme involved in the metabolism of estetrol to form a soluble glucuronide is UGT2B7. Estetrol also undergoes sulfation, mainly with the participation of sulfotransferase 1E1 (SULT1E1).

Elimination

The terminal T_1/2 of estetrol at steady state is 24 hours. After a single oral dose of a solution containing 15 mg of ¹⁴C-estetrol, approximately 69% of the total radioactivity was determined in urine and 21.9% in feces.

Linearity

When taking the drug Esteretta^® in the range from 1 to 5 doses, the plasma concentration of estetrol did not significantly deviate from dose-proportional values, both after a single dose and at steady state.

Steady state

Steady state is achieved after 5 days of starting the drug. The mean plasma concentration is 2.46 ng/ml. Drug accumulation is limited, the daily AUC value at steady state is 60% higher than that after a single dose.

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed. C_max in plasma is 48.7 ng/ml and is achieved 1-3 hours after multiple administration of the drug Esteretta^®. Bioavailability is 76%-85%. The rate of absorption when the drug is taken after a meal is somewhat lower than when taken on an empty stomach; the C_max achieved in this case is also somewhat lower. Concurrent administration of the drug Esteretta^® with food does not affect the overall exposure of drospirenone.

Distribution

Drospirenone binds to plasma albumin and does not bind to SHBG or CBG. Only 3%-5% of the total drospirenone concentration is in free form. The mean apparent V_d is 3.7±1.2 L/kg.

Metabolism

After oral administration, Drospirenone undergoes intensive metabolism. The main metabolites present in plasma are the acid form of drospirenone and 4,5-dihydro-Drospirenone-3-sulfate. Drospirenone is also a substrate for oxidative metabolism catalyzed by the CYP3A4 isoenzyme.

Elimination

The terminal T_1/2 of drospirenone after oral administration of the drug Esteretta^® is approximately 34 hours. The metabolic clearance rate of drospirenone in plasma is 1.5±0.2 ml/min/kg. Drospirenone is excreted unchanged only in trace amounts. Drospirenone metabolites are excreted by the kidneys and through the intestine in a ratio of approximately 1.2 to 1.4. The half-life of metabolites by the kidneys and through the intestine is approximately 40 hours.

Linearity

The plasma concentration of drospirenone after a single oral dose or at steady state was proportional to the drug dose in the dose range of 3-15 mg, without significant deviations.

Steady state

Steady state is achieved after 10 days of starting the drug. The mean steady-state concentration with once-daily administration is approximately 22 ng/ml. Drug accumulation is limited, the daily AUC value at steady state is 80% higher than that after a single dose.

Pharmacokinetics in special patient groups

Patients with renal impairment

Studies evaluating the effect of kidney disease on the pharmacokinetics of estetrol have not been conducted. The C_ss of drospirenone in plasma after administration of a 3 mg dose orally for 14 days in women with mild renal impairment (CrCl 50-80 ml/min) was comparable to that in women with normal renal function. The plasma concentration of drospirenone was on average 37% higher in women with moderate renal impairment (CrCl 30-50 ml/min) compared to that in women with normal renal function. Drospirenone therapy was well tolerated by women with mild and moderate renal impairment. The use of drospirenone did not have a clinically significant effect on plasma potassium concentration.

Patients with hepatic impairment

Studies evaluating the effect of liver disease on the pharmacokinetics of estetrol have not been conducted. In a single-dose study in volunteers with moderate hepatic impairment, the apparent total clearance (CL/F) of drospirenone was reduced by approximately 50% compared to volunteers with normal liver function. The noted decrease in drospirenone clearance in volunteers with moderate hepatic impairment did not lead to any significant differences in plasma potassium concentration. Even in patients with diabetes mellitus and concomitant use of spironolactone (both conditions are considered as factors predisposing to hyperkalemia), no increase in plasma potassium concentration above the upper limit of normal was observed. Drospirenone is well tolerated by patients with mild and moderate hepatic impairment (Child-Pugh class B).

Children

The pharmacokinetics of estetrol and drospirenone when using the drug Esteretta^® in adolescent girls after menarche have not been studied.

Ethnic groups

The pharmacokinetic parameters of estetrol and drospirenone after a single dose of the drug Esteretta^® in women of Japanese origin and women of Caucasian race did not differ clinically significantly.

Preclinical safety data

The results of repeated dose toxicity, genotoxicity, and reproductive toxicity studies of estetrol, drospirenone, and the combination were consistent with their pharmacological profile; no special risks to humans were identified.

