Marvelon®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MARVELON®

Composition:

Active substances: desogestrel, ethinylestradiol;

One tablet contains 0.150 mg desogestrel and 0.030 mg ethinylestradiol;

Excipients: potato starch; colloidal anhydrous silicon dioxide; alpha-tocopherol; stearic acid; povidone; lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round, biconvex tablets, with the word ORGANON* embossed on one side and the inscription TR/5 on the other.

Pharmacotherapeutic group. Genitourinary system and sex hormones. Sex hormones and modulators of the genital system. Hormonal contraceptives for systemic use. Estrogens and progestogens in fixed combinations. ATC code G03A A09.

Pharmacological Properties.

Pharmacodynamics.

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

Ethinylestradiol is a well-known synthetic estrogen.

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

Pharmacokinetics of desogestrel.

Absorption. Desogestrel is rapidly and completely absorbed after oral administration and is converted into etonogestrel. Peak serum concentration of approximately 2 ng/mL is reached 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 is present as free steroid, while 40–70% is specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG affects distribution among serum proteins, resulting in an increased SHBG-bound fraction and a decreased albumin-bound fraction. The expected volume of distribution of desogestrel is 1.5 L/kg.

Metabolism. Etonogestrel is completely metabolized via well-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.

Excretion. 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 in 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 levels of the substance increase approximately 2–3 times, reaching a stable concentration in the second half of the treatment cycle.

Pharmacokinetics of 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 exhibits strong but non-specific binding to serum albumin (approximately 98.5%) and induces an increase in serum SHBG concentration. The expected volume of distribution is 5 L/kg.

Metabolism. Presystemic conjugation of ethinylestradiol occurs both in the intestinal mucosa and in the liver. Ethinylestradiol is initially metabolized via aromatic hydroxylation, forming a large number of hydroxylated and methylated metabolites, which are present as free metabolites and as glucuronide and sulfate conjugates. Metabolic clearance rate is approximately 5 mL/min/kg.

Excretion. Plasma levels of ethinylestradiol decline in two phases; the terminal elimination phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is not excreted unchanged; excretion of its metabolites occurs via urine and bile in a ratio of 4:6. The elimination half-life of metabolites is approximately 1 day.

Steady state. Steady-state concentrations are achieved within 3–4 days, when serum levels are 30–40% higher than after a single dose.

Clinical characteristics.

Indications.

Oral contraception.

When considering prescribing Marvelon®, individual risk factors in each woman should be taken into account, especially the risk of venous thromboembolism (VTE), as well as comparing the risk of VTE development associated with the use of Marvelon® and other combined hormonal contraceptives (see sections "Contraindications" and "Special precautions").

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used in the presence of any of the conditions listed below. If any of the following conditions develop for the first time during CHC use, the product must be discontinued immediately.

Presence of or risk of venous thromboembolism (VTE).

• Venous thromboembolism – current VTE (anticoagulant therapy in progress) or history of VTE (e.g., deep vein thrombosis (DVT) or pulmonary embolism (PE)).
• Known acquired or hereditary risk factors for 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 the presence of multiple risk factors (see section "Special precautions").

Presence of or risk of arterial thromboembolism (ATE)

• Arterial thromboembolism – current or past history of arterial thromboembolism (e.g., myocardial infarction) or prodromal conditions (e.g., angina pectoris).

• Cerebrovascular disease – stroke, history of stroke, or transient ischemic attack (TIA).

• Known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (antibodies to anticardiolipin, lupus anticoagulant).

• History of migraine with focal neurological symptoms.

• High risk of arterial thromboembolism due to multiple risk factors (see section "Special precautions") or one serious risk factor:

• diabetes mellitus with vascular complications;

• severe arterial hypertension;

• severe dyslipoproteinemia.

Pancreatitis or history of pancreatitis 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).

Established or suspected estrogen-dependent tumors (see section "Special precautions").

Endometrial hyperplasia.

Vaginal bleeding of unknown etiology.

Established or suspected pregnancy.

Hypersensitivity to any active or excipient ingredient.

Marvelon® is contraindicated with combination therapy for hepatitis C containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir or drugs containing glecaprevir/pibrentasvir (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Warning. The package leaflet of the concomitant medicinal product should be carefully reviewed to identify possible interactions.

Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions are reported in the literature.

Hepatic metabolism. Interactions may occur 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 Marvelon®. 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 (Hypericum perforatum).

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.

Concomitant use of hormonal contraceptives with many HIV protease inhibitors (e.g., nelfinavir), 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 enzyme-inducing medicinal or herbal products should be aware that the effectiveness of Marvelon® may be reduced. During treatment with enzyme-inducing agents, a barrier method of contraception should be used in addition to Marvelon® throughout the entire duration of the enzyme-inducing drug treatment and for 28 days after discontinuation of such drug.

If the duration of concomitant treatment extends beyond the active tablet period of the oral contraceptive pack, the next pack should be started without the usual tablet-free interval. In cases of long-term treatment with enzyme-inducing agents, an alternative contraceptive method not affected by such agents should be considered.

