Drovelis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DROVELIS (DROVELIS®)

Composition:

Active substances: drospirenone, estetrol monohydrate;

1 pink active tablet contains 3 mg drospirenone and estetrol monohydrate in an amount equivalent to 14.2 mg estetrol;

1 white placebo tablet contains no active substances;

Excipients:

Pink active film-coated tablets:

Tablet core: lactose monohydrate, sodium starch glycolate, maize starch, povidone K30, magnesium stearate (E470b);

Tablet coating: hypromellose (E464), hydroxypropylcellulose (E463), talc (E553b), hydrogenated cottonseed oil, titanium dioxide (E171), iron oxide red (E172);

White placebo film-coated tablets:

Tablet core: lactose monohydrate, maize starch, magnesium stearate (E470b);

Tablet coating: hypromellose (E464), hydroxypropylcellulose (E463), talc (E553b), hydrogenated cottonseed oil, titanium dioxide (E171), iron oxide red (E172).

Pharmaceutical form. Film-coated tablets.

Active tablets: pink, round, biconvex film-coated tablets with a droplet-shaped imprint on one side.

Placebo tablets: white or almost white, round, biconvex film-coated tablets with a droplet-shaped imprint on one side.

Pharmacotherapeutic group. Sex hormones and drugs used in disorders of the reproductive system. Hormonal contraceptives for systemic use. Progestogens and estrogens, fixed combinations.

ATC code G03A A18.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

Drovelis contains the oestrogen estetrol and the progestogen drospirenone. Estetrol is an oestrogen produced only by the human fetal liver during pregnancy.

Estetrol demonstrates antigonadotropic activity, characterised by dose-dependent suppression of serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels.

The progestogen drospirenone exhibits progestogenic, antigonadotropic, antiandrogenic, and mild antimineralocorticoid properties, and has no oestrogenic, glucocorticoid, or antiglucocorticoid activity. These pharmacological properties are similar to those of the natural hormone progesterone.

The contraceptive effect of Drovelis is based on the interaction of several factors, the most important of which is the inhibition of ovulation.

Clinical efficacy and safety

Two clinical studies were conducted worldwide: a main study in the EU and Russia, and a supporting study in the US, involving women aged 16 to 50 years over 13 cycles for 1 year.

In the main study conducted in the EU and Russia, based on 14,759 cycles, excluding cycles with additional contraception and cycles without sexual activity, the Pearl indices were established in women aged 18–35 years as follows:

contraceptive failures: 0.26 (upper limit of 95%, confidence interval 0.77);

contraceptive failures + user errors: 0.44 (upper limit of 95%, confidence interval 1.03).

The study in the US showed higher Pearl indices than those established in the EU and Russia study. It is known that Pearl indices in studies conducted in the US are higher than those reported in EU studies, but the reason for this discrepancy is unknown.

In a randomised open-label study, ovulation resumed by the end of the first post-treatment cycle in 97% of women in the Drovelis treatment group.

Endometrial histology after 13 treatment cycles was evaluated in a subgroup (n = 108) in one clinical study. No abnormalities were detected.

Pediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Drovelis for oral contraception in one or more subgroups of the pediatric population (see section "Children" for information on use in pediatric patients).

Pharmacokinetics.

Estetrol

Absorption

Estetrol is rapidly absorbed after administration. Following administration of Drovelis, the mean maximum plasma concentration of estetrol is 17.9 ng/mL, reached within 0.5–2 hours after single administration.

Overall exposure to estetrol is not altered by food intake. However, the Cmax of estetrol is reduced by approximately 50% when taken with food.

Distribution

Estetrol does not bind to sex hormone-binding globulin (SHBG). Estetrol is moderately bound to human plasma proteins (45.5–50.4%) and human serum albumin (58.6%), and weakly bound to human alpha-1-acid glycoprotein (11.2%). Estetrol distributes evenly between erythrocytes and plasma.

In vitro studies have shown that estetrol is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. However, it is unlikely that concomitant administration of drugs affecting P-gp and BCRP activity will result in clinically significant drug interactions with estetrol.

Biotransformation

Following oral administration, estetrol undergoes extensive phase 2 metabolism, forming glucuronide and sulfate conjugates. The two main metabolites – estetrol-3-glucuronide and estetrol-16-glucuronide – have minimal oestrogenic activity. The predominant isoform of UDP-glucuronosyltransferase (UGT) involved in the direct glucuronidation of estetrol is UGT2B7. Estetrol undergoes sulfation primarily via the specific estrogen sulfotransferase (SULT1E1).

Elimination

The terminal half-life (T1/2) of estetrol is approximately 24 hours at steady state.

After a single oral dose of 15 mg of [14C]-estetrol solution, approximately 69% of total radioactivity was recovered in urine and 21.9% in faeces.

Linearity/Non-linearity

Following administration of Drovelis at 1–5 times the recommended dose, plasma levels of estetrol do not show any significant deviations from dose proportionality after single administration or at steady state.

Steady state

Steady state is reached after 5 days. The Cmax of estetrol is approximately 17.9 ng/mL, reached within 0.5–2 hours after dosing. The mean serum concentration is 2.46 ng/mL. Accumulation is very limited: the daily area under the curve (AUC) at steady state is 60% higher than after a single dose.