At exposures exceeding those in women taking the drug Esteretta^® (approximately 27 times for estetrol and 3.5 times for drospirenone), histological changes in ventricular tissue without clinical manifestations were observed in monkeys after repeated administration of the Drospirenone+estetrol combination.

In reproductive toxicity studies using estetrol in animals, embryotoxic and fetotoxic effects were identified, which were considered consistent with estrogen exposure.

Genotoxicity and carcinogenicity studies using this combination have not been conducted. Estetrol and Drospirenone are considered non-genotoxic. However, it should be remembered that sex steroid hormones, due to their hormonal activity, can promote the growth of certain hormone-dependent tissues and tumors.

In environmental risk assessment studies using drospirenone, it was shown that Drospirenone carries a potential risk to the aquatic environment. In environmental risk assessment studies for estetrol using an extended test for reproductive impairment in first-generation Japanese medaka (Oryzias latipes), it was shown that the predicted environmental exposure to estetrol does not pose a risk to aquatic ecosystems.

Indications

• Oral contraception in adult women (over 18 years of age).

Before prescribing the drug Esteretta^®, the woman’s individual risk factors, especially those related to venous thromboembolism (VTE), should be carefully assessed, and the risk of VTE when taking Esteretta^® should be compared with the risk of VTE when using other combined hormonal contraceptive drugs.

ICD codes

Dosage Regimen

Orally, regardless of meals, with a small amount of water.

How to take Esteretta^®

Esteretta^® is taken daily, 1 tablet/day, continuously for 28 days, at approximately the same time, in the order indicated on the packaging. The package includes self-adhesive strips with the names of the days of the week; to mark the 1st day of starting the drug, the strip should be placed on the blister above the corresponding day of the week.

Use of Esteretta^® begins with taking 24 light pink tablets containing hormones, followed by taking 4 white placebo tablets (not containing hormones). Taking tablets from the next package starts immediately after taking the last tablet from the previous package, regardless of the presence or absence of withdrawal bleeding. Withdrawal bleeding usually begins 2-4 days after taking the last hormone-containing tablet (light pink), i.e., during the intake of the second or third placebo tablet (white), and may not have stopped by the start of taking tablets from the next blister.

Starting the drug

If hormonal contraceptives have not been used previously (or were not used during the previous month)

Tablets should be started on the 1st day of the menstrual cycle; in this case, additional contraceptive methods are not required. If the first tablet is taken on days 2-5 of the menstrual cycle, the contraceptive effect will be achieved no earlier than after 7 days of continuous intake of light pink tablets. During the first 7 days, it is necessary to additionally use a barrier method of contraception (e.g., a condom). Before starting Esteretta^®, pregnancy must be excluded.

Switching from another combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, or transdermal patch)

The first tablet from the Esteretta^® package containing hormones (light pink) is recommended to be taken the day after the last hormone-containing tablet from the previously used COC package, but no later than the day after the usual tablet-free interval or placebo tablet intake of the previously used COC.

In case of using a vaginal ring or transdermal patch, starting Esteretta^® is recommended on the day of removal of the vaginal ring or patch, but no later than the day scheduled for insertion of a new ring or patch replacement.

Switching from progestogen-only preparations (“mini-pills”, implants, injectable forms) or from a progestogen-releasing IUD

Switching from “mini-pills” to Esteretta^® is possible on any day: stop taking the “mini-pills” and start Esteretta^® the next day. Switching from an implant or IUD to Esteretta^® can be done on the day of its removal; from an injectable contraceptive – on the day the next injection is scheduled.

In all the above cases, during the first 7 days of taking the light pink hormone-containing tablets, it is necessary to additionally use reliable barrier methods of contraception.

After abortion, including spontaneous, in the first trimester of pregnancy

Esteretta^® can be started immediately; in this case, there is no need for an additional method of contraception.

After childbirth or termination of pregnancy in the second trimester

Esteretta^® should be started on day 21-28 after childbirth (in the absence of breastfeeding) or termination of pregnancy in the second trimester. If intake is started later, it is necessary to additionally use a reliable barrier method of contraception during the first 7 days of taking the light pink hormone-containing tablets. If sexual intercourse occurred before starting the drug, pregnancy must first be excluded or wait for the first menstruation, and only then start taking Esteretta^®.

