Desofemin® 30

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEZOFEMIN® 30

Composition:

Active substances: ethinylestradiol, desogestrel;

One film-coated tablet contains ethinylestradiol 0.03 mg, desogestrel 0.15 mg;

Excipients: lactose monohydrate, corn starch, maltodextrin, transparent isolating mixture for coating, sodium starch glycolate (type A), alpha-tocopherol, white mixture for film coating.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, film-coated tablets with a square imprint on one side, free from coating defects.

Pharmacotherapeutic group. Genitourinary system and sex hormones. Sex hormones and modulators of the genital system. Systemic hormonal contraceptives. Estrogens and progestogens in fixed combinations. ATC code G03A A09.

Pharmacological properties.

Pharmacodynamics

Desofemin® 30 is a combined oral contraceptive containing 150 mcg of desogestrel and 30 mcg of ethinylestradiol.

Ethinylestradiol is a well-known synthetic estrogen.

Desogestrel is a synthetic progestogen. After oral administration, it exerts a potent effect directed at inhibition of ovulation, demonstrates strong progestogenic and antiestrogenic activity, lacks estrogenic activity, and shows very weak androgenic/anabolic activity.

Pharmacokinetics.

Desogestrel.

Absorption. After oral administration, desogestrel is rapidly and completely absorbed and converted into etonogestrel. Maximum serum concentration of approximately 2 ng/mL is reached within about 1.5 hours after a single dose. Bioavailability ranges from 62% to 81%.

Distribution. Etonogestrel binds to serum albumin and sex hormone-binding globulin (SHBG). Only 2–4% of the total drug concentration in serum exists as free steroid, while 40–70% is specifically bound to SHBG. Ethinylestradiol-induced increase in SHBG affects the distribution among serum proteins, resulting in an increased SHBG-bound fraction and a decreased albumin-bound fraction. The apparent volume of distribution of desogestrel is 1.5 L/kg.

Metabolism. Etonogestrel is completely metabolized via known steroid metabolic pathways. The clearance rate of metabolites from serum is approximately 2 mL/min/kg. No interaction has been observed with concomitantly administered ethinylestradiol.

Elimination. Serum levels of etonogestrel decline in two phases. The terminal elimination phase is characterized by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted via urine and bile in a ratio of approximately 6:4.

Steady state. The threefold increase in SHBG levels induced by ethinylestradiol affects the pharmacokinetics of etonogestrel. With daily administration, serum concentrations of the substance increase approximately 2–3 times, reaching stable levels during the second half of the treatment cycle.

Ethinylestradiol.

Absorption. After oral administration, ethinylestradiol is rapidly and completely absorbed. Maximum serum concentration of approximately 80 pg/mL is reached within 1–2 hours. Absolute bioavailability, due to presystemic conjugation and first-pass metabolism, is nearly 60%.

Distribution. Ethinylestradiol binds strongly but non-specifically to serum albumin (approximately 98.5%) and induces an increase in serum SHBG concentrations. The apparent volume of distribution of ethinylestradiol is approximately 5 L/kg.

Metabolism. Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. It is primarily metabolized via aromatic hydroxylation, but a large number of hydroxylated and methylated metabolites are also formed, including both free metabolites and conjugates with glucuronides and sulfates. Clearance is approximately 5 mL/min/kg.

Elimination. Serum levels of ethinylestradiol decline in two phases, with the terminal elimination phase characterized by a half-life of approximately 24 hours. Ethinylestradiol is not excreted unchanged; its metabolites are excreted in urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately one day.

Steady state. Steady state is achieved within 3–4 days, when serum levels exceed those after a single dose by 30–40%.

Clinical characteristics.

Indications.

Contraception.

When considering the prescription of Desofemine® 30, individual risks in each woman should be taken into account, especially the risk of venous thromboembolism (VTE), as well as comparing the risk of VTE development during use of Desofemine® 30 and other combined contraceptives (see sections "Contraindications" and "Special precautions").

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the conditions listed below are present. If any of these conditions or diseases newly develops during CHC use, the drug should be discontinued immediately.