Drospirenone

Absorption

Drospirenone is rapidly and almost completely absorbed. After administration of Drovelis, Cmax is approximately 48.7 ng/mL, reached about 1–3 hours after multiple dosing. Bioavailability ranges from 76 to 85%. Total exposure to drospirenone is not affected by food intake taken before or after Drovelis tablets.

Distribution

Drospirenone binds to serum albumin and does not bind to SHBG or corticosteroid-binding globulin (CBG). Only 3–5% of the total concentration of the active substance in serum is present as free steroid. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 L/kg.

Biotransformation

Following oral administration, drospirenone is extensively metabolised. The main metabolites in plasma are the acid form of drospirenone, formed by opening of the lactone ring, and 4,5-dihydrodrospirenone-3-sulfate, formed by reduction followed by sulfation. Drospirenone is also subject to oxidative metabolism catalysed by cytochrome CYP3A4.

Elimination

After oral administration of Drovelis, serum levels of drospirenone decline with a terminal half-life of approximately 34 hours. The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 mL/min/kg. Drospirenone is excreted unchanged only in trace amounts. Metabolites of drospirenone are excreted in faeces and urine in an excretion ratio of approximately 1.2 to 1.4. The T1/2 of metabolite elimination in urine and faeces is approximately 40 hours.

Linearity/Non-linearity

At doses of 3–15 mg, plasma levels of drospirenone do not show any significant deviations from dose proportionality after single administration or at steady state.

Steady state

Steady state is reached after 10 days. The Cmax of drospirenone is approximately 48.7 ng/mL, reached about 1–3 hours after dosing. The mean concentration over the 24-hour dosing interval at steady state is approximately 22 ng/mL. Accumulation is very limited, with the daily AUC at steady state being 80% higher than after a single dose.

Special patient populations

Renal impairment

No studies have been conducted on the effect of renal disease on the pharmacokinetics of estetrol. In a study using drospirenone 3 mg administered orally for 14 days, steady-state serum levels of drospirenone in women with mild renal impairment (creatinine clearance (CLcr) 50–80 mL/min) were comparable to those in women with normal renal function. Serum levels of drospirenone were on average 37% higher in women with moderate renal impairment (CLcr 30–50 mL/min) compared to women with normal renal function.

Hepatic impairment

Estetrol

A study was conducted in which women with normal liver function, mild hepatic impairment (Child-Pugh class A), moderate hepatic impairment (Child-Pugh class B), and severe hepatic impairment (Child-Pugh class C) received a single oral dose of 20 mg estetrol monohydrate.

Results showed that the Cmax and AUCinf ratios for estetrol were approximately 1.7 and 1.1 times higher, respectively, in women with mild hepatic impairment compared to women with normal liver function; approximately 1.9 and 1.0 times higher, respectively, in women with moderate hepatic impairment compared to women with normal liver function; and approximately 5.4 and 1.9 times higher, respectively, in women with severe hepatic impairment compared to women with normal liver function.

Drospirenone

In a study using a single dose, the oral clearance of drospirenone (CL/F) was reduced by approximately 50% in volunteers with moderate hepatic impairment compared to volunteers with normal liver function.

Pediatric population

The pharmacokinetics of estetrol and drospirenone in children after menarche (under 16 years of age) following administration of Drovelis have not been studied.

Other specific population groups

Ethnic groups

No clinically significant differences in the pharmacokinetics of estetrol or drospirenone were observed between Japanese women and Caucasian women after a single dose of Drovelis.

Clinical characteristics.

Indications.

For oral contraception.

Contraindications.

Since epidemiological data on combined hormonal contraceptives (CHCs) containing estetrol are currently lacking, it is considered that contraindications for CHCs containing ethinylestradiol apply to the medicinal product Drovelis. CHCs must not be used in the conditions listed below. If any of these conditions occur for the first time during treatment with Drovelis, the medication should be discontinued immediately.

• Presence or risk of venous thromboembolism (VTE):
• VTE – current VTE, including cases requiring anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
• known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;
• major surgery with prolonged immobilization (see section "Special precautions");
• high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
• ATE – current ATE, history of ATE (e.g., myocardial infarction), or prodromal conditions (e.g., angina pectoris);
• cerebrovascular disorders – current or past stroke, or presence of prodromal conditions (e.g., transient ischemic attack (TIA));
• known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia or presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• history of migraine with focal neurological symptoms;
• high risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or due to the presence of any of the following serious risk factors:
• diabetes mellitus with vascular complications;
• severe arterial hypertension;
• severe dyslipoproteinemia.
  • Current or past history of severe liver disease, if liver function tests have not returned to normal.
  • Severe renal insufficiency or acute renal failure.
  • Current or past history of liver tumors (benign or malignant).
  • Known or suspected hormone-dependent malignant neoplasms (e.g., of genital organs or breast).
  • Vaginal bleeding of unknown etiology.
  • Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition".

Interaction with other medicinal products and other forms of interaction.

Note. Information on concomitantly administered medicinal products should be reviewed to identify potential interactions.

Pharmacokinetic interactions

Effect of other medicinal products on Drovelis.

