Drospifem® 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DROSPYFEM® 20

Composition:

Active substances: ethinylestradiol, drospirenone;

1 pink active tablet contains 0.02 mg of ethinylestradiol and 3 mg of drospirenone;

1 white placebo tablet contains no active substances;

Excipients:

1 active tablet contains lactose monohydrate, maize starch, maltodextrin, magnesium stearate, Opadry 10A240000 pink (hypromellose, talc, titanium dioxide (E 171), polysorbate 80, iron oxide red (E 172));

1 placebo tablet contains lactose monohydrate, maize starch, maltodextrin, magnesium stearate, white film-coating mixture (hypromellose, lactose monohydrate, titanium dioxide (E 171), macrogol 4000, sodium citrate).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Active tablets: round, film-coated pink tablets without coating defects;

Placebo tablets: round, biconvex oval-shaped tablets, film-coated white tablets without coating defects.

Pharmacotherapeutic group. Sex gland hormones and drugs used in disorders of the genital system. Hormonal contraceptives for systemic use.

Progestogens and estrogens, fixed combinations. Drospirenone and ethinylestradiol.

ATC code G03A A12.

Pharmacological properties.

Pharmacodynamics.

Pearl Index of contraceptive failures for the drug: 0.41 (upper two-sided 95% confidence interval (CI): 0.85).

Overall Pearl Index (contraceptive failures + patient errors) for the drug: 0.80 (upper two-sided 95% confidence interval (CI): 1.30).

Drosperifem® 20 is a combined oral contraceptive containing ethinylestradiol and drospirenone. At therapeutic doses, drospirenone exhibits antiandrogenic and moderate antimineralocorticoid properties. It has no estrogenic, glucocorticoid, or antiglucocorticoid activity. Therefore, drospirenone has a pharmacological profile similar to natural progesterone.

The contraceptive effect of the drug is based on the interaction of several factors, the most important of which are inhibition of ovulation and changes in cervical secretion.

According to clinical study data, the moderate antimineralocorticoid properties of Drosperifem® 20 exert a moderate antimineralocorticoid effect.

In a three-cycle clinical study comparing the ovulation suppression effect of the combination drospirenone 3 mg/ethinylestradiol 0.02 mg administered in a 24-day regimen versus a 21-day regimen, the 24-day regimen was associated with greater suppression of follicular development. After intentional dosing errors during the third treatment cycle, ovarian activity, including ovulation, was observed in the majority of women in the 21-day regimen group compared to those in the 24-day regimen group. Ovarian activity returned to pre-treatment levels during the cycle after therapy in 91.8% of women in the 24-day regimen group.

Pharmacokinetics.

Drospirenone

Absorption. After oral administration, drospirenone is rapidly and almost completely absorbed. Maximum serum concentration – 38 ng/mL – is reached approximately 1–2 hours after single administration. Bioavailability is 76–85%. Concomitant food intake does not affect the bioavailability of drospirenone.

Distribution. After oral administration, serum drospirenone concentration declines with a terminal half-life of 31 hours. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 3–5% of its total amount in serum is present in free form. The ethinylestradiol-induced increase in SHBG does not affect the binding of drospirenone to serum proteins. The mean volume of distribution of drospirenone is 3.7±1.2 L/kg.

Metabolism. Drospirenone is extensively metabolized after oral administration. The main metabolites in plasma are acid forms of drospirenone formed by opening of the lactone ring, and 4,5-dihydrodrospirenone-3-sulfate, formed via hydration followed by sulfation. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. In vitro, drospirenone may weakly or moderately inhibit cytochrome P450 enzymes: CYP1A1, CYP2C9, CYP2C19, and CYP3A4.

Excretion. The metabolic clearance rate of drospirenone from serum is 1.5±0.2 mL/min/kg. Drospirenone is excreted unchanged only in very small amounts. Metabolites are excreted in urine and feces in a ratio of approximately 1.2 to 1.4. The elimination half-life of metabolites in urine and feces is approximately 40 hours.

Steady state. During the treatment cycle, the maximum steady-state concentration of drospirenone in serum is approximately 70 ng/mL and is reached after about 8 days of administration. Serum drospirenone levels increased by approximately 3-fold as a result of the relationship between the terminal half-life and the dosing interval.

Special patient populations:

• Renal impairment: Steady-state serum concentration of drospirenone in women with mild renal impairment (creatinine clearance 50–80 mL/min) was comparable to that in women with normal renal function. Serum drospirenone levels were on average 37% higher in women with moderate renal impairment (creatinine clearance 30–50 mL/min) compared to women with normal renal function. Drospirenone administration demonstrated good tolerability in patients with mild to moderate renal impairment. It has been shown that drospirenone intake does not have a clinically significant effect on serum potassium concentration;
• Hepatic impairment: In a single-dose study, oral clearance of drospirenone decreased by approximately 50% in subjects with moderate hepatic impairment compared to volunteers with normal liver function. The marked reduction in drospirenone clearance in volunteers with moderate hepatic impairment did not result in a significant difference in serum potassium concentration. Even in the presence of diabetes mellitus and concomitant spironolactone therapy (two factors that may provoke hyperkalemia), no increase in serum potassium concentration above the upper limit of normal was observed. It can be concluded that drospirenone is well tolerated in individuals with mild or moderate hepatic impairment (Child-Pugh class B).

Ethinylestradiol

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Maximum serum concentration of 33 pg/mL is reached within 1–2 hours after single administration. Absolute bioavailability due to presystemic conjugation and first-pass hepatic metabolism is approximately 60%. Concomitant food intake reduces the bioavailability of ethinylestradiol by approximately 25% in the studied subjects, while bioavailability remains unchanged in the rest.

Distribution. Serum ethinylestradiol levels decline in a biphasic manner, with a terminal half-life of approximately 24 hours. Ethinylestradiol binds strongly but non-specifically to serum albumin (approximately 98.5%) and induces an increase in serum SHBG and CBG concentrations. Apparent volume of distribution is approximately 5 L/kg.

Metabolism. Ethinylestradiol is extensively metabolized in the gastrointestinal tract and during first-pass through the liver. This occurs mainly via hydroxylation of the aromatic ring, resulting in a wide spectrum of hydroxylated and methylated metabolites, present in free form and as glucuronide and sulfate conjugates. Metabolic clearance of ethinylestradiol is about 5 mL/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1, and CYP1A2, and also an inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Excretion. Ethinylestradiol is practically not excreted unchanged. Ethinylestradiol metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day.

Steady state. Steady state is reached in the second half of the treatment cycle, when the serum level of ethinylestradiol increases by 2–2.3 times.

Preclinical safety data.

In laboratory animals, effects of drospirenone and ethinylestradiol were limited to those associated with known pharmacological activity. In particular, studies assessing reproductive toxicity in animals showed species-specific embryotoxic and fetotoxic effects. At exposures exceeding those in users of Drosperifem® 20, effects on sexual differentiation were observed in certain animal species.

Clinical characteristics.

Indications.

Oral contraception.

The decision to prescribe Drospifem® 20 should be made considering the individual risk factors of the patient, particularly the risk factors for venous thromboembolism (VTE). The VTE risk during treatment with Drospifem® 20 should also be compared with that during treatment with other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

CHCs must not be used if any of the following conditions are present. If any of these conditions occur for the first time during CHC use, the drug should be discontinued immediately.

• Presence of or risk of venous thromboembolism (VTE):
  • current venous thromboembolism, including anticoagulant therapy, or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE));
  • hereditary or acquired predisposition to venous thromboembolism, including 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 multiple risk factors (see section "Special precautions").
• Presence of or risk of arterial thromboembolism (ATE):
  • current or past arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • current or past cerebrovascular accident, or presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • hereditary or acquired predisposition to arterial thromboembolism, including hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin 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 a single serious risk factor such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia.
• Current or past severe liver disease until liver function tests return to normal limits.
• Severe renal impairment or acute renal failure.
• Current or past liver tumors (benign or malignant).
• Current or past hormone-sensitive breast cancer (see section "Special precautions", subsection "Tumors").
• Vaginal bleeding of unknown etiology.
• Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").
• Hypersensitivity to the active substances or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Information regarding the concomitantly used medicinal product should be reviewed to identify potential interactions.

Effect of other medicinal products on Drospifem® 20

Interactions are possible 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 generally occurs after several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 4 weeks.

Short-term therapy

Women taking enzyme-inducing medicinal products should temporarily use a barrier method or another contraceptive method in addition to the combined oral contraceptive (COC). The barrier method should be used throughout the duration of concomitant therapy and for an additional 28 days after its discontinuation.

If concomitant therapy continues beyond the last active tablet in the COC pack, the placebo tablets should be skipped and active tablets from the next COC pack should be started.

Long-term therapy

Women undergoing long-term therapy with enzyme-inducing substances are advised to use a barrier method or another reliable non-hormonal contraceptive method.

The following interactions have been reported according to published data:

Substances increasing COC clearance (reducing COC efficacy via enzyme induction), e.g.:

barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; HIV medications: ritonavir, nevirapine, and efavirenz; also possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and herbal products containing St. John's wort (hypericum perforatum).

Substances with variable effects on COC clearance

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

Therefore, information on the medical use of the HIV/HCV medicinal product being co-administered should be reviewed to identify potential interactions and any additional 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 decreasing COC clearance (enzyme inhibitors):

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

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

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

When etoricoxib was administered at doses of 60 to 120 mg/day concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol, plasma concentrations of ethinylestradiol increased by 1.4 to 1.6 times, respectively.

Effect of Drospifem® 20 on other medicinal products. Oral contraceptives may affect the metabolism of other active substances. They may alter plasma and tissue concentrations of active substances: increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Based on in vivo interaction studies conducted in female volunteers who received omeprazole, simvastatin, and midazolam as indicator substrates, the effect of drospirenone 3 mg on other medicinal products metabolized by cytochrome P450 is unlikely.

Clinical data indicate that ethinylestradiol inhibits the clearance of CYP1A2 substrates, resulting in mild (e.g., theophylline) or moderate (e.g., tizanidine) increases in their plasma concentrations.

Other forms of interaction. In patients with renal impairment, concomitant use of drospirenone and ACE inhibitors or nonsteroidal anti-inflammatory drugs does not show a significant effect on serum potassium levels. However, concomitant use of Drospifem® 20 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").

Laboratory tests

Use of COCs may affect results of certain laboratory tests, such as liver, thyroid, adrenal, and kidney function biochemical parameters, plasma concentrations of transport proteins such as corticosteroid-binding globulin, plasma concentrations of lipid/lipoprotein fractions, carbohydrate metabolism, coagulation, and fibrinolysis parameters. These changes are usually within normal limits. Drospirenone increases plasma renin and aldosterone activity, induced by its moderate antimineralocorticoid activity.

Pharmacodynamic interactions

During clinical trials in patients treated for hepatitis C virus (HCV) infection with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, ALT levels increased significantly, exceeding the upper limit of normal (ULN) 5 times more frequently in women using ethinylestradiol-containing products, such as combined hormonal contraceptives (CHCs). Furthermore, increased ALT levels were also observed when using antiviral medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir in women using ethinylestradiol-containing products, such as CHCs (see section "Contraindications"). Therefore, patients taking Drospifem® 20 should switch to an alternative method of contraception (e.g., progestogen-only contraception or non-hormonal contraceptive methods) before initiating treatment with these combined drug regimens. Treatment with Drospifem® 20 may be resumed 2 weeks after completion of treatment with these combined drug regimens.

Special precautions.

If any of the conditions/factors listed below are present, the appropriateness of using Drospifem® 20 should be discussed with the woman.