Recommendations in case of a missed dose

• In case of missing a light pink hormone-containing tablet (Days 1-24)

If less than 24 hours have passed since missing a hormone-containing (light pink) tablet

If the delay in taking a light pink tablet is less than 24 hours, contraceptive protection is not reduced. The woman should take the missed tablet as soon as possible and continue taking the next tablets at the usual time.

If more than 24 hours have passed since missing a hormone-containing (light pink) tablet

If the delay in taking a light pink tablet exceeds 24 hours, contraceptive protection may be reduced.

In this case, when missing a scheduled dose, two main rules should be followed.

1. Adequate suppression of the hypothalamic-pituitary-ovarian system requires 7 days of continuous intake of light pink hormone-containing tablets.
2. The more light pink hormone-containing tablets were missed, and the closer the misses were to the start of taking the 4 white placebo tablets, the higher the risk of pregnancy.

Days 1-7 (see scheme)

The last missed tablet should be taken as soon as the woman remembers, even if it means taking 2 tablets at the same time. The next tablets are taken at the usual time. During the next 7 days of taking hormone-containing tablets, it is necessary to additionally use reliable barrier contraceptive methods (e.g., a condom). If unprotected sexual intercourse occurred during the 7 days preceding the missed first tablet, the possibility of pregnancy should be considered.

Days 8-17 (see scheme)

The last missed tablet should be taken as soon as the woman remembers, even if it means taking 2 tablets at the same time. The next tablets are taken at the usual time. Provided that the woman took the tablets correctly for the 7 days preceding the first missed tablet, there is no need to use additional contraceptive methods. However, if the woman missed more than 1 tablet, an additional barrier method of contraception, such as a condom, must be used for the next 7 days of continuous intake of light pink tablets.

Days 18-24 (see scheme)

The risk of reduced contraceptive effect and pregnancy is highest as the phase of taking the 24 light pink hormone-containing tablets nears completion.

In this case, two options are possible, depending on whether the woman adhered to the dosing regimen before the first missed tablet. Provided that for the 7 days preceding the day of the first missed tablet, the dosing regimen was followed, then either of the two schemes below can be followed, with no need for additional contraceptive methods. Otherwise, it is recommended to follow the first of the schemes proposed below and also use an additional method of contraception for the next 7 days.

Scheme 1. The last missed tablet should be taken as soon as the woman remembers, even if it means taking 2 tablets at the same time. Then continue taking tablets at the usual time until the hormone-containing tablets are finished. All 4 placebo tablets from the last row of the blister should be discarded and immediately start taking tablets from a new blister. Withdrawal bleeding will most likely not start until the end of taking the hormone-containing tablets from the second blister, but spotting or breakthrough bleeding may be observed during drug intake.

Scheme 2. The woman can also be advised to stop taking the hormone-containing tablets from the current blister. Start taking the white placebo tablets and take them for a maximum of 3 days, so that the total number of placebo tablets taken and missed light pink hormone-containing tablets does not exceed 4. Then start taking tablets from the next blister.

No more than 2 tablets per day are allowed.

If a woman missed tablets and subsequently does not have withdrawal bleeding during the placebo tablet period, the possibility of pregnancy should be considered.

Attention if a woman is unsure of the number of missed tablets or their color and, accordingly, does not know which recommendations to follow, a barrier method of contraception should be used until the woman has taken light pink tablets for 7 consecutive days.

• In case of missing a white placebo tablet (days 25-28)

Missed placebo tablets should be discarded to avoid accidentally prolonging the placebo tablet phase; the remaining tablets should be taken at the usual time. Contraceptive protection is not reduced; the use of additional barrier methods of contraception, e.g., a condom, is not required.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (e.g., vomiting or diarrhea), absorption of active substances may be incomplete, so additional contraceptive methods should be used.

If vomiting occurs within 4 hours after taking a tablet, the intake should be considered missed, and a new tablet should be taken as soon as possible. If possible, the new tablet should be taken within 24 hours of the usual tablet intake time. The next tablet should be taken at the usual time.

If more than 24 hours have passed since the last tablet was taken, follow the recommendations for missed doses (see “Recommendations in case of a missed dose”).

If a woman does not want to change the usual tablet intake schedule, she can take an additional light pink tablet (or tablets) from another package.

Delaying the onset of withdrawal bleeding

To delay the onset of withdrawal bleeding, do not take and discard the placebo tablets from the current blister and start taking the light pink tablets from a new blister. Continue taking light pink tablets for as long as the woman wishes until the light pink tablets in the second package run out. During the extended intake of light pink tablets, the woman may experience spotting or breakthrough bleeding. Esteretta^® intake according to the usual scheme should be resumed after taking the white placebo tablets from the second package.