• Hypersensitivity to the active substances or to any of the excipients of the drug.
• Venous thromboembolism (VTE) or risk of its development:
  • current VTE (while on anticoagulant therapy) or history of VTE [e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)];
  • inherited or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden), 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 presence of multiple risk factors (see section "Special precautions").
• Arterial thromboembolism (ATE) or risk of its development:
  • current arterial thromboembolism, history of arterial thromboembolism (e.g., myocardial infarction) or prodromal condition (e.g., angina pectoris);
  • cerebrovascular disease — current stroke, history of stroke, or prodromal condition [e.g., transient ischemic attack (TIA)];
  • inherited or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and presence of antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of arterial thromboembolism due to presence of multiple risk factors (see section "Special precautions") or presence of one serious risk factor such as:
  • diabetes mellitus with vascular complications;
  • severe hypertension;
  • severe dyslipoproteinemia.
• Pancreatitis, including history of pancreatitis, if associated with severe hypertriglyceridemia.
• Current or past history of severe liver disease (until liver function tests return to normal).
• Current or past history of liver tumors (benign or malignant).
• Known or suspected estrogen-dependent malignant neoplasms (e.g., of genital organs or breasts).
• Endometrial hyperplasia.
• Vaginal bleeding of unknown etiology.
• Established or suspected pregnancy.

Desofemine® 30 is contraindicated for concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, and with medicinal products containing glecaprevir/pibrentasviror sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Warning. The instructions for medical use of concomitant medicinal products should be carefully read to identify possible interactions.

Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or reduced effectiveness of the oral contraceptive. The interactions listed below have been reported in the literature.

Hepatic metabolism. Interaction is possible with medicinal or herbal products that induce microsomal enzymes, particularly cytochrome P450 (CYP) enzymes, leading to increased clearance of sex hormones and potentially reducing the effectiveness of combined oral contraceptives, including Desofemine® 30. Such medicinal products include phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, certain HIV protease inhibitors (e.g., ritonavir), non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz), and herbal products containing St. John's wort.

Enzyme induction may occur within a few days of treatment. Maximum enzyme induction is usually observed within several weeks. After discontinuation of the inducing drug, enzyme induction may persist for approximately 28 days.

When used concomitantly with hormonal contraceptives, many HIV protease inhibitors (e.g., nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine), and/or antiviral drugs for hepatitis C virus (HCV) (e.g., boceprevir, telaprevir) may increase or decrease plasma concentrations of progestins, including etonogestrel, the active metabolite of desogestrel, or estrogens. The net effect of these changes may be clinically significant in some cases.

Women taking any of these medicinal or herbal products that induce liver enzymes should be aware that the effectiveness of Desofemine® 30 may be reduced. During treatment with enzyme-inducing agents, a barrier method of contraception should be used in addition to Desofemine® 30 throughout the entire duration of use of the enzyme-inducing drug and for 28 days after discontinuation of such drug.

If the duration of treatment with the concomitant medicinal product extends beyond the active tablet phase of the oral contraceptive pack, the next pack should be started without the usual tablet-free interval. In cases of prolonged treatment with enzyme-inducing agents, an alternative method of contraception not affected by enzyme-inducing drugs should be considered.

Concomitant use with strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) inhibitors of CYP3A4 may lead to increased serum concentrations of estrogens or progestins, including etonogestrel, the active metabolite of desogestrel.

Oral contraceptives may affect the metabolism of other medicinal products. Consequently, plasma and tissue concentrations of such drugs may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

In clinical trials involving patients receiving HCV treatment regimens containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) were observed. This occurred with significantly higher frequency in women using ethinylestradiol-containing medicinal products, including combined hormonal contraceptives (CHCs). Additionally, in patients receiving treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, increased ALT levels were observed in women taking ethinylestradiol-containing products such as CHCs (see section "Contraindications"). Resumption of Desofemine® 30 should occur approximately 2 weeks after completion of combination therapy.

Laboratory tests. The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver and kidney function, thyroid and adrenal gland function, serum protein (carrier) levels such as corticosteroid-binding globulin and/or lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within normal limits.

Special precautions.

The presence of any of the conditions/factors listed below should be discussed with a woman before prescribing Desofemin® 30. If any of these conditions worsen, intensify, or occur for the first time, the woman should consult her physician. The physician must decide whether it is necessary to discontinue the use of COCs.

Disorders of circulation.

Risk of venous thromboembolism (VTE)

The use of any COC increases the risk of venous thromboembolism (compared to non-use of COCs). Medicinal products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Other medicinal products, such as Desofemin® 30, may increase the risk approximately two-fold. The decision to use any contraceptive that is not a medicinal product with the lowest risk of VTE should only be made after discussing with the woman the risks of VTE associated with the use of Desofemin® 30, the impact of her individual risk factors on this risk, and the fact that the risk of VTE is highest during the first year of use. The risk also increases when restarting COC use after a break of 4 weeks or more.