Interactions may occur with medicinal products that induce microsomal enzymes. This may lead to increased clearance of sex hormones, which in turn may result in breakthrough bleeding and/or loss of contraceptive efficacy.

Therapy

Enzyme induction may be observed within a few days of starting treatment. Maximum enzyme induction is generally reached after several weeks. After discontinuation of the inducing agent, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to CHCs. The barrier method should be used throughout the treatment period with the enzyme-inducing agent and for an additional 28 days after its discontinuation. If treatment is initiated after taking the last pink active tablets of the CHC pack, the white placebo tablets should not be taken; instead, the next pack of CHC tablets should be started immediately after the pink tablets from the previous pack.

Long-term treatment

Women undergoing long-term therapy with enzyme-inducing substances are advised to use an appropriate alternative non-hormonal contraceptive method.

The following interactions have been reported according to published data.

Substances that increase CHC clearance (enzyme induction), e.g., barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; medicinal products used in HIV infection (e.g., ritonavir, nevirapine, and efavirenz), and possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing the herbal remedy St. John’s wort (Hypericum perforatum).

Substances with variable effects on CHC clearance

When used concomitantly with CHCs, numerous combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) antivirals, may either increase or decrease plasma concentrations of estrogens or progestins. The overall effect of these changes may be clinically significant in some cases.

Therefore, information on the medical use of the medicinal product for treatment of HIV/HCV taken concomitantly should be reviewed to identify potential interactions and any other recommendations. In case of any doubts, women should additionally use a barrier method of contraception during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Substances that decrease CHC clearance (enzyme inhibitors)

The clinical significance of potential interactions with enzyme inhibitors remains unknown.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestin, or both components.

Possible interaction with drospirenone

In a multiple-dose study combining drospirenone (3 mg/day)/ethinylestradiol (0.02 mg/day) and the strong CYP3A4 inhibitor ketoconazole for 10 days, the AUC(0–24 h) of drospirenone and ethinylestradiol increased by 2.7 and 1.4 times, respectively.

Possible interaction with estetrol

Estetrol is predominantly glucuronidated by the enzyme UGT2B7 (see section "Pharmacokinetics"). No clinically relevant interaction between estetrol and the strong UGT inhibitor valproic acid was observed.

Effect of Drovelis on other medicinal products

Oral contraceptives may affect the metabolism of other drugs. As a result, plasma and tissue concentrations of active substances may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin, or midazolam as marker substrates, interaction with drospirenone at a dose of 3 mg with other active substances is unlikely.

In vivo interaction studies have shown that estetrol contained in Drovelis is unlikely to interact with other active substances.

Pharmacodynamic interactions

Concomitant use of hepatitis C treatments containing ombitasvir/paritaprevir/ritonavir, used with or without dasabuvir and ribavirin, may increase the risk of elevated ALT levels in women taking medicinal products containing ethinylestradiol, such as CHCs (see section "Special precautions"). In women taking estrogen-containing products other than ethinylestradiol, ALT elevations were similar to those in women not taking estrogens; however, due to the limited number of women taking these other estrogens, caution is advised when co-administering with the combination therapy ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, as well as with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Special precautions").

In patients without renal impairment, concomitant use of drospirenone with angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) did not show a significant effect on serum potassium levels. However, concomitant use of Drovelis with aldosterone antagonists or potassium-sparing diuretics has not been studied. In such cases, serum potassium levels should be monitored during the first treatment cycle. See also section "Special precautions".

Pediatric population

Interaction studies have been conducted only in adults.

Special precautions for use

The decision to prescribe Drovelis should be made taking into account individual risk factors present in a woman at the time of prescription, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with Drovelis compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions for use").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Drovelis should be discussed with the woman before initiating treatment.

In case of exacerbation or first signs of any of the mentioned conditions or risk factors, women are advised to consult a physician to determine whether Drovelis should be discontinued. All data provided below are based on epidemiological data obtained from CHCs containing ethinylestradiol. Drovelis contains estetrol. Since epidemiological data on CHCs containing estetrol are currently lacking, the warnings are considered applicable to Drovelis.

In suspected or confirmed arterial thromboembolism (ATE) or VTE, CHC use should be discontinued. If anticoagulant therapy is initiated, an alternative non-hormonal effective contraceptive method should be used due to the teratogenic effects of anticoagulants (coumarins).

Circulatory disorders

Risk of VTE occurrence

The use of any CHC increases the risk of developing VTE compared to non-use. CHCs containing low doses of ethinylestradiol (< 50 mcg ethinylestradiol) in combination with levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. It is currently unknown how the risk with Drovelis compares to this lower risk. The decision to prescribe any CHC not belonging to the group with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure that she understands the VTE risk associated with CHC use, how her individual risk factors affect this risk level, and that the risk of VTE is highest during the first year of use.

Some data suggest that the risk of VTE may increase when resuming CHC use after a break of 4 weeks or more.

In women who do not use CHCs and are not pregnant, the incidence of VTE is approximately 2 cases per 10,000 women per year. However, in any individual woman, the risk level may be significantly higher depending on her underlying risk factors (see below).

Epidemiological studies in women using low-dose (< 50 mcg ethinylestradi0l) combined hormonal contraceptives have shown that approximately 6–12 out of 10,000 women will develop VTE within one year.