Changing the day of onset of withdrawal bleeding

To shift the onset of withdrawal bleeding to another day of the week, shorten the period of taking white placebo tablets by the desired number of days. The shorter the period of taking placebo tablets, the higher the likelihood of no withdrawal bleeding and the risk of breakthrough bleeding and/or spotting during the intake of tablets from the next package (just as when delaying the onset of withdrawal bleeding).

Special patient groups

Elderly patients. Esteretta^® is not indicated for use in the postmenopausal period.

Patients with impaired liver function. The use of Esteretta^® in patients with hepatic insufficiency has not been studied in clinical trials. Esteretta^® is contraindicated in patients with hepatic insufficiency, severe liver disease until liver function tests normalize.

Patients with impaired renal function. Clinical studies of Esteretta^® use in patients with impaired renal function have not been conducted. Esteretta^® is contraindicated in patients with severe renal insufficiency.

Children and adolescents under 18 years. The use of Esteretta^® in adolescent girls under 18 years of age is contraindicated due to the lack of clinical data on the efficacy and safety of the drug in this age population.

Adverse Reactions

The most frequently occurring adverse reactions with Esteretta^® are metrorrhagia, headache, acne, vaginal bleeding, and dysmenorrhea.

The table below presents adverse reactions reported in women receiving Esteretta^® and possibly associated with its use.

All adverse reactions are classified by system-organ class and frequency of occurrence: common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), and rare (from ≥1/10000 to <1/100).

N=3790 women (100%)

¹Including: emotional lability, anger, euphoric mood, irritability, mood alterations, mood swings.

² Including: depressed mood, depressive symptoms, tearfulness, depression.

³ Including: agitation, anxiety, generalized anxiety disorder, panic attack.

⁴ Including: emotional disorder, emotional shock, tearfulness.

⁵Including: night sweats, hyperhidrosis, cold sweat.

⁶ Including: dry skin, rash, skin swelling.

⁷Including: dermatitis, eczema.

⁸ Including: chloasma, skin hyperpigmentation.

⁹ Including: pathological withdrawal bleeding, amenorrhea, menstrual cycle disorders, irregular menstruation, oligomenorrhea, polymenorrhea.

¹⁰ Including: vaginal odor, vaginal discomfort, vaginal dryness, vulvovaginal pain, genital and vaginal itching, genital and vaginal burning.

¹¹ Including: breast induration, fibrocystic breast disease.

¹² Including: malaise, decreased performance.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, TIA, venous thrombosis, and PE, has been observed in women taking CHCs (see section “Special Instructions”).

Exogenous estrogens may provoke or exacerbate symptoms of hereditary and acquired angioedema.

Interaction

Breakthrough bleeding and/or contraceptive failure may result from the interaction of COCs with other drugs (inducers of hepatic microsomal enzymes) (see section “Drug Interactions”).

Contraindications

• Hypersensitivity to drospirenone, estetrol or to any of the excipients;
• Venous thrombosis or thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), currently or in history;
• Arterial thrombosis or thromboembolism (ATE), including myocardial infarction and stroke; or prodromal conditions (transient ischemic attack (TIA), angina) currently or in history;
• Identified hereditary or acquired predisposition to VTE or ATE, including activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of severe or multiple high-risk factors for VTE or ATE (smoking at age over 35 years, obesity with BMI ≥30 kg/m², any surgery on lower extremities, pelvic area or neurosurgical intervention, complicated heart valve defects, atrial fibrillation), or one serious risk factor, such as:
  • Uncontrolled arterial hypertension;
  • Diabetes mellitus with diabetic angiopathy;
  • Severe dyslipoproteinemia;
• Extensive surgical interventions with prolonged immobilization;
• Migraine with focal neurological symptoms currently or in history;
• Severe chronic renal failure or acute renal failure;
• Hepatic failure, acute or chronic severe liver diseases (until liver function test parameters normalize);
• Liver tumors (benign or malignant) currently or in history;
• Diagnosed hormone-dependent malignant neoplasms (including of genital organs or breast) or suspicion thereof;
• Vaginal bleeding of unknown etiology.

If any of these diseases/conditions or risk factors are identified or develop for the first time during the use of Esteretta^®, the drug should be discontinued immediately.

Use in Pregnancy and Lactation

Pregnancy

The use of the Drospirenone+estetrol combination during pregnancy is contraindicated.