Among women who do not use COCs and are not pregnant, approximately 2 in 10,000 will develop VTE within the first year. However, for any individual woman, the risk may be significantly higher, depending on underlying risk factors.

It has been established¹ that among 10,000 women using a COC containing desogestrel, 9–12 women will develop VTE within 1 year; in comparison, among women using COCs containing levonorgestrel, VTE will occur in 6–7 women.

In both cases, the number of VTE events per year is lower than the expected number during pregnancy and the postpartum period.

VTE can be fatal in 1–2% of cases.

¹ Frequency based on epidemiological data using relative risks for different medicinal products compared to COCs containing levonorgestrel.

² Average range of 5–7 per 10,000 woman-years established from relative risk associated with use of COCs containing levonorgestrel compared to non-use – from 2.3 to 3.6.

Number of VTE cases per 10,000 women per year

Women not using COCs COCs containing levonorgestrel COCs containing desogestrel

• Rare cases of thrombosis have been reported in other vascular sites, such as hepatic, mesenteric, renal, cerebral, or retinal veins and arteries, in women using COCs.

Risk factors for VTE

• The risk of venous thromboembolic complications may be substantially increased in women with additional risk factors, especially when multiple risk factors are present (see Table 1).
• Desofemin® 30 is contraindicated in women with multiple risk factors that lead to a 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 individual factors. In such cases, the overall risk of VTE should be carefully evaluated. If the benefit-risk balance is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 1

VTE Risk Factors

• 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 during pregnancy, especially within 6 weeks after delivery, should be taken into account (see section "Use in pregnancy or breast-feeding").

Symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

If any symptoms occur, women should seek immediate medical attention and inform their doctor that they are taking a COC.

Symptoms of deep vein thrombosis (DVT) may include:

• Unilateral swelling of the leg and/or foot or swelling along the vein of the leg;
• Pain or tenderness in the leg, which may only be felt while standing or walking;
• A leg that feels warmer to the touch;
• Redness or discoloration of the skin of the leg.

Symptoms of pulmonary embolism may include:

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

Some of these symptoms (e.g., shortness of breath, cough) are non-specific and may be mistaken for conditions that are common and less serious (e.g., respiratory tract infection).

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

If occlusion of a blood vessel in the eye occurs, symptoms may range from painful blurred vision to loss of vision. Sometimes, vision loss may occur almost immediately.

Risk of arterial thromboembolism (ATE)

• Epidemiological studies have shown an association between the use of COCs and an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular disorders (such as transient ischemic attack, stroke). Arterial thromboembolic events can be fatal.

Risk factors for ATE

• The risk of developing arterial thromboembolic complications or cerebrovascular disorders while using COCs is increased in women with risk factors (see Table 2). The medicinal product Desofemine® 30 is contraindicated in women with one serious or multiple risk factors for ATE that lead to a high 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 the individual factors. In such cases, the overall risk for the woman should be assessed. If the benefit-risk balance is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for ATE

Symptoms of ATE

If symptoms occur, a woman should seek immediate medical attention and inform her doctor that she is taking COCs.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arm, or leg, especially on one side of the body;
• sudden disturbances of gait, dizziness, loss of balance or coordination;
• sudden confusion, speech or comprehension difficulties;
• sudden vision disturbances in one or both eyes;
• sudden severe or prolonged headache with no apparent cause;
• loss of consciousness or syncope with or without seizures.

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

Symptoms of myocardial infarction may include:

• pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or below the sternum;
• discomfort radiating to the back, jaw, throat, arm, or stomach;
• sensation of stomach fullness, dyspepsia, or constipation;
• sweating, nausea, vomiting, or dizziness;
• extreme weakness, anxiety, or shortness of breath;
• rapid or irregular heartbeat.

Tumors

Some studies have shown an increased risk of cervical cancer in women who have used oral contraceptives for a long time. However, uncertainty remains regarding the extent to which this risk is influenced by confounding factors such as differences in sexual behavior or other factors, including human papillomavirus (HPV) infection.

