Modelle^® Trend (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® Trend

Film-coated tablets 3 mg+0.02 mg: 28, 84 or 168 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets (active) light pink in color, round, biconvex, with the marking “D2” on one side, applied by embossing; the core on the cross-section is white to almost white; (24 pcs. in a blister).

Excipients (core) lactose monohydrate – 43.38* 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 pink 03B34091 – 2 mg (hypromellose 6cP – 62.5%, titanium dioxide – 31.07%, macrogol 400 – 6.25%, iron oxide red dye – 0.18%).

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

Film-coated tablets (placebo) white in color, round, biconvex, with the marking “PC” on one side, applied by embossing; (4 pcs. in a blister).

Excipients (core) lactose monohydrate – 60 mg, pregelatinized starch – 19.2 mg, magnesium stearate – 0.8 mg.

Excipients (coating) opadry white 03B28796 – 2 mg (hypromellose 6cP – 62.5%, titanium dioxide – 31.25%, macrogol 400 – 6.25%).

28 pcs. (24 active tablets and 4 placebo tablets) – PVC/Aluminum foil blisters (1) – cardboard packs.
28 pcs. (24 active tablets and 4 placebo tablets) – PVC/Aluminum foil blisters (3) – cardboard packs.
28 pcs. (24 active tablets and 4 placebo tablets) – PVC/Aluminum foil blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Contraceptive drug (estrogen + progestogen)

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

Modelle^® Trend is a low-dose combined monophasic oral hormonal contraceptive drug containing Ethinylestradiol and Drospirenone.

The contraceptive effect of Modelle^® Trend is mainly achieved by suppressing ovulation, increasing the viscosity of cervical mucus, and altering the endometrium. In women taking combined oral contraceptives (COCs), the menstrual cycle becomes more regular, painful menstruation is less common, the intensity of withdrawal bleeding decreases, thereby reducing the risk of iron deficiency anemia. Furthermore, there is evidence that the risk of endometrial cancer and ovarian cancer is reduced.

Drospirenone contained in Modelle^® Trend has antimineralocorticoid activity. It prevents weight gain and peripheral edema associated with estrogen-induced hormone-dependent fluid retention, which ensures good tolerability of the drug. Drospirenone has a positive effect on premenstrual syndrome (PMS). The clinical efficacy of Modelle^® Trend in alleviating symptoms of severe PMS, such as pronounced psychoemotional disorders, breast tenderness, headache, muscle and joint pain, weight gain, and other symