Modelle^® PRO (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Oman Pharmaceutical Products, Co. LLC (Sultanate of Oman)

Contact Information

TEVA (Israel)

ATC Code

G03AA12 (Drospirenone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Dosage Form

Modelle® PRO

Film-coated tablets 3 mg+0.03 mg: 21, 63, or 126 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light yellow in color, round, biconvex, with the marking “D3” on one side, applied by embossing; the core on the cross-section is white to almost white.

Excipients (core) lactose monohydrate – 43.37* mg, corn starch – 12.8 mg, pregelatinized starch – 15.4 mg, povidone K25 – 3.4 mg, croscarmellose sodium – 1.6 mg, magnesium stearate – 0.4 mg.

Excipients (coating) opadry yellow 03B38204 – 2 mg (hypromellose 6cP – 62.5%, titanium dioxide – 29.5%, macrogol 400 – 6.25%, iron oxide yellow dye – 1.75%).

* the amount of lactose monohydrate may vary depending on the purity of the active substance.

21 pcs. – PVC/Aluminum foil blisters (1) – cardboard packs.
21 pcs. – PVC/Aluminum foil blisters (3) – cardboard packs.
21 pcs. – PVC/Aluminum foil blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Contraceptive drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

A low-dose combined monophasic oral hormonal contraceptive containing Ethinylestradiol and Drospirenone.

The contraceptive effect of the drug Modelle^® PRO is mainly achieved by suppressing ovulation, increasing the viscosity of cervical mucus, and changing the endometrium. In women taking combined oral contraceptive drugs (COCs), the menstrual cycle becomes more regular, painful menstruation is less common, the intensity of menstrual-like bleeding decreases, thereby reducing the risk of iron deficiency anemia. In addition, there is evidence of a reduced risk of endometrial cancer and ovarian cancer.

Drospirenone contained in the drug Modelle^® PRO has an antimineralocorticoid effect and is able to prevent weight gain and the appearance of other symptoms (for example, peripheral edema) associated with hormone-dependent fluid retention. Drospirenone also has antiandrogenic activity and helps reduce acne, oily skin and hair. This action of drospirenone is similar to the action of natural progesterone produced in the female body. This should be taken into account when choosing a contraceptive, especially for women with hormone-dependent fluid retention, as well as for women with acne and seborrhea.

When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using a contraceptive for a year) is less than 1. If tablets are missed or used incorrectly, the Pearl index may increase.

Pharmacokinetics

Drospirenone

Absorption

After oral administration, Drospirenone is rapidly and almost completely absorbed from the gastrointestinal tract. After a single dose of the drug, C_max of drospirenone in blood plasma is reached in 1-2 hours and is 37 ng/ml. The bioavailability of drospirenone is 76-85%. Food intake does not affect its bioavailability.

Distribution

Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Estradiol-induced increase in SHBG does not affect the binding of drospirenone to plasma proteins.

During the treatment cycle, C_ss of drospirenone is achieved in the second half of the cycle.

A further increase in concentration is noted after approximately 1-6 treatment cycles; no subsequent increase in concentration is observed.

Metabolism

After oral administration, Drospirenone is completely metabolized. Most metabolites in plasma are represented by acidic forms of drospirenone, which are formed without the involvement of cytochrome P450 isoenzymes.

Excretion

It is excreted as metabolites through the intestines and kidneys in a ratio of approximately 1.2:1.4. T_1/2 of metabolites is approximately 40 hours.

Pharmacokinetics in special patient groups

Renal impairment. C_ss of drospirenone in the blood plasma of women with mild renal impairment (creatinine clearance 50-80 ml/min) is comparable to that in women with normal renal function. In women with moderate renal impairment (creatinine clearance 30-50 ml/min), the concentration of drospirenone in blood plasma is on average 37% higher than in women with normal renal function.

Hepatic impairment. In women with moderate hepatic impairment (Child-Pugh class B), AUC is comparable to the corresponding indicator in healthy women with similar C_max values in the absorption and distribution phases. T_1/2 of drospirenone in patients with moderate hepatic impairment is 1.8 times higher than in healthy volunteers with preserved liver function. In patients with moderate hepatic impairment, a decrease in the clearance of drospirenone by approximately 50% was noted compared to women with preserved liver function, while no differences in plasma potassium concentration were noted in the studied groups. No change in potassium concentration was noted even in the case of a combination of factors predisposing to its increase (concomitant diabetes mellitus or treatment with spironolactone).

Ethinylestradiol

Absorption

After oral administration of the drug, Ethinylestradiol is rapidly and completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached in 1-2 hours and is 54-100 pg/ml. Ethinylestradiol undergoes a first-pass effect through the liver, as a result, its bioavailability when taken orally averages 60%.

Distribution

Binding to plasma proteins (with albumin) is about 98%. Ethinylestradiol induces the synthesis of SHBG. The decrease in the concentration of ethinylestradiol in blood plasma is biphasic.

C_ss is established during the second half of the first treatment cycle.

Metabolism

Ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation.

Excretion

Ethinylestradiol is excreted as metabolites by the kidneys and through the intestines in a ratio of approximately 4:6. T_1/2 of metabolites is about 24 hours.

Indications

• Contraception.

ICD codes

Dosage Regimen

The drug is taken orally. The tablets should be taken in the order indicated on the package, every day at approximately the same time, with a small amount of water. Take 1 tablet continuously for 21 days. Taking tablets from the next package starts after a 7-day break, during which menstrual-like bleeding (withdrawal bleeding) usually occurs. As a rule, it begins on the 2-3rd day after taking the last tablet and may not end until starting to take tablets from a new package.

Starting to take the drug Modelle^® PRO

If no hormonal contraceptives were taken in the previous month, the use of the drug Modelle^® PRO should be started on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding). It is permissible to start taking it on the 2nd-5th day of the menstrual cycle, but in this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking tablets from the first package.

Switching from other combined hormonal contraceptive drugs (COCs, vaginal ring, or contraceptive patch)

It is preferable to start taking the drug Modelle^® PRO on the day after taking the last tablet from the previous package, but in no case later than the next day after the usual 7-day break. Taking the drug Modelle^® PRO should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch applied.

Switching from contraceptives containing only progestogens (“mini-pills”, injectable forms, implant, or intrauterine systems (IUS) with controlled release of progestogen)

You can switch from “mini-pills” to taking the drug Modelle^® PRO on any day (without a break), from an implant or IUS – on the day of their removal, from an injectable contraceptive – on the day when the next injection should be made. In all cases, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets.

After an abortion in the first trimester of pregnancy, you can start taking the drug immediately – on the day of the abortion. If this condition is met, the woman does not need additional methods of contraception.

After childbirth or abortion in the second trimester of pregnancy

It is recommended to start taking the drug on the 21st-28th day after childbirth (in the absence of breastfeeding) or abortion in the second trimester of pregnancy. If intake is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. If sexual intercourse has taken place, then before starting to take the drug Modelle^® PRO, pregnancy should be excluded or it is necessary to wait for the first menstruation.

Taking missed tablets

If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. The tablet should be taken as soon as possible, the next tablet is taken at the usual time. If the delay in taking the drug was more than 12 hours, contraceptive protection may be reduced. The more tablets are missed and the closer the miss is to the 7-day break in taking the tablets, the greater the likelihood of pregnancy. In this case, you can be guided by the following two basic rules

• Taking the drug should never be interrupted for more than 4 days;
• 7 days of continuous tablet intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking the tablet was more than 12 hours (the interval from the moment of taking the last tablet is more than 36 hours), the woman should follow the recommendations below.

First week of drug use

It is necessary to take the last missed tablet as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablet is taken at the usual time. Additionally, a barrier method of contraception (for example, a condom) should be used for the next 7 days. If sexual intercourse took place during the week before missing the tablet, the possibility of pregnancy must be considered.

Second week of drug use

It is necessary to take the last missed tablet as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablet is taken at the usual time. Provided that the woman has taken the tablets correctly for the 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, as well as if two or more tablets are missed, it is necessary to additionally use barrier methods of contraception (for example, a condom) for 7 days.

Third week of drug use

The risk of pregnancy increases due to the upcoming break in taking the tablets. The woman must strictly adhere to one of the two following options. In this case, if during the 7 days preceding the first missed tablet, all tablets were taken correctly, there is no need to use additional contraceptive methods. Otherwise, it is necessary to use the first of the following schemes and additionally use a barrier method of contraception (for example, a condom) for 7 days.

1. It is necessary to take the last missed tablet as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The following tablets are taken at the usual time until the tablets in the current package run out. The next package should be started immediately without a break. Withdrawal bleeding is unlikely until the second package is finished, but spotting and breakthrough bleeding may occur while taking the tablets.

2. You can also interrupt taking the tablets from the current package, thus starting a 7-day break (including the day of missing the tablet), and then start taking tablets from a new package.