It has been established¹ that among 10,000 women using CHCs containing ethinylestradiol and drospirenone, 9–12 women will develop VTE within one year. This compares to a rate of approximately 6 women² per 10,000 women using CHCs containing levonorgestrel.

It is currently unknown how the risk of VTE with a CHC containing estetrol and drospirenone compares to the risk with CHCs containing low-dose levonorgestrel.

The number of VTE cases per year with low-dose CHCs is lower than typically expected during pregnancy or the postpartum period.

VTE may result in fatal outcomes in 1–2% of cases.

Very rare cases of thrombosis in other vessels, such as hepatic, renal, retinal, or mesenteric arteries and veins, have been reported in women using CHCs.

¹These rates are based on all available epidemiological data, taking into account relative risks associated with different CHCs compared to CHCs containing levonorgestrel.

²Average of 5–7 cases per 10,000 woman-years, based on relative risk calculation of levonorgestrel-containing CHCs compared to non-CHC users (approximately 2.3–3.6 cases).

VTE risk factors

The risk of venous thromboembolic complications during CHC use may increase substantially in women with additional risk factors, especially with multiple risk factors (see Table 1).

Drovelis is contraindicated in women with multiple risk factors that place them in a high-risk group for venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor; therefore, the overall risk of VTE should be considered. CHCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 1

VTE risk factors

Risk factor	Note
Obesity (body mass index (BMI) greater than 30 kg/m²).	Risk increases significantly with increasing BMI. Particular attention is required in women with other risk factors.
Long-term immobilization, major surgery, any surgery on legs or pelvic organs, neurosurgical procedures, or extensive trauma. Note: temporary immobilization, including air travel lasting more than 4 hours, may also be a risk factor for VTE, especially in women with other risk factors.	In such cases, it is recommended to discontinue the use of tablets (at least 4 weeks before elective surgery) and not resume use until at least 2 weeks after full recovery of mobility. To avoid unintended pregnancy, an alternative method of contraception should be used. Consideration should be given to antithrombotic therapy if use of Drovelis has not been discontinued in advance.
Positive family history (VTE in a sibling or parent, especially at a relatively young age, e.g., before age 50).	In case of hereditary predisposition, women are advised to consult a specialist before using any COC.
Other medical conditions associated with VTE	Cancer, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), and sickle cell anemia.
Increasing age	Especially over 35 years.

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

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially during the first 6 weeks postpartum (see section "Use during pregnancy or breastfeeding").

Symptoms of VTE (DVT and PE)

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their physician that they are taking COCs.

Symptoms of DVT may include:

• Unilateral swelling of the leg and/or foot, or along a vein in the leg;
• Pain or increased tenderness in the leg, which may occur only when standing or walking;
• A sensation of warmth in the affected leg;
• Redness or change in skin color of the leg.

Symptoms of PE may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden onset of cough, which may be accompanied by hemoptysis;
• Sudden chest pain;
• Pre-syncope or dizziness;
• Rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are non-specific and may be misinterpreted as more common or less serious conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include sudden pain, swelling, and slight bluish discoloration of a limb.

In cases of ocular vessel occlusion, initial symptoms may include blurred vision without pain, which may progress to vision loss. Sometimes, vision loss develops almost instantaneously.

Risk of ATE

Epidemiological studies have shown that the use of any COCs is associated with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular events (e.g., TIA, stroke). Arterial thromboembolic events may be fatal.

ATE risk factors

When using COCs, the risk of developing arterial thromboembolic complications or cerebrovascular events increases in women with risk factors (see Table 2). The drug Drovelis is contraindicated if a woman has one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor, so the overall risk of ATE should be considered. COCs should not be prescribed if the benefit-risk balance is unfavorable (see section "Contraindications").

Table 2

ATE Risk Factors

Increased age	Especially over 35 years.
Smoking	Women who wish to use COCs should be advised to stop smoking. Women over 35 years of age who continue to smoke should be strongly advised to use a different method of contraception.
Arterial hypertension
Obesity (BMI > 30 kg/m²)	Risk increases significantly with increasing BMI. Particular attention is required if women have other risk factors.
Family history of thromboembolic events (arterial thromboembolism in a sibling or parent, especially at a relatively young age, e.g., before 50 years).	In case of hereditary predisposition, women should be advised to consult a specialist before using any COCs.
Migraine	An increase in frequency or severity of migraine during COC use (which may be a prodromal sign of cerebrovascular events) may necessitate immediate discontinuation.
Other conditions associated with vascular adverse reactions	Diabetes mellitus, hyperhomocysteinemia, cardiac valve disorders, atrial fibrillation, dyslipoproteinemia, and systemic lupus erythematosus.

ATE symptoms

If any of the symptoms listed below occur, women should seek immediate medical attention and inform their doctor that they are taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arms, or legs, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision changes in one or both eyes;
• sudden severe or prolonged headache with no known cause;
• loss of consciousness or fainting with or without seizures.

Transient symptoms may indicate a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, or squeezing sensation in the chest, arm, or behind the breastbone;
• discomfort radiating to the back, jaw, throat, arm, or stomach;
• feeling of fullness, indigestion, or gas;
• excessive sweating, nausea, vomiting, or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeat.