• A meta-analysis of 54 epidemiological studies showed a slight increase in relative risk (RR = 1.24) of breast cancer among women currently using combined oral contraceptives (COCs). Breast cancer cases diagnosed in women currently using or who have used COCs within the last ten years are more likely to be localized in the breast compared to cases diagnosed in women who have never used COCs.
• Breast cancer is rare in women under 40 years of age, regardless of COC use. As this background risk increases with age, the additional number of breast cancer cases among women currently or previously using COCs is small compared to the overall risk of developing breast cancer (see chart).
• The most important risk factor for breast cancer among COC users is the age at which a woman stops taking COCs; the older the woman at discontinuation, the higher the likelihood of breast cancer diagnosis. Duration of use is less significant, and the increased risk gradually disappears within 10 years after stopping COCs, so that after 10 years the risk no longer exceeds the baseline.
• The potential increased risk of breast cancer should be discussed with the woman, weighing the benefits of COC use against data showing that COCs provide significant protection against the risk of developing certain other cancers (ovarian and endometrial cancer); see the chart below.
• In another epidemiological study involving 1.8 million women from Denmark, followed on average for 10.9 years, the RR of breast cancer among current COC users increased with longer duration of use compared to women who had never used COCs (overall RR = 1.19; RR ranged from 1.17 for 1–5 years of COC use to 1.46 for more than 10 years of use). The known absolute difference in RR (number of breast cancer cases in women who have never used COCs compared to those currently using or who recently discontinued) was small: 13 per 100,000 woman-years.
• Epidemiological studies do not provide evidence of a causal relationship for these findings. The observed pattern of increased risk may be related to earlier diagnosis of breast cancer in COC users, biological effects of COCs, or a combination of both factors.
• In rare cases, benign and even more rarely malignant liver tumors have been reported in women using COCs. In individual cases, such tumors have led to life-threatening intra-abdominal hemorrhage. Therefore, liver tumors should be considered in the differential diagnosis if women using COCs develop upper abdominal pain, hepatomegaly, or signs of intra-abdominal bleeding.

Other conditions

• Women with hypertriglyceridemia or a family history of hypertriglyceridemia may have an increased risk of pancreatitis when using COCs.
• Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.
• Although a slight increase in blood pressure has been reported in many women taking COCs, clinically significant elevations are rare. A direct relationship between COC use and clinical hypertension has not been established. However, if sustained clinically significant hypertension develops during COC use, the physician should discontinue COC use and treat the hypertension. COC use may be resumed if blood pressure normalizes with antihypertensive therapy.
• The following conditions have been reported to occur or worsen during pregnancy and with COC use: cholestatic jaundice and/or pruritus; gallbladder stone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.
• Acute or chronic liver function disorders require immediate discontinuation of COCs until liver function tests return to acceptable levels. Recurrences of cholestatic jaundice and/or pruritus previously experienced during pregnancy or with sex steroid use also require discontinuation of COCs.
• Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no need to alter treatment regimens for diabetic patients taking COCs. However, women with diabetes should be closely monitored during COC use.
• Melasma may occur occasionally, particularly in women with a history of melasma during pregnancy. Women predisposed to melasma are advised to avoid sun exposure or ultraviolet radiation while using this medicinal product.
• Crohn's disease and ulcerative colitis have been associated with COC use.

Medical examination

Before initiating or resuming use of Desofemine® 30, the physician should carefully review the woman’s personal and family medical history and exclude pregnancy. Considering the contraindications (see section "Contraindications") and precautions (see section "Special precautions for use") for this medicinal product, a complete medical examination and blood pressure measurement should be performed. The woman should be informed about venous and arterial thrombosis, including risks associated with the use of Desofemine® 30 compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis. The woman should also be advised to carefully reread the package leaflet and follow the instructions provided. The frequency and nature of follow-up examinations should be determined by the physician according to official guidelines and individual patient needs.

The woman should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases. If there is a risk of infection (including during pregnancy or postpartum), appropriate use of condoms in combination with other contraceptive methods is recommended.

Reduced efficacy

The effectiveness of Desofemine® 30 may be reduced, for example, if doses are missed, gastrointestinal disturbances occur (see section "Dosage and administration"), or when certain concomitant medications that reduce plasma concentrations of etonogestrel, the active metabolite of desogestrel, are used (see section "Interaction with other medicinal products and other forms of interaction").

Menstrual cycle control disturbances

Irregular (light or heavy) bleeding may occur during COC use, especially during the first few months of use. Therefore, evaluation of any irregular bleeding should only be considered after an adaptation period of approximately three cycles.

If irregular bleeding persists or occurs after previous regular cycles, non-hormonal causes should be considered and appropriate diagnostic measures, including curettage, should be performed to exclude pregnancy or malignant tumors.