Concomitant use of strong (e.g., ketoconazole, itraconazole, clarithromycin) or moderate (e.g., fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors 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 of combination therapy for hepatitis C containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevations in ALT levels greater than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol-containing products (CHCs). Similarly, increased ALT levels were observed in women using ethinylestradiol (CHCs) when co-administered with glecaprevir/pibrentasvir. Use of Marvelon® should be discontinued prior to starting combination therapy for hepatitis C containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir or glecaprevir/pibrentasvir (see sections "Contraindications" and "Special precautions"). Resumption of Marvelon® should occur approximately 2 weeks after completion of combination therapy.

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

Special precautions for use.

If any of the conditions or risk factors listed below are present, the use of Marvelon® should be discussed with the woman. In case of new onset, worsening or first occurrence of any of these conditions, the woman should consult her physician. The physician must determine whether discontinuation of the COC is necessary.

Disorders of circulation.

Risk of venous thromboembolism (VTE)

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 Marvelon®, may increase the risk approximately two-fold. The decision to use any contraceptive that is not a lowest-risk COC should only be made after discussing with the woman the risks of VTE associated with the use of Marvelon®, 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 out of 10,000 will develop VTE within the first year. However, for each 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; for comparison, among women using a COC containing levonorgestrel, VTE will occur in 6 out of 10,000 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 Incidence based on epidemiological data using relative risks for different products compared to COCs containing levonorgestrel.

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

Number of VTE cases per 10,000 women per 1 year

• In another epidemiological study involving 1.8 million Danish women followed for an average of 10.9 years, the relative risk (RR) of breast cancer was reported to increase with longer duration of COC use compared to women who had never used COCs (overall RR = 1.19; the 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 COCs) was small: 13 per 100,000 woman-years.

• Epidemiological studies do not provide evidence of a causal relationship for these data. The observed pattern of increased risk may be related to earlier diagnosis of breast cancer in COC users, the biological effects of COCs, or a combination of both factors.

• In women using COCs, benign and, much more rarely, malignant liver tumors have been reported in rare cases. In isolated 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.

Hepatitis C

• During clinical trials of a combined hepatitis C treatment regimen containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ALT levels exceeding 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using medicinal products containing ethinylestradiol (COCs). ALT elevations were also observed in women using ethinylestradiol (COCs) when co-administered with glecaprevir/pibrentasvir. Use of Marvelon® should be discontinued prior to initiating combination hepatitis C therapy containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir or glecaprevir/pibrentasvir (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). Resumption of Marvelon® should occur approximately 2 weeks after completion of combination hepatitis C therapy.

Other conditions.

• Use of COCs in women with hypertriglyceridemia or a family history of hypertriglyceridemia may increase the risk of pancreatitis.
• Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.
• Although minor increases in blood pressure have been reported in many women taking COCs, clinically significant elevations are rare. A causal 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 occurrence or worsening of the following conditions has been reported 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 jaundice and/or pruritus associated with cholestasis that occurred previously during pregnancy or with sex steroid use also require discontinuation of COC use.
• Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no need to alter treatment regimens in diabetic patients taking COCs. However, careful monitoring of diabetic women is recommended during COC use.
• Melasma may occasionally occur, particularly in women with a history of melasma during pregnancy. Women predisposed to melasma are advised to avoid sun exposure or ultraviolet radiation during use of this medicinal product.
• Crohn’s disease and ulcerative colitis have been associated with COC use.
• The medicinal product Marvelon® contains lactose (<80 mg per tablet). This medicinal product is not recommended in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption.

Medical examination

Before initiating or resuming use of Marvelon®, the physician should carefully review the woman’s personal and family medical history and exclude pregnancy. A complete medical examination, including blood pressure measurement, should be performed, taking into account the contraindications (see section "Contraindications") and warnings (see section "Special precautions for use") for use of this medicinal product. The woman should be informed about venous and arterial thrombosis, including information on risks associated with Marvelon® 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 recommendations provided. The frequency and nature of follow-up examinations should be determined by the physician according to official practice 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 efficacy of Marvelon® may be reduced, for example, in case of missed tablets, gastrointestinal disturbances (see section "Dosage and administration"), or concomitant use of certain medicinal products that reduce plasma concentrations of etonogestrel, the active metabolite of desogestrel (see section "Interaction with other medicinal products and other forms of interaction").

Worsening of menstrual cycle control.

During COC use, irregular (light or heavy) bleeding may occur, particularly during the first months of use. Therefore, evaluation of any irregular bleeding may only be appropriate 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 initiated, including curettage, to exclude pregnancy or malignancy.

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 deviations from these recommendations occurred before the first missed withdrawal bleed during the tablet-free interval, or if withdrawal bleeding is absent for two consecutive cycles, possible pregnancy should be excluded before continuing COC use.

Use during pregnancy or breastfeeding.

Pregnancy

Pregnancy is a contraindication for the use of Marvelon®. If a woman becomes pregnant while taking Marvelon®, further use should be discontinued. However, extensive epidemiological studies have not shown an increased risk of congenital anomalies in children born to mothers who used COCs before pregnancy, nor teratogenic effects from inadvertent COC use in early pregnancy.