If pregnancy is diagnosed during the use of Esteretta^®, it should be discontinued immediately. Numerous epidemiological studies have not revealed an increased risk of developmental defects in children of women who received sex hormones before pregnancy, nor the presence of a teratogenic effect when sex hormones were taken inadvertently in early pregnancy. Animal studies revealed a negative effect of estetrol on the reproductive system (see section “Pharmacokinetics”, subsection “Preclinical safety data”). Based on these data, the possibility of adverse reactions related to the hormonal effects of the drug’s active substances cannot be excluded. Data based on a limited number of cases of use during pregnancy indicate no adverse effect of Esteretta^® on the fetus or the condition of the newborn.

Breastfeeding

The use of Esteretta^®, like other combined oral contraceptives (COCs), may reduce the amount of breast milk and change its composition; therefore, the drug is contraindicated until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites may pass into breast milk and affect the child’s health.

Fertility

Information on the restoration of fertility is provided in the section “Pharmacological action”.

Use in Hepatic Impairment

Contraindicated in liver diseases with abnormal liver function tests.

Contraindicated in malignant or benign liver tumor (including in history).

Use in Renal Impairment

Contraindicated in renal impairment and renal failure.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Not applicable.

Special Precautions

In the presence of any of the diseases/conditions or risk factors listed below, a thorough assessment of the potential risk and expected benefit of using Esteretta^® should be conducted in each individual case and discussed with the woman before starting the drug. In case of worsening, exacerbation, or first occurrence of any of these diseases/conditions or risk factors, the woman should consult her doctor to decide whether to discontinue or continue taking the drug.

Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptives (CHCs) increases the risk of VTE in women using CHCs compared to those who do not use them.

The lowest risk of VTE is observed with the use of drugs containing low doses of ethinylestradiol (< 50 μg) in combination with levonorgestrel, norgestimate, or norethisterone. The increased risk of VTE is most pronounced during the first year of CHC use. Furthermore, there is data suggesting that the risk increases upon resumption of CHC use after a break of 4 weeks or more.

Approximately 2 out of 10,000 women who are not pregnant and not using CHCs develop VTE per year. However, an individual woman’s risk may be much higher, considering her existing risk factors (see below).

Epidemiological studies in women using low-dose CHCs (< 50 μg ethinylestradiol) showed that VTE develops in 6¹-12 out of 10,000 women per year.

According to the results of a randomized study that investigated the effect of Esteretta^® on hemostasis parameters, the thrombogenic potential of Esteretta^® does not exceed that of the ethinylestradiol (30 μg)/levonorgestrel (150 μg) combination. The frequency of VTE development during the use of Esteretta^® in clinical studies was 1 per 2735 woman-years.

The number of VTE per year in women using low-dose CHCs is lower than the number expected during pregnancy or in the postpartum period.

VTE can be fatal in 1-2% of cases.

Thrombosis of other vessels, including hepatic, mesenteric, renal, retinal arteries and veins, developed very rarely in women taking CHCs.

¹ Median of the range 5-7 per 10,000 woman-years, calculated on the relative risk of VTE for CHCs containing levonorgestrel compared to the risk of non-use, being approximately 2.3-3.6.

VTE risk factors

The risk of developing venous thromboembolic complications when using CHCs can increase significantly in women with additional risk factors, especially with multiple risk factors (see table).

In women with a combination of several risk factors or a high degree of severity of one factor, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than the simple summation of factors. In this case, the use of the Drospirenone+estetrol combination is contraindicated (see section “Contraindications”).

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the development or progression of venous thrombosis.

The increased risk of thromboembolism in the postpartum period, especially in the first 6 weeks, should be considered.

Symptoms of VTE (DVT and PE)

The woman should be instructed to seek immediate medical attention if any of the symptoms listed below appear and to inform the doctor about taking the contraceptive.

Symptoms of DVT unilateral swelling of the lower limb/foot or along a vein, pain or discomfort only in an upright position or when walking, local increase in temperature, redness or discoloration of the skin in the affected lower limb.

Symptoms of PE sudden, unexplained shortness of breath or rapid, difficult breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep inspiration; feeling of anxiety; severe dizziness; rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of other more common and less severe conditions (e.g., respiratory tract infection).

In case of eye vessel occlusion, symptoms can range from blurred vision (without pain) to vision loss (with progression). In some cases, vision loss can develop almost immediately.

Risk of arterial thromboembolism (ATE)

ATE risk factors

The use of CHCs is associated with an increased risk of developing ATE.