• In case of worsening or occurrence of any of these conditions or risk factors, it is recommended to consult a physician to determine whether use of Drospifem® 20 should be discontinued.
• If venous thromboembolism (VTE) or arterial thromboembolism (ATE) is suspected or confirmed, the use of the drug should be stopped. If anticoagulant therapy has been initiated, an alternative effective contraception should be provided due to the teratogenic effects of anticoagulants (coumarins).
• Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any combined oral contraceptives (COCs) increases the risk of venous thromboembolism (VTE) in women who use them compared to those who do not, although the frequency is lower than that associated with pregnancy (60 cases per 100,000 pregnancies). Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with a lower risk of VTE. The use of other medicinal products such as Drospifem® 20 may double the risk. The decision to use medicinal products other than those with the lowest risk of VTE should only be made after discussion with the woman. It is essential to ensure that she understands the risk of VTE associated with the use of Drospifem® 20, the impact of her individual risk factors, and the fact that the risk of VTE is highest during the first year of use. According to some data, the risk of VTE may increase when resuming COC use after a break of 4 weeks or longer.

The risk of developing venous thromboembolic complications in women using COCs may be substantially higher if additional risk factors are present, especially multiple ones (see table).

Drospifem® 20 is contraindicated in women with a combination of risk factors that result in a very high risk of 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 the risks associated with each individual factor, so the overall risk of VTE should be considered. If the benefit-risk ratio is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Approximately 2 out of 10,000 women who do not use COCs and are not pregnant will develop VTE during one year of observation. However, for any individual woman, the risk may be much higher depending on risk factors (see below).

It has been established that among 10,000 women using COCs containing drospirenone, 9 to 12 women will develop VTE over one year. These figures are based on all available epidemiological data, taking into account relative risks associated with different COCs compared to COCs containing levonorgestrel.

This compares to a rate of 6 among women using COCs containing levonorgestrel. On average, 5–7 cases per 10,000 woman-years, based on the relative risk calculation of using levonorgestrel-containing COCs compared to women not using COCs (approximately 2.3–3.6 cases).

In both cases, the annual incidence of VTE was lower than typically expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Number of VTE cases per 10,000 women per year

Risk factors for VTE development

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

Particular attention should be paid to the increased risk of thromboembolism during pregnancy, especially within 6 weeks after delivery (for information on pregnancy or breastfeeding, see section "Use in pregnancy or breastfeeding").

Signs and symptoms of VTE (venous thromboembolism, including deep vein thrombosis and pulmonary embolism)

Women are advised to seek immediate medical attention and inform their physician that they are taking a COC if any of the symptoms listed below occur.

Symptoms of deep vein thrombosis (DVT) may include:

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

Symptoms of pulmonary embolism (PE) may include:

• Sudden onset of unexplained shortness of breath or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis (coughing up blood);
• Sudden, sharp chest pain;
• Severe dizziness or vertigo;
• Rapid or irregular heartbeat.

Some of the above symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as signs of more common and less serious conditions (e.g., respiratory infection).

Other signs of vascular occlusion may include: sudden limb pain, swelling, acute abdomen, and mild cyanosis of the skin of the extremities.

Relevant studies on the risk of breast cancer associated with combined oral contraceptives

Three studies compared the risk of developing breast cancer in women who were currently using combined oral contraceptives (COCs) or had used them recently (<6 months since last use) with women who had never used COCs. One of these studies reported no association between COC use and breast cancer risk. The other two studies found an increased relative risk of 1.19–1.33 with current or recent COC use. Both of these studies observed an increased risk of breast cancer with longer duration of use at the time of the study, with relative risk ranging from 1.03 for use of less than 1 year to approximately 1.4 for use exceeding 8–10 years.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is very important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 4 years.

Storage conditions. Store out of reach of children, in the original packaging, at a temperature not exceeding 30 °C.

Packaging.

28 tablets per blister pack (24 active tablets + 4 placebo tablets); 1, 3, or 6 blister packs per cardboard box.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address and location of operations.

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.