Tumours

Results of some epidemiological studies suggest an increased risk of cervical cancer with long-term use of COCs containing ethinylestradiol (> 5 years). However, this remains controversial, as it is not fully established to what extent study results account for confounding risk factors such as sexual behaviour and other factors, including human papillomavirus (HPV) infection.

The use of COCs at high doses (50 µg ethinylestradiol) reduces the risk of endometrial and ovarian cancer. It remains to be confirmed whether these data also apply to COCs containing estetrol.

A meta-analysis of data from 54 epidemiological studies indicates a slight increase in relative risk (RR 1.24) of breast cancer in women using COCs. This increased risk gradually disappears within 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases among women currently or recently using COCs is small in relation to the overall risk of breast cancer. There is a tendency for breast cancer diagnosed in women who have ever used COCs to be less clinically advanced than in those who have never used COCs. The increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors.

In rare cases, benign and even more rarely malignant liver tumours have been observed in women using COCs containing ethinylestradiol. In some cases, these tumours have led to life-threatening intra-abdominal haemorrhage. In the event of complaints of severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the possibility of a liver tumour should be considered in the differential diagnosis of women taking COCs.

Hepatitis C

During clinical trials involving patients undergoing treatment for hepatitis C virus (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, a significant increase in ALT levels exceeding the upper limit of normal by 5 times was observed. Additionally, ALT elevations were observed in patients taking glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir concurrently with medicinal products containing ethinylestradiol, such as COCs. In women taking oestrogens other than ethinylestradiol, ALT elevations were similar to those in women not taking oestrogens; however, due to the limited number of women taking these other oestrogens, caution is advised when co-administering with combination therapy containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, as well as with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir. See also section "Interaction with other medicinal products and other forms of interaction".

Other conditions

The progestogenic component of Drovelis is an aldosterone antagonist with potassium-sparing properties. In most cases, an increase in serum potassium levels is not expected during use. However, in a clinical study, slight but non-significant increases in serum potassium levels were observed in some patients with mild to moderate renal impairment and concomitant use of potassium-sparing medicinal products during 14 days of treatment with 3 mg drospirenone. Therefore, monitoring of serum potassium levels is recommended during the first cycle of Drovelis use in patients with renal impairment, and serum potassium levels should be maintained below the upper limit of normal before starting treatment, especially when potassium-sparing medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Women with hypertriglyceridaemia or a family history of this condition are at increased risk of pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant hypertension is rare. A causal relationship between COC use and clinically significant hypertension has not been established. However, if persistent clinically significant hypertension develops during COC use, the physician should discontinue the tablets and treat the hypertension. COC use may be resumed after normotension is achieved with antihypertensive therapy, if appropriate.

The following conditions have been reported to occur or worsen during pregnancy and COC use, but their relationship to COC use has not been definitively established: cholestasis and/or cholestatic pruritus; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic-uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

Exogenous oestrogens may cause or exacerbate symptoms of hereditary and acquired angioedema.

Acute or chronic liver function disorders may require discontinuation of COCs until liver function parameters return to normal. COC use should be discontinued in case of recurrence of cholestatic jaundice previously experienced during pregnancy or prior use of sex hormones.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there are no data indicating a need to change the therapeutic regimen in women with diabetes mellitus using low-dose COCs (containing < 50 µg ethinylestradiol). However, women with diabetes mellitus should be carefully monitored during COC use, especially at the beginning of treatment.

Exacerbations of endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis have also been observed during COC use.

Depressed mood and depression are common adverse reactions with hormonal contraceptives (see section "Adverse reactions"). Depression can be severe and is a known risk factor for suicidal behaviour and suicide. Women should be informed to consult their doctor if they experience mood changes or symptoms of depression, even if they occur shortly after starting treatment.

Chloasma may occasionally occur, particularly in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid direct exposure to sunlight or ultraviolet radiation during COC use.

Medical examination/consultation

Before initiating or resuming Drovelis, a complete medical history (including family history) should be taken and pregnancy excluded. Blood pressure should be measured, and a physical examination performed, taking into account contraindications (see section "Contraindications") and warnings (see section "Special precautions"). It is important to inform women about the risk of venous and arterial thrombosis, including the risk associated with Drovelis compared to other COCs, regarding symptoms of VTE and ATE, as well as known risk factors and actions to take in case of suspected thrombosis.

Patients should be advised to carefully read the patient information leaflet and follow the recommendations provided. The frequency and nature of examinations should be based on current medical practice guidelines, taking into account the individual characteristics of each woman.

Women should be informed that oral contraceptives do not protect against human immunodeficiency virus (HIV) and/or acquired immunodeficiency syndrome (AIDS) or other sexually transmitted infections.

Reduced efficacy

The efficacy of COCs may be reduced in case of missed tablet intake (see section "Dosage and administration"), gastrointestinal disturbances during intake of the pink active tablets (see section "Dosage and administration"), or concomitant use of other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Cycle control

Irregular bleeding (spotting or breakthrough bleeding) may occur during COC use, particularly during the first months of treatment. Therefore, evaluation of irregular bleeding is meaningful only after three adaptation cycles. Irregular bleeding or spotting occurred in 14–20% of women using Drovelis. In most of these cases, spotting was observed.