If a woman missed taking tablets, and then during the break in taking she does not have withdrawal bleeding, pregnancy must be excluded.

Recommendations in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (vomiting, diarrhea), absorption may be incomplete, so additional methods of contraception should be used. If vomiting occurs within 4 hours after taking the tablet, you should follow the recommendations for missed tablets.

Changing the day of the start of the menstrual cycle

In order to delay the onset of menstruation, it is necessary to continue further taking tablets from a new package of Modelle^® PRO without a 7-day break. Tablets from a new package can be taken for as long as necessary, including until the package runs out. While taking the drug from the second package, spotting from the vagina or breakthrough uterine bleeding is possible. Regular intake of Modelle^® PRO from the next package should be resumed after the usual 7-day break. In order to move the start of menstruation to another day of the week, the woman should shorten the nearest break in taking the tablets by the desired number of days. The shorter the interval, the higher the risk that she will not have withdrawal bleeding, and subsequently spotting and breakthrough bleeding will be observed while taking the second package (just as in the case when she would like to delay the onset of menstruation).

Additional information for special categories of patients

Use in children. The efficacy and safety of the drug as a contraceptive have been studied in women of reproductive age. It is assumed that the efficacy and safety of the drug in postpubertal age under 18 years are similar to those in women over 18 years of age. The use of the drug before menarche is not indicated.

Use in the elderly. After the onset of menopause, the drug Modelle^® PRO is not indicated.

Use in hepatic impairment. The use of the drug is contraindicated in the presence of current or history of severe liver diseases (until liver function tests normalize), current or history of benign or malignant liver tumors.

The use of the drug is contraindicated in acute renal failure and severe renal failure.

Adverse Reactions

The frequency of adverse reactions that were identified when using the drug is defined as follows: common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000).

From the immune system rare – bronchial asthma, hypersensitivity reactions.

From the nervous system common – headache.

Mental disorders common – depressive state; uncommon – change in libido.

From the hearing organ rare – hearing loss.

From the cardiovascular system common – migraine; uncommon – increased blood pressure, decreased blood pressure; rare – thromboembolism.

From the digestive system common – nausea; uncommon – vomiting, diarrhea.

From the skin and subcutaneous tissues uncommon – acne, eczema, itching; rare – erythema nodosum, erythema multiforme.

From the reproductive system and mammary gland common – menstrual cycle disorders, acyclic bleeding, breast tenderness, increased breast sensitivity, leucorrhea, candidal vulvovaginitis; uncommon – breast enlargement, vaginitis; rare – breast discharge.

Other uncommon – fluid retention, change in body weight.

The following serious adverse events have been reported in women taking COCs: venous thromboembolism; arterial thromboembolism; increased blood pressure; liver tumors; the appearance or worsening of conditions, the connection of which with taking COCs has not been definitively established (Crohn’s disease, ulcerative colitis, epilepsy, migraine, uterine fibroids, porphyria, systemic lupus erythematosus, herpes during a previous pregnancy, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice); chloasma.

In women with hereditary angioedema, the use of estrogens may cause or worsen its symptoms.

Contraindications

• Thrombosis (venous and arterial) currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders);
• Conditions preceding thrombosis (including transient ischemic attacks, atrial fibrillation, angina pectoris) currently or in history;
• Migraine with focal neurological symptoms currently or in history;
• Identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antibodies to phospholipids (anticardiolipin antibodies, lupus anticoagulant);
• Diabetes mellitus with vascular complications;
• Multiple or pronounced risk factors for venous or arterial thrombosis (including complicated lesions of the heart valves, atrial fibrillation, cerebrovascular or coronary artery diseases; uncontrolled arterial hypertension, prolonged immobilization, major surgical intervention, surgical interventions on the lower limbs, extensive trauma, smoking at the age over 35 years, obesity with BMI >30 kg/m²);
• Pancreatitis with severe hypertriglyceridemia currently or in history;
• Hepatic insufficiency and severe liver diseases (until liver function parameters normalize);
• Liver tumors (benign or malignant) currently or in history;
• Severe and/or acute renal failure;
• Identified hormone-dependent malignant diseases (including of the genital organs or mammary glands) or suspicion thereof;
• Vaginal bleeding of unknown origin;
• Pregnancy or suspicion thereof;
• Lactation period (breastfeeding);
• Hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome;
• Hypersensitivity to the components of the drug.

If any of the above-mentioned diseases or conditions develop for the first time during the use of the drug, it should be immediately discontinued.