It should be remembered that the risk of VTE is increased in the postpartum period when resuming use of Marvelon® (see sections "Dosage and administration" and "Special precautions for use").

Breastfeeding

COCs may affect breastfeeding by reducing the quantity and altering the quality of breast milk. Therefore, COC use is generally not recommended until full weaning is completed. 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

The tablets should be taken in the order indicated on the package, daily at approximately the same time, swallowing them with a small amount of liquid if necessary. One tablet should be taken every day for 21 consecutive days. After a 7-day tablet-free interval, during which withdrawal bleeding usually occurs, the next pack is started. This bleeding typically begins on the 2nd–3rd day after the last tablet and may continue until the start of the next pack.

Hormonal contraceptives were not used in the previous period (last month).

Tablet administration should begin on the first day of the woman’s natural cycle (i.e., the first day of menstrual bleeding). It is also possible to start on days 2–5 of the cycle; 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.

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

It is recommended that a woman start taking Marvelon® the day after taking the last active tablet (the last tablet containing active substances) of the previous COC, but no later than the day after the tablet-free interval or after taking the last inactive tablet of the previous COC. When switching from a vaginal ring or transdermal patch, the woman should ideally start Marvelon® on the day of removal, but no later than the following day of the next scheduled application.

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 tablet-free interval should not exceed the recommended duration.

Transition from progestogen-only contraceptives (mini-pill, injection, or implant) or from an intrauterine system (IUS) releasing progestogen.

A woman may start taking Marvelon® 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 administered). In all these cases, an additional barrier method of contraception should be used during the first 7 days of tablet use.

After first-trimester abortion.

A woman may start taking the medication immediately after an abortion. In this case, there is no need to use additional contraceptive methods.

After childbirth or second-trimester abortion.

Use of the medication during breastfeeding (see section "Use during pregnancy or breastfeeding").

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

Missed tablet instructions

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

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

1. Do not interrupt tablet use for more than 7 days.
2. Adequate suppression of the hypothalamus–pituitary–ovary axis is achieved after 7 consecutive days of tablet use.

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 the 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 more tablets missed and the closer the missed dose is 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 the tablets at her usual time. If she has taken the previous tablets correctly for the preceding 7 days, no additional contraceptive methods are required. 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 options is followed, additional contraceptive methods are not required, provided the woman has taken the 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 options 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 the medication at her usual time. The next pack should be started immediately after finishing the current pack, i.e., without a tablet-free interval. Withdrawal bleeding before finishing the second pack is unlikely, although breakthrough bleeding or spotting may occur during the course of treatment.
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 use should then resume with the next pack.

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

Recommendations in case of gastrointestinal disorders.

In the event of severe gastrointestinal disturbances, absorption of the medication may be incomplete, so additional contraceptive precautions should be taken. If vomiting occurs within 3–4 hours after taking a tablet, the recommendations for missed tablets should be followed (see "Missed tablet instructions"). If a woman does not wish to change her usual tablet-taking schedule, she should take an additional tablet (or 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. Any delay is possible within the number of tablets in the second pack, up to its completion. During the delay, the woman may experience breakthrough bleeding or spotting. Regular tablet intake resumes after the next scheduled 7-day tablet-free interval.

To shift the onset of menstruation to another day of the week from the usual schedule, the woman may be advised to shorten the upcoming tablet-free interval by the desired number of days. The shorter this interval, the higher the likelihood of absent withdrawal bleeding and the occurrence of spotting or breakthrough bleeding during the next pack (similar to when delaying menstruation).

Children

There are no clinical data on the efficacy and safety of using the medication 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

An increased risk of arterial and venous thromboembolism, including myocardial infarction, stroke, transient ischaemic attack, deep vein thrombosis, and pulmonary embolism, has been observed during use of combined hormonal contraceptives (CHCs); for further information, see section "Special precautions for use".

During the initial use of COCs, changes in the pattern of vaginal bleeding were observed, especially during the first months of treatment. Changes in frequency (absence, less frequent, more frequent or prolonged bleeding), intensity (decrease or increase), or alteration in the overall duration of vaginal bleeding have also been reported.

Possible adverse reactions1 reported during use of the medicinal product Marvelon® or COCs (combined oral contraceptives) are listed in Table 3. All adverse reactions are classified by organ systems and frequency: common (≥ 1/100), uncommon (≥ 1/1000, < 1/100), rare (< 1/1000), not known (cannot be estimated from available data).

Table 3

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

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

The following adverse reactions have been reported in women using combined hormonal contraceptives: 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, change 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".

For data on the effect of COCs on laboratory tests, see section "Interaction with other medicinal products and other forms of interaction".

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging.

21 tablets per blister, 1 blister per sachet, 3 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

N.V. Organon.

Manufacturer's address and place of business.

Registered address: 5349 AB Oss, Kloosterstraat 6, the Netherlands.

Place of business: Molensestraat 110, 5342 SS Oss, the Netherlands.