If irregular bleeding persists or occurs after several normal cycles, non-hormonal causes should be considered and appropriate diagnostic measures (curettage if necessary) undertaken to exclude malignancy or pregnancy.

In some women (6–8%), withdrawal bleeding may not occur during placebo tablet intake. If Drovelis has been taken according to the instructions described in the section "Dosage and administration", pregnancy is unlikely. However, if Drovelis has been taken irregularly or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be excluded before continuing treatment.

Laboratory tests

The use of contraceptive steroids may affect the results of certain laboratory tests, including liver function biochemical parameters, thyroid function, adrenal and kidney function; as well as levels of plasma (transport) proteins such as corticosteroid-binding globulin (CBG) and lipid/lipoprotein fractions; carbohydrate metabolism parameters; and coagulation and fibrinolysis parameters. Changes usually remain within normal laboratory reference ranges. Drospirenone causes an increase in plasma renin activity and plasma aldosterone, due to its weak anti-mineralocorticoid activity.

Excipients

This medicinal product contains lactose.

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

Drovelis is not indicated during pregnancy.

If pregnancy occurs while taking Drovelis, treatment must be discontinued immediately.

There is limited data on the use of Drovelis in pregnant women.

Animal studies have shown reproductive toxicity. Based on animal experience, a harmful hormonal effect of the active substances cannot be excluded.

When resuming Drovelis, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and administration", "Special precautions").

Period of breastfeeding

Small amounts of contraceptive steroids and/or their metabolites may pass into breast milk during COC use. These amounts may affect the infant.

COCs may affect breastfeeding, as they may reduce the quantity and alter the composition of breast milk. Therefore, COC use should not be recommended until a woman has completely stopped breastfeeding. Women who wish to breastfeed should be offered an alternative method of contraception.

Fertility

Drovelis is indicated for oral contraception. Information on fertility recovery is provided in the section "Pharmacodynamics".

Ability to influence the speed of reactions while driving or operating machinery

Drovelis has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage.

Dosage

How to take DROVELIS

One tablet should be taken daily for 28 consecutive days. Tablets must be taken every day at approximately the same time, swallowed with a small amount of liquid if necessary, in the order indicated on the blister pack. Each pack starts with 24 pink active tablets, followed by 4 white placebo tablets. Each subsequent pack should be started the day after the last tablet of the previous pack.

Stickers indicating the seven days of the week are provided; the appropriate sticker with the specified day of the week should be affixed to the blister pack as an indicator of when the first tablet was taken.

Withdrawal bleeding usually begins on days 2–3 after starting the white placebo tablets and may not cease before starting tablets from the next pack (see section "Cycle Control" in section "Special Instructions").

How to start taking DROVELIS

If hormonal contraception was not used previously

Tablet intake should begin on the first day of the natural menstrual cycle (i.e., the first day of menstrual bleeding); no additional contraceptive measures are required.

If the first tablet is taken on days 2–5 of the menstrual cycle, the medicinal product will be effective only after the first 7 consecutive days of taking pink active tablets. Therefore, during the first 7 days, a reliable barrier method of contraception (e.g., condom) must be used additionally. Before starting DROVELIS, pregnancy must be excluded.

Transition from COCs (combined oral contraceptives (COCs), vaginal ring, or transdermal patch)

It is recommended that a woman start taking DROVELIS tablets the day after taking the last active tablet of the previous COC; in such cases, DROVELIS intake should not begin later than the day after the usual tablet-free interval or after taking the last inactive tablet of the previous COC. When transitioning from a vaginal ring or transdermal patch, DROVELIS intake should preferably begin on the day of removal of the previous system; in such cases, DROVELIS intake should not be delayed beyond the scheduled time.

Transition from a method based solely on progestogen use (progestogen-only pills, injections, implants) or intrauterine system containing progestogen (IUS)

A woman may start taking DROVELIS at any day after discontinuation of progestogen-only pills (in case of implant or IUS – on the day of removal, in case of injection – instead of the next scheduled injection). However, in all cases, it is recommended to additionally use a barrier method of contraception during the first 7 days of DROVELIS intake.

After first-trimester abortion

DROVELIS intake should begin immediately. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester abortion

Women should be advised to start taking DROVELIS on days 21–28 after childbirth or second-trimester abortion. If a woman starts taking tablets later, she should be advised to additionally use a barrier method of contraception during the first 7 days of tablet intake. However, if sexual intercourse has already occurred, possible pregnancy should be excluded before starting COC use, or the woman should wait for the first menstruation.

For breastfeeding, see section "Use during pregnancy or breastfeeding".

What to do if a tablet is missed

The white placebo tablets in the last row of the blister may be disregarded. However, they should be discontinued to avoid unintentional prolongation of the placebo tablet phase.

The information below applies only to missing pink active tablets.

If the delay in taking a pink active tablet does not exceed 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as it is remembered. The next tablet from the pack should be taken at the usual time.

If the delay in taking the forgotten pink active tablet exceeds 12 hours, contraceptive protection may be reduced. In case of a missed tablet, two main rules should be followed:

1. The recommended interval for taking hormone-free tablets is 4 days; tablet intake should not be interrupted for more than 4 days.
2. Adequate suppression of the hypothalamus-pituitary-ovary system is achieved by continuous tablet intake for 7 days.