With caution

The ratio of potential risk and expected benefit of using the drug MODELL^® PRO should be evaluated in each individual case in the presence of the following diseases/conditions and risk factors

• Risk factors for thrombosis and thromboembolism: smoking, obesity (BMI <30 kg/m²), dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve defects, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives);
• Other diseases in which peripheral circulation disorders may be noted: diabetes mellitus without diabetic angiopathy, SLE, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• Liver diseases not classified as contraindications;
• Diseases that first appeared or worsened during pregnancy or against the background of previous use of sex hormones (for example, jaundice and/or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestations, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

Pregnancy. If pregnancy is detected during the use of MODELL^® PRO, the drug should be discontinued immediately. Extensive epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy, or a teratogenic effect in cases where sex hormones were taken inadvertently in early pregnancy. In animal studies, the effects of drospirenone and ethinylestradiol were associated with their pharmacological action. In particular, reproductive toxicity studies in animals revealed embryotoxic and fetotoxic effects, but these effects were considered to be species-specific. At animal exposure levels exceeding the corresponding levels in women taking Drospirenone and Ethinylestradiol, an effect on the sex differentiation of rat embryos was observed, which was absent in small monkeys. According to data obtained in animal studies, the possibility of adverse effects caused by the hormonal activity of the active substances in humans cannot be excluded. However, the cumulative experience with the use of COCs during pregnancy has not provided evidence of adverse effects in humans. Data on the results of using the drug MODELL^® PRO during pregnancy are limited, which does not allow any conclusions to be drawn about the negative impact of the drug on pregnancy, fetal health and the newborn. Currently, there are no significant epidemiological data.

Breastfeeding period. The drug is contraindicated during breastfeeding. It may reduce the amount of breast milk and change its composition, therefore the use of the drug is not recommended until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites may be excreted in breast milk, but there is no confirmation of their negative impact on the child’s health.

Use in Hepatic Impairment

The use of the drug is contraindicated in the presence of severe liver diseases currently or in history (until liver function tests normalize), and in the presence of benign or malignant liver tumors currently or in history.

Use in Renal Impairment

The use of the drug is contraindicated in acute renal failure and severe renal failure.

Pediatric Use

The efficacy and safety of the drug in postpubertal age under 18 years are assumed to be similar to those in women over 18 years of age. The use of the drug before menarche is not indicated.

Geriatric Use

After menopause the drug MODELL^® PRO is not indicated.

Special Precautions

Before starting or resuming the use of the drug MODELL^® PRO, it is necessary to review the woman’s life history, family history, conduct a thorough general medical (including measurement of BP, heart rate, determination of BMI) and gynecological examination, including examination of the mammary glands and cytological examination of a cervical smear (Papanicolaou test), and exclude pregnancy. The scope of additional examinations and the frequency of follow-up visits are determined individually. Usually, follow-up examinations should be carried out at least once every 6 months.

The woman should be informed that MODELL^® PRO does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

If any of the conditions, diseases and risk factors listed below are currently present, then the potential risk and expected benefit of using COCs should be carefully weighed in each individual case and discussed with the woman before she decides to start taking the drug. If risk factors worsen, intensify, or first appear, discontinuation of the drug may be required.

Cardiovascular diseases

The results of epidemiological studies indicate a relationship between the use of COCs and an increased incidence of venous and arterial thrombosis and thromboembolism, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular diseases. These diseases are rare. The risk of developing venous thromboembolism (VTE) is highest in the first year of taking such drugs. An increased risk is present after initial use of COCs or resumption of use of the same or different COCs (after a break in taking the drug of 4 weeks or more). Data from a large prospective study involving 3 patient groups show that this increased risk is present predominantly during the first 3 months.

The overall risk of VTE in patients taking low-dose COCs (containing <50 mcg ethinylestradiol) is 2-3 times higher than in non-pregnant patients who do not take COCs, nevertheless this risk remains lower compared to the risk of VTE during pregnancy and childbirth. VTE can be fatal (in 1-2% of cases).

VTE, manifested as deep vein thrombosis or pulmonary embolism, can occur with the use of any COCs.

Very rarely, thrombosis of other blood vessels, such as hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels, occurs with the use of COCs. There is no consensus regarding the connection between the occurrence of these events and the use of COCs.

Symptoms of deep vein thrombosis (DVT) include: unilateral swelling of the lower limb or along a vein in the lower limb, pain or discomfort in the lower limb only in an upright position or when walking, local increase in temperature in the affected lower limb, redness or discoloration of the skin on the lower limb.