In some women, withdrawal bleeding may not occur during the tablet-free interval. If COCs have been taken according to the recommendations in the section "Dosage and administration," the likelihood of pregnancy is low. However, if these recommendations were not followed before the first missed withdrawal bleed during the tablet-free interval, or if withdrawal bleeding is absent for two consecutive cycles, pregnancy must be ruled out before continuing COC use.

Desofemine® 30 contains lactose and sodium.

If a woman has been diagnosed with an intolerance to certain sugars, she should consult her doctor before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) per dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Pregnancy is a contraindication for the use of Desofemine® 30. If a woman becomes pregnant while taking Desofemine® 30, further use should be discontinued. However, results from epidemiological studies do not indicate an increased risk of congenital malformations in children whose mothers used COCs prior to pregnancy, nor is there evidence of teratogenic effects from inadvertent COC use in early pregnancy.

The increased risk of VTE in the postpartum period should be considered when resuming use of Desofemine® 30 (see sections "Dosage and administration" and "Special precautions for use").

Breastfeeding

COCs may affect lactation, as they can reduce the quantity and alter the composition of breast milk. Therefore, COC use is generally not recommended until full weaning. Small amounts of contraceptive steroids and/or their metabolites may be excreted in breast milk, but there is no evidence that this negatively affects infant health.

Ability to influence reaction speed when driving or operating machinery

The medicinal product does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

For oral use.

Dosing

One tablet is taken daily for 21 consecutive days. Tablets from the next pack should be started after a 7-day tablet-free interval, during which withdrawal bleeding usually occurs. This bleeding typically begins on the 2nd–3rd day after the last tablet and may continue until the start of the next pack.

How to take Desofemine® 30

Tablets must be taken in the order indicated on the packaging, daily at approximately the same time, with a small amount of liquid if needed.

Starting Desofemine® 30

If hormonal contraceptives have not been used previously (in the past month)

Tablet intake should begin on the first day of the woman’s natural cycle (i.e., the first day of menstrual bleeding). Starting on days 2–5 is also possible; however, in this case, an additional barrier method of contraception should be used during the first 7 days of the first cycle of tablet use.

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

It is recommended that the woman start taking Desofemine® 30 the day after the last active tablet (the last tablet containing active ingredients) of the previous CHC. This should be no later than the day after the tablet-free interval or after taking the last inactive tablet of the previous hormonal contraceptive. For users of a vaginal ring or transdermal patch, it is recommended to start Desofemine® 30 on the day of removal, but no later than the next scheduled application day.

If the previous contraceptive method was used correctly and consistently, and the woman is completely certain she is not pregnant, she may switch from another combined hormonal contraceptive at any day of the cycle.

The hormone-free interval must not exceed the recommended duration.

Switching from progestogen-only preparations ("mini-pill", injection, or implant) or from a progesterone-releasing intrauterine system (IUS)

A woman may start taking Desofemine® 30 at any day after discontinuing the "mini-pill" (in the case of an implant or IUS—on the day of removal; in the case of an injection—on the day the next injection would have been due). In all these cases, an additional barrier method must be used for the first 7 days of tablet intake.

After first-trimester abortion

The woman may start taking the drug immediately after the abortion. In this case, additional contraceptive methods are not required.

After childbirth or second-trimester abortion

For information on use during breastfeeding, see section "Use during pregnancy or breastfeeding".

Women are recommended to start taking the drug on day 21 or 28 after childbirth or second-trimester abortion. If starting later, an additional barrier method should be used for the first 7 days of tablet intake. In any case, if sexual intercourse has already occurred during this period, pregnancy should be ruled out before starting CHC use, or the woman should wait until her first menstruation.

What to do if a tablet is missed

If the woman is less than 12 hours late in taking the next tablet, contraceptive protection is not reduced. She should take the tablet as soon as she remembers and continue taking tablets at the usual time.

If the woman is more than 12 hours late in taking the next tablet, contraceptive protection may be reduced. In this case, two main rules apply:

1. Do not interrupt tablet intake for more than 7 days.
2. Adequate suppression of the hypothalamic–pituitary–ovarian system is achieved after 7 consecutive days of tablet intake.

Accordingly, the following practical advice should be followed:

• Week 1

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time. Additionally, a barrier method of contraception (e.g., condom) should be used for the next 7 days. If sexual intercourse occurred in the previous 7 days, the possibility of pregnancy should be considered. The greater the number of missed tablets and the closer to the tablet-free interval, the higher the risk of pregnancy.