Accordingly, in everyday practice, the following recommendations should be followed:

Days 1–7 of tablet intake

The woman should take the last missed tablet as soon as possible, even if this means taking two tablets at the same time. After that, she continues taking tablets at the usual time. Additionally, for the next 7 days of consecutive intake of pink tablets, a barrier method of contraception (e.g., condom) should be used. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer to the time of starting placebo tablets, the higher the risk of pregnancy.

Days 8–17 of tablet intake

The woman should take the last missed tablet as soon as she remembers, even if two tablets have to be taken simultaneously. After that, she continues taking tablets at the usual time. Provided the woman has taken tablets correctly for the 7 days prior to the missed dose, no additional contraceptive methods are required. Otherwise, or if more than one tablet is missed, an additional contraceptive method is recommended for 7 days of consecutive intake of active pink tablets.

Days 18–24 of tablet intake

The likelihood of reduced contraceptive effect is significant due to the proximity to the placebo tablet phase. However, by adjusting the tablet intake schedule, a reduction in contraceptive protection can be prevented. If one of the options below is followed, there is no need to use additional contraceptive methods, provided tablets were taken correctly for 7 days before the missed dose. Otherwise, it is recommended to follow the first of the proposed options and use additional methods for the next 7 days of consecutive intake of active pink tablets.

1. The woman should take the last missed tablet as soon as she remembers, even if two tablets have to be taken simultaneously. After that, tablets should be taken at the usual time until the pink active tablets in the current pack are finished. All 4 placebo tablets in the last row should not be taken. The woman should immediately start taking tablets from the next pack after finishing the pink active tablets from the previous pack. Withdrawal bleeding is unlikely until the active pink tablets from the second pack are finished, but slight spotting or breakthrough bleeding may occur during the intake of active pink tablets.
2. The woman may also stop taking active pink tablets from the current pack. In this case, one placebo tablet from the last row should be taken daily for 4 days, including the days of missed tablets, then start taking tablets from a new pack.

If a woman has missed tablets and has no withdrawal-like bleeding during the placebo tablet phase, pregnancy should be considered.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (vomiting, diarrhea), incomplete absorption of the drug may occur; in such cases, additional contraceptive methods should be used. If vomiting occurs within 3–4 hours after taking the tablet, a new tablet should be taken as soon as possible to replace the previous one. A new pink active tablet, if possible, should be taken within 12 hours after the usual time of intake. If more than 12 hours have passed, the rules for tablet intake described in the section "What to do if a tablet is missed" should be followed. If the woman does not wish to change her usual tablet intake schedule, she should take an additional tablet(s) from another pack.

How to change the timing of withdrawal bleeding

If a woman wishes to delay the onset of menstrual bleeding, she should start taking tablets from the next pack of DROVELIS, skipping the placebo tablets. Intake from the next pack can be continued as long as desired (until the active pink tablets in the pack are finished). Breakthrough bleeding or spotting may occur during this period. After taking the placebo tablets, the woman should resume regular intake of DROVELIS.

If a woman wishes to shift the onset of bleeding to another day of the week, the placebo tablet phase should be shortened by as many days as desired. The shorter this interval, the higher the risk of absence of withdrawal bleeding and occurrence of breakthrough bleeding and spotting during intake of the second pack (similar to delaying the onset of bleeding).

Special patient categories

Elderly patients

DROVELIS is not indicated after menopause.

Patients with renal impairment

DROVELIS has not been specifically studied in patients with renal insufficiency. DROVELIS is contraindicated in women with severe renal impairment (see section "Contraindications").

Patients with hepatic impairment

Data on the effect of liver disease on the pharmacokinetics of estetrol are presented in the section "Pharmacokinetics". Study results indicate that increased plasma concentrations of estetrol in patients with severe hepatic impairment (Child-Pugh class C) compared to patients with normal liver function may be clinically significant. Based on currently available data, DROVELIS is contraindicated in women with severe liver disease until liver function parameters normalize (see section "Contraindications").

Based on currently available data, dose adjustment of DROVELIS in patients with mild or moderate hepatic impairment is not required (see section "Pharmacokinetics").

Method of Administration

Oral.

Children

DROVELIS is indicated for use only after menarche. The safety and efficacy of DROVELIS in children under 16 years of age have not been studied. Data are lacking.

Overdose

There are no data on overdose with DROVELIS to date.

Based on general data on combined oral contraceptives, symptoms that may occur in case of overdose with pink active tablets include nausea, vomiting, and withdrawal bleeding. Withdrawal bleeding may even occur in girls before the onset of the first menstruation if they accidentally take the medicinal product. No antidotes exist; further treatment should be symptomatic.

Adverse reactions

Summary of safety profile

The most commonly reported adverse reactions were metrorrhagia (4.3%), headache (3.2%), acne (3.2%), vaginal bleeding (2.7%), and dysmenorrhea (2.4%).

Tabulated list of adverse reactions

The identified adverse reactions are listed below (see Table 3).

Adverse reactions are listed by MedDRA organ system class and categorized by frequency as follows: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000).