Symptoms of pulmonary embolism (PE): difficult or rapid breathing; sudden cough, including with hemoptysis; acute chest pain that may worsen with deep inspiration; feeling of anxiety; severe dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., shortness of breath, cough) are nonspecific and may be misinterpreted as symptoms of other more or less severe events (e.g., respiratory infection).

Arterial thromboembolism can lead to stroke, vascular occlusion or myocardial infarction. Symptoms of stroke: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, problems with speech and understanding; sudden one- or two-sided loss of vision; sudden gait disturbance, dizziness, loss of balance or coordination; sudden, severe or prolonged headache for no apparent reason; loss of consciousness or fainting with or without an epileptic seizure. Other signs of vascular occlusion: sudden pain, swelling and slight blueness of the limbs, “acute” abdomen symptom complex.

Symptoms of myocardial infarction include: pain; discomfort; feeling of pressure, heaviness; feeling of squeezing or fullness in the chest, in the arm or behind the breastbone; discomfort in the left half of the chest with radiation to the back, cheekbone, larynx, arm, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, feeling of anxiety or shortness of breath; rapid or irregular heartbeat.

Arterial thromboembolism can be fatal.

The risk of developing thrombosis (venous and/or arterial) and thromboembolism increases

• With age;
• In smokers (with an increase in the number of cigarettes or with increasing age the risk increases, especially in women over 35 years old);
• With obesity (BMI > than 30 kg/m²);
• In the presence of a family history (e.g., venous or arterial thromboembolism ever in close relatives or parents at a relatively young age). In case of hereditary or acquired predisposition, the woman should be referred to an appropriate specialist to decide on the possibility of using COCs;
• With prolonged immobilization, major surgery, any operation on the lower limbs or extensive trauma. In these situations, it is advisable to discontinue the use of COCs (in the case of planned surgery, at least 4 weeks before it) and not resume intake for 2 weeks after the end of immobilization;
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism remains controversial. The increased risk of thromboembolism in the postpartum period should be taken into account.

Peripheral circulation disorders can also be observed in diabetes mellitus, SLE, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine attacks during the use of COCs (which may precede cerebrovascular disorders) should be the basis for immediate discontinuation of these drugs.

Biochemical parameters indicating a hereditary or acquired predisposition to venous or arterial thrombosis include: resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk-benefit ratio, it should be taken into account that adequate treatment of the corresponding condition can reduce the associated risk of thrombosis. It should also be taken into account that the risk of thrombosis and thromboembolism during pregnancy is higher than when taking low-dose COCs (containing less than 50 mcg ethinylestradiol).

Medicinal products containing levonorgestrel, norgestimate or norethindrone have a low risk of developing venous thromboembolism. For drugs containing Drospirenone, the risk of developing thromboembolic complications is 2 times higher, therefore the woman should be warned about this increased risk before prescribing the drug MODELL^® PRO.

Tumors

The most significant risk factor for cervical cancer is persistent papillomavirus infection. There are reports of a slight increase in the risk of cervical cancer with long-term use of COCs. However, the connection with taking COCs has not been proven. There is conflicting data regarding the extent to which these data are related to screening for cervical pathology or to sexual behavior characteristics (less frequent use of barrier contraception methods).

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking or recently taking COCs is insignificant relative to the overall risk of this disease. The relationship between the development of breast cancer and taking COCs has not been proven. The observed increase in risk may also be a consequence of careful monitoring and earlier diagnosis of breast cancer in women using COCs. In women who have ever used COCs, earlier stages of breast cancer are detected than in women who have never used them.

In rare cases, the development of benign, and in extremely rare cases, malignant liver tumors has been observed during the use of COCs, which in some cases led to life-threatening intra-abdominal bleeding. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when conducting a differential diagnosis.

Other conditions

Clinical studies have shown no effect of drospirenone on serum potassium concentration in patients with mild to moderate renal failure. Theoretically, there is a risk of developing hyperkalemia in patients with impaired renal function and initial potassium levels at the upper limit of normal or while taking medications that lead to potassium retention in the body.

In women with hypertriglyceridemia (or with a family history of this condition), the risk of developing pancreatitis may increase while taking COCs. Although a slight increase in BP has been described in many women taking COCs, clinically significant arterial hypertension was rare. However, if a persistent, clinically significant increase in BP develops during the use of COCs, these drugs should be discontinued and treatment for arterial hypertension should be started. The use of COCs may be continued if normal BP values are achieved with antihypertensive therapy.