• Week 2

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time. If she has taken the previous tablets correctly for the past 7 days, no additional contraceptive methods are needed. However, if this is not the case, or if more than one tablet has been missed, additional contraceptive methods should be used for the next 7 days.

• Week 3

The risk of reduced effectiveness increases as the tablet-free interval approaches. However, by following a specific dosing schedule, a reduction in contraceptive protection can be avoided. If one of the following instructions is followed, additional contraceptive methods are not required, provided the woman has taken tablets correctly for the 7 days prior to the missed dose. If this is not the case, the woman should follow the first of the instructions below and use additional contraceptive methods for the next 7 days.

1. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time. Tablets from the next pack should be started immediately after finishing the current pack—there should be no tablet-free interval. Withdrawal bleeding is unlikely to occur before finishing the second pack, although spotting or breakthrough bleeding may occur during tablet intake.
2. The woman may also stop taking tablets from the current pack. In this case, the tablet-free interval should be 7 days, including the days of missed tablets; tablet intake should then resume with the next pack.

If a woman misses tablets and does not have withdrawal bleeding during the first scheduled tablet-free interval, pregnancy may have occurred.

Recommendations in case of gastrointestinal disturbances

In the case of severe gastrointestinal disturbances, drug absorption may be incomplete, and additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking a tablet, follow the recommendations for missed tablets (see section "What to do if a tablet is missed" above). If the woman does not wish to alter her usual tablet-taking schedule, she should take an additional tablet (tablets) from another pack.

How to delay or change the onset of menstruation

To delay menstruation, the woman should simply continue taking tablets from the next pack without a break after finishing the previous pack. Any delay is possible, up to the end of the second pack. During the delay, breakthrough bleeding or spotting may occur. Regular tablet intake resumes after the next scheduled 7-day tablet-free interval.

To shift the onset of menstruation to a different day of the week compared to the normal cycle (when Desofemine® 30 is not used), the woman may be advised to shorten the tablet-free interval by the desired number of days. The shorter the interval, the higher the likelihood of absent withdrawal bleeding and the occurrence of spotting or short breakthrough bleeding during intake of tablets from the next pack (similar to when delaying menstruation).

Children

There are no clinical data on the efficacy and safety of the medicinal product in children (under 18 years of age).

Overdose

No serious or life-threatening complications have been reported in cases of overdose. Symptoms of overdose may include nausea, vomiting, and slight vaginal bleeding in girls. There is no specific antidote; treatment of overdose should be symptomatic.

Adverse reactions.

Description of individual adverse reactions

When using combined oral contraceptives (COCs), an increased risk of arterial and venous thromboembolism has been observed, including myocardial infarction, stroke, transient ischemic attack, deep vein thrombosis, and pulmonary embolism (see section "Special precautions" for details).

Other adverse reactions observed in women using COCs are discussed in the section "Special precautions".

Changes in the pattern of vaginal bleeding have been observed with all COCs, especially during the first months of use. Changes in the frequency of bleeding (absence, less frequent, more frequent, or prolonged bleeding), intensity of bleeding (decreased or increased), or total duration of vaginal bleeding have also been reported.

Possible adverse reactions¹, reported during the use of ethinylestradiol/desogestrel or COCs, are summarized in the table below. All adverse reactions are listed by system organ class and frequency.

1 The most appropriate MedDRA term for describing a specific adverse reaction. Synonyms or similar conditions are not listed but should also be considered.

2 Frequency of observations in cohort studies from ≥ 1/10,000 to 1/1,000 women-years.

In women using combined hormonal contraceptives, the following adverse reactions have been reported: angioneurotic edema and/or exacerbation of hereditary angioneurotic edema, acne, alopecia, ovarian cysts, menstrual disorders, dysmenorrhea, ectopic pregnancy, pruritus, fatigue, somnolence, insomnia, hyperthermia, gynecomastia, premenstrual syndrome, hirsutism, changes in plasma lipids, changes in appetite. More detailed information on adverse reactions reported during use of COCs (venous thromboembolic disorders, arterial thromboembolic disorders, arterial hypertension, hormone-dependent neoplasms (e.g. liver tumors, breast cancer), chloasma) is provided in the section "Special precautions for use".

Data on the effect of COCs on laboratory tests are given in the section "Interaction with other medicinal products and other forms of interaction".

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorized is of great importance. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach and sight of children.

Packaging. 21 tablets per blister. 1, 3, or 6 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

mibe GmbH & Co. KG Arzneimittel.

Manufacturer's address and place of business.

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