ATE can lead to stroke, vessel occlusion, or myocardial infarction.

The risk of developing arterial thromboses/thromboembolisms or cerebrovascular disorders when using CHCs is higher in women with risk factors (see table). Esteretta^® is contraindicated in women with one serious risk factor or multiple risk factors for ATE. In women with a combination of several risk factors or a high degree of severity of one factor, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than the simple summation of factors. In this case, the use of the Drospirenone+estetrol combination is contraindicated (see section “Contraindications”).

Symptoms of ATE

The woman should be instructed to seek immediate medical attention if any of the symptoms listed below appear and to inform the doctor about taking the contraceptive.

Symptoms of stroke sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, severe or prolonged headache for no apparent reason, unilateral or bilateral vision loss; speech disorders or comprehension of speech; sudden gait disturbance, dizziness, loss of balance or coordination; sudden loss of consciousness or fainting with or without a seizure.

Other signs of vessel occlusion sudden pain, swelling and slight bluish discoloration of the limbs, “acute” abdomen.

Symptoms of myocardial infarction pain, discomfort, feeling of pressure, heaviness, squeezing or fullness in the chest or behind the breastbone, with radiation to the back, jaw, upper limb, epigastric area; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat.

ATE can be life-threatening and fatal.

Tumors

The most significant risk factor for cervical cancer (CC) is persistent papillomavirus infection. There are reports of an increased risk of CC with long-term use of COCs (more than 5 years). However, the association with COC use has not been proven. Controversy remains regarding the extent to which these data are related to cervical pathology screening or to women’s sexual behavior characteristics (less frequent use of barrier contraception methods, a larger number of sexual partners). There are no data from studies on the risk of CC in women taking the Drospirenone+estetrol combination.

A meta-analysis of 54 epidemiological studies in women receiving COCs containing ethinylestradiol revealed a small increase in the relative risk (RR) of breast cancer (BC) (RR=1.24). The increased risk gradually disappears within 10 years after discontinuation of COCs. BC rarely develops in women under 40 years of age, so the additional number of BC cases in women who are taking or have taken COCs is small compared to the overall risk of BC. BC in women who have ever taken COCs is generally diagnosed at an earlier stage than in women who have never taken them. The observed pattern of increased risk may be a consequence of earlier diagnosis of BC in women taking COCs, the biological effect of COCs, or a combination of both factors.

In rare cases, the development of benign liver tumors and, in extremely rare cases, malignant ones, has been observed in women taking COCs containing ethinylestradiol. In some cases, these tumors led to life-threatening intra-abdominal bleeding. If severe pain in the upper abdomen, liver enlargement, or symptoms of intra-abdominal bleeding occur in women taking COCs, a liver tumor must be ruled out.

Other conditions

The progestogenic component of Esteretta^® Drospirenone is an aldosterone antagonist with potassium-sparing properties. In most cases, no increase in plasma potassium concentration should be observed. In clinical studies, in some women with mild or moderate renal insufficiency and concomitant use of potassium-sparing drugs, plasma potassium concentration slightly increased during the use of drospirenone at a dose of 3 mg for 14 days. Therefore, it is necessary to monitor plasma potassium concentration during the 1st cycle of drug use in women with renal insufficiency and with initial potassium concentration at the upper limit of normal, especially with concomitant use of potassium-sparing drugs (see section “Drug interactions”).

In women with hypertriglyceridemia or a corresponding family history, the possibility of an increased risk of pancreatitis should be considered when taking COCs containing ethinylestradiol. For women taking Esteretta^®, this risk is unknown.

Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. However, if a persistent clinically significant increase in blood pressure develops during the use of COCs, the contraceptive should be discontinued and arterial hypertension should be treated. COC use may be continued if normal blood pressure values are achieved with antihypertensive therapy.

During pregnancy and during the use of COCs, the development or worsening of the following conditions has been noted, although their connection with contraceptive use has not been definitively established: jaundice and/or itching associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; gestational herpes; hearing loss associated with otosclerosis.

Exogenous estrogens may cause or worsen symptoms of hereditary and acquired angioedema.

In acute and chronic liver function disorders, it may be necessary to discontinue COCs until liver function tests normalize. If cholestatic jaundice recurs, first observed during pregnancy or during previous use of sex hormones, COC use must be discontinued.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no need to change the dosage regimen of hypoglycemic drugs in patients with diabetes mellitus taking low-dose COCs (less than 50 μg ethinylestradiol). However, periodic examinations of women with diabetes mellitus taking COCs should be carefully conducted, especially in the early stages of COC use.