The following conditions have been reported to develop or worsen both during pregnancy and when taking COCs, but their connection with taking COCs has not been proven: jaundice and/or itching associated with cholestasis; formation of gallstones; porphyria; SLE; hemolytic-uremic syndrome; Sydenham’s chorea; herpes gestations; hearing loss associated with otosclerosis. Cases of Crohn’s disease or ulcerative colitis during the use of COCs have also been described.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen the symptoms of angioedema.

In acute or chronic liver function disorders, it may be necessary to discontinue the drug until liver function parameters return to normal. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of COCs.

Although COCs may affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in patients with diabetes mellitus using low-dose COCs (containing less than 50 mcg ethinylestradiol). Nevertheless, women with diabetes mellitus require careful monitoring of blood glucose concentration during the use of the drug.

The development of chloasma is possible when using the drug, especially in women with a history of chloasma of pregnancy. Women prone to chloasma during the use of COCs should avoid prolonged exposure to the sun and ultraviolet radiation.

The effectiveness of COCs may be reduced if tablets are missed, due to vomiting and diarrhea, or as a result of drug interactions.

Effect on the menstrual cycle

Irregular (acyclic) bleeding (spotting or breakthrough bleeding) may occur during the use of COCs, especially during the first months of use. Therefore, the assessment of any irregular bleeding should be carried out only after an adaptation period of approximately 3 cycles.

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

In some women, withdrawal bleeding may not develop during the break in taking the pills. If the COC was taken in accordance with the instructions, then pregnancy is unlikely. However, if the COC was taken irregularly before or if two consecutive withdrawal bleedings are absent, then pregnancy must be excluded before continuing to take the drug.

Effect on laboratory test parameters

Taking COCs may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, adrenal function, the content of transport proteins in blood plasma, parameters of carbohydrate metabolism, coagulation and fibrinolysis parameters. The changes usually do not go beyond the normal limits. Drospirenone increases plasma renin activity and aldosterone, which is associated with its antimineralocorticoid effect.

Effect on the ability to drive vehicles and mechanisms

Studies on the effect of the drug on the ability to drive vehicles and mechanisms have not been conducted. No effect of COCs on the ability to drive vehicles and mechanisms has been observed.

Overdose

No serious disorders due to overdose have been reported.

Symptoms based on experience with COC overdose may include nausea, vomiting, vaginal spotting or metrorrhagia.

Treatment administration of symptomatic therapy; there is no specific antidote.

Drug Interactions

Interaction of oral contraceptives with other medicinal products may lead to breakthrough bleeding and/or a decrease in contraceptive reliability. Women taking such drugs should temporarily use barrier methods of contraception in addition to MODELLE^® PRO or choose another method of contraception.

Interaction leading to a decrease in the efficacy of MODELLE^® PRO

Effect on hepatic metabolism. The use of drugs that induce hepatic microsomal enzymes may lead to an increase in the clearance of sex hormones, which in turn may lead to breakthrough bleeding or reduced contraceptive reliability. Such medicinal products include phenytoin, barbiturates, primidone, carbamazepine, rifampicin, rifabutin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and preparations containing St. John’s wort.

During the use of drugs affecting hepatic microsomal enzymes and for 28 days after their discontinuation, a barrier method of contraception should be additionally used.

HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and their combinations may also potentially affect hepatic metabolism.

Effect on enterohepatic recirculation. Some antibiotics (e.g., penicillins and tetracycline) may reduce the enterohepatic circulation of estrogens, thereby lowering the concentration of ethinylestradiol. During the use of antibiotics (such as penicillins and tetracyclines) and for 7 days after their discontinuation, a barrier method of contraception should be additionally used. If the period of using the barrier method of protection ends later than the tablets in the pack, it is necessary to proceed to the next pack of MODELLE PRO without the usual tablet-free interval.

Other interactions

The main metabolites of drospirenone are formed in plasma without the involvement of the cytochrome P450 system. Therefore, the influence of cytochrome P450 system inhibitors on the metabolism of drospirenone is unlikely.

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

Based on in vitro interaction studies, as well as studies in female volunteers taking omeprazole, simvastatin, and midazolam, it was found that the influence of drospirenone at a dose of 3 mg on the metabolism of other medicinal products is unlikely.

There is a theoretical possibility of an increase in serum potassium concentration in women receiving MODELLE^® PRO concurrently with other drugs that may increase serum potassium concentration. These drugs include ACE inhibitors, angiotensin II receptor antagonists, some anti-inflammatory drugs, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone with ACE inhibitors or indomethacin, no significant difference in serum potassium concentration compared to placebo was detected.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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