Table 3

List of adverse reactions

System organ class	Common	Uncommon	Rare
Infections and infestations		Fungal infection Vaginal infection Urinary tract infection	Mastitis
Benign, malignant and unspecified neoplasms (including cysts and polyps)			Fibroadenoma of breast
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Appetite disorder	Hyperkalaemia Fluid retention
Psychiatric disorders	Mood disorder(1) Libido disorder	Depression(2) Anxiety disorder(3) Insomnia Emotional disorder(4) Stress	Nervousness
Nervous system disorders	Headache	Migraine Dizziness Paraesthesia Somnolence	Amnesia
Eye disorders			Visual disturbance Blurred vision Dry eyes
Ear and labyrinth disorders			Dizziness
Vascular disorders		Hot flushes	Arterial hypertension Venous thrombosis Thrombophlebitis Arterial hypotension Varicose veins
Gastrointestinal disorders	Abdominal pain Nausea	Abdominal distension Vomiting Diarrhoea	Gastroesophageal reflux disease Colitis Gastrointestinal motility disorder Constipation Dyspepsia Flatulence Dry mouth Lip swelling
Skin and subcutaneous tissue disorders	Acne	Alopecia Hyperhidrosis(5) Skin disorder(6)	Dermatitis(7) Pigmentation disorder(8) Hirsutism Seborrhoea Pruritus Facial swelling Urticaria Skin colour change
Musculoskeletal and connective tissue disorders		Back pain	Muscle spasms Limb discomfort Joint swelling Limb pain
Renal and urinary disorders			Bladder spasm Abnormal urine odour
Pregnancy, puerperium and perinatal conditions			Ectopic pregnancy
Reproductive system and breast disorders	Breast pain Metrorrhagia Vaginal bleeding Dysmenorrhoea Menorrhagia	Abnormal withdrawal bleeding(9) Breast swelling Vulvovaginal disorder(10) Vaginal discharge Pre-menstrual syndrome Breast induration(11) Uterine spasm Uterine haemorrhage Menometrorrhagia Dyspareunia	Ovarian cyst Lactation disorder Endometrial disorder Dysfunctional uterine bleeding Pelvic pain Nipple disorder Colour change of breast Coital bleeding
General disorders and administration site conditions		Fatigue Swelling Chest pain Malaise	Malaise(12) Pain Hyperthermia
Investigations	Weight fluctuation	Increased liver enzymes Lipid level disorder	Increased blood pressure Renal function test abnormal Increased blood potassium Increased blood glucose Decreased haemoglobin Decreased serum ferritin Haematuria

(1) Including affect lability, anger, euphoria, irritability, mood changes, and mood swings.

(2) Including depressed mood, depressive symptoms, tearfulness, and depression.

(3) Including excitement, anxiety, generalized anxiety disorder, and panic attacks.

(4) Including emotional disturbance, emotional stress, and crying.

(5) Including night sweats, hyperhidrosis, and cold sweats.

(6) Including dry skin, rash, and skin swelling.

(7) Including dermatitis and eczema.

(8) Including chloasma and skin hyperpigmentation.

(9) Including abnormal withdrawal bleeding, amenorrhea, menstrual cycle disturbances, irregular menstruation, oligomenorrhea, and polymenorrhea.

(10) Including vaginal odor, vulvovaginal discomfort, vulvovaginal dryness, vulvovaginal pain, vulvovaginal itching, and vulvovaginal burning sensation.

(11) Including breast induration and fibrocystic breast disease.

(12) Including malaise and reduced tolerance.

Description of selected adverse reactions

Women using COCs have been observed to have an increased risk of arterial or venous thrombotic/thromboembolic complications, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism. More detailed information is provided in the section "Special precautions for use".

The following serious adverse reactions have been reported in women taking COCs, also described in the section "Special precautions for use":

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Arterial hypertension;
• Liver tumors;
• Onset or worsening of conditions whose relationship with COC use has not been definitively established: Crohn’s disease, ulcerative colitis, epilepsy, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• Chloasma;
• Acute or chronic liver function disorders, which may require discontinuation of COC use until liver function parameters normalize;
• Exogenous estrogens may cause or exacerbate symptoms of hereditary and acquired angioedema.

The frequency of breast cancer diagnosis is slightly increased in women taking COCs. Since breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed cases of breast cancer in women currently or recently using COCs is small relative to the overall risk of breast cancer. The relationship with COC use is unknown. For more detailed information, see sections "Contraindications" and "Special precautions for use".

Interactions

Breakthrough bleeding and/or reduced contraceptive efficacy may occur due to interactions between other medicinal products (enzyme inducers) and oral contraceptives (see section "Interaction with other medicinal products and other forms of interaction").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 4 years.

Storage conditions. This medicinal product does not require special storage conditions.

Keep out of the reach of children.

Medicinal products containing drospirenone may pose a risk to the environment. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Packaging. 28 film-coated tablets per blister (24 pink active tablets and 4 white placebo tablets); 1, 3, 6, or 13 blisters together with a cardboard blister holder and 1, 3, 6, or 13 self-adhesive weekly calendar stickers, all packed in a cardboard box labeled in Ukrainian and English.

Prescription status. Prescription only.

Manufacturer.

JSC "Gedeon Richter", Hungary.

Manufacturer's address and location of its operations.

H-1103 Budapest, Dózsa György út 19-21, Hungary.