Progression of endogenous depression, epilepsy, Crohn’s disease and ulcerative colitis has been reported during COC use.

Depressed mood and depression are well-known adverse reactions when using hormonal contraceptives (see section “Adverse reactions”). Depression can be serious and is a well-known risk factor for suicidal behavior and suicide. Women should consult their doctor in case of mood swings and the appearance of depressive symptoms, including after starting the drug.

Chloasma sometimes developed, especially in women with a history of chloasma during pregnancy. Women prone to chloasma during COC use should avoid prolonged exposure to the sun and UV radiation.

Effect on Liver Function Parameters

In clinical studies of the combination of medicinal products for the treatment of viral hepatitis C, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, an increase in ALT activity of more than 5 times the ULN was observed significantly more often in women using medicinal products containing ethinylestradiol, such as COCs.

Furthermore, among patients receiving therapy with glecaprevir/pibrentasvir, an increase in ALT activity was also observed in women using ethinylestradiol-containing drugs, for example, COCs.

In women using medicinal products containing estrogens other than ethinylestradiol, the degree of increase in ALT activity was similar to that in women not using any estrogens.

However, due to the limited number of women taking other estrogens, caution should be exercised when co-administering the drug with the combination of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with therapy with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir.

Excipients

Each hormone tablet contains 39.9 mg of lactose monohydrate; each placebo tablet contains 67.7 mg of lactose monohydrate.

Women with hereditary galactose intolerance, lactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

The drug contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially sodium-free.

Medical Examinations / Consultations

Before starting or resuming taking Esteretta^®, it is necessary to review the woman’s life history and family history, conduct a thorough general medical (including measurement of blood pressure, determination of BMI) and gynecological examination (with mandatory breast examination and cytological examination of the cervical epithelium), and rule out pregnancy.

The scope of additional tests and the frequency of follow-up examinations are determined individually. Usually, follow-up examinations should be performed at least once every 6 months.

It is necessary for the woman to carefully read the consumer information leaflet and follow the recommendations provided therein.

It must be remembered that the drug does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced Efficacy

The efficacy of COCs may decrease in case of missed tablets, gastrointestinal disorders while taking hormone-containing tablets (see section “Dosage Regimen”), or in case of concomitant use of medicinal products (see section “Drug Interactions”).

Cycle Control

While taking COCs, irregular bleeding (“spotting” and/or “breakthrough” bleeding) may occur, especially during the first months of use.

Therefore, assessment of any irregular bleeding should be performed only after an adaptation period of approximately 3 cycles of taking the drug.

While using Esteretta^®, most such episodes occurred in the form of “spotting”.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant neoplasms or pregnancy.

In most women taking Esteretta^® (92%-94%), scheduled “withdrawal” bleeding/”spotting” was observed, which remained stable over time.

In some women, withdrawal bleeding may not occur during the tablet-free interval.

If Esteretta^® was taken as recommended, the likelihood of pregnancy is low.

However, if the drug regimen was violated, or if 2 consecutive withdrawal bleedings are absent, pregnancy must be ruled out before continuing its use.

Effect of Esteretta^® on Laboratory Tests

Taking sex hormone preparations may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, as well as concentrations of plasma (transport) proteins such as SHBG, and on lipid/lipoprotein fractions, parameters of carbohydrate metabolism, coagulation and fibrinolysis.

Changes usually do not exceed the normal limits of laboratory parameters.

Drospirenone increases plasma renin activity and aldosterone concentration, which is associated with its antimineralocorticoid effect.

Effect on Ability to Drive and Operate Machinery

Esteretta^® has no or negligible influence on the ability to drive and use machines.

Overdose

Symptoms nausea, vomiting, vaginal bleeding (based on the overall experience with COCs).

Treatment symptomatic therapy. There is no specific antidote.

Drug Interactions

Note: to determine possible interactions, it is necessary to review the information for the use of concomitant drugs.

Pharmacokinetic Interactions

Effect of Other Medicinal Products on Esteretta^®

Interaction with drugs that induce hepatic microsomal enzymes is possible, which may lead to an increase in the clearance of sex hormones, which can result in breakthrough bleeding and/or reduced contraceptive efficacy.

Risk Reduction Measures

Induction of hepatic microsomal enzymes can be observed within a few days of taking the drug.

Maximum induction of hepatic microsomal enzymes is usually observed within several weeks.

After discontinuation of the drug, enzyme induction may persist for up to 4 weeks.

Short-term Therapy

Women receiving treatment with drugs that induce hepatic microsomal enzymes are advised to temporarily use a barrier or other methods of contraception in addition to COCs.

The barrier method of contraception should be used throughout the period of concomitant therapy and for 28 days after its discontinuation.

If the use of the hepatic microsomal enzyme inducer continues after taking the last hormone tablet from the current blister pack, the contraceptive tablets from the next blister pack should be started, skipping the placebo tablets.

Long-term Therapy

Women on long-term treatment with drugs that induce hepatic microsomal enzymes are advised to use another reliable non-hormonal method of contraception.

The following types of interactions related to the effect on the cytochrome P450 system have been described in the literature for women taking COCs containing ethinylestradiol.

The estrogen in Esteretta^® is metabolized without the involvement of cytochrome P450 system enzymes, therefore the interactions described below do not apply to estetrol.

Drospirenone, the progestogen in Esteretta^®, is metabolized with the involvement of cytochrome P450 system enzymes.

Substances that increase the clearance of COCs (reduce the efficacy of COCs by inducing hepatic microsomal enzymes): barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, drugs for the treatment of HIV infection (ritonavir, nevirapine and efavirenz), and possibly felbamate, griseofulvin, oxcarbazepine, topiramate and herbal preparations containing St. John’s wort (Hypericum perforatum).

Substances with variable effects on the clearance of COCs

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus protease inhibitors, may increase or decrease the plasma concentrations of estrogen or progestogen.

In some cases, this effect may be clinically significant.

To identify possible drug interactions and related recommendations, the information presented in the prescribing information of concomitant drugs intended for the treatment of HIV infection/hepatitis C should be considered.

During therapy with such drugs, a woman should additionally use a barrier method of contraception.

Substances that decrease the clearance of COCs (enzyme inhibitors)

• Potential interaction with drospirenone – concomitant use of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) inhibitors of the CYP3A4 isoenzyme may lead to an increase in the plasma concentration of drospirenone.

In a multiple-dose study of a drug containing a combination of Drospirenone (3 mg/day)/ethinylestradiol (0.02 mg/day), concomitant use of the strong CYP3A4 inhibitor ketoconazole for 10 days demonstrated an increase in the AUC_(0-24h) of drospirenone (and ethinylestradiol) by 2.7 times (and 1.4 times, respectively).

• Potential interaction with estetrol – estetrol undergoes glucuronidation, with the main UDP-glucuronosyltransferase (UGT) isoenzyme involved in its metabolism being UGT2B7.

A study showed that concomitant use of Esteretta^® with the strong UGT2B7 isoenzyme inhibitor valproic acid for 12 days led to an increase in the AUC_(0-∞) and maximum plasma concentration C_max of estetrol by 1.13 and 1.36 times, respectively; but no effect on the pharmacokinetics of drospirenone was detected.

According to the researchers, these changes are not clinically significant.

Effect of Esteretta^® on Other Medicinal Products

COCs may affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in plasma and tissue concentrations.

In vitro, Drospirenone is a weak to moderate inhibitor of cytochrome P450 isoenzymes – CYP1A1, CYP2C9, CYP2C19 and CYP3A4.

Based on in vivo interaction studies in female volunteers taking omeprazole, simvastatin and midazolam as marker substrates, it can be concluded that a clinically significant effect of taking 3 mg of drospirenone on the metabolism of drugs mediated by cytochrome P450 isoenzymes is unlikely.

Pharmacodynamic Interactions

In patients with normal renal function, concomitant use of drospirenone and ACE inhibitors or NSAIDs does not have a significant effect on plasma potassium concentration.

Concomitant use of the Drospirenone+estetrol combination with aldosterone antagonists or potassium-sparing diuretics has not been studied.

When co-administered with these drugs, plasma potassium concentration should be monitored during the first cycle of contraceptive use.

When used concomitantly with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, the risk of increased ALT activity may increase in women receiving drugs containing ethinylestradiol, for example, COCs.

In women using medicinal products containing estrogens other than ethinylestradiol, the degree of increase in ALT activity was similar to that in women not using any estrogens.

However, due to the limited number of women taking other estrogens, caution should be exercised when co-administering the contraceptive Esteretta^® with the combination of drugs ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, as well as with therapy with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir.

Storage Conditions

The drug should be stored out of the reach of children. No special storage conditions are required.

Shelf Life

The shelf life is 4 years. Do not use the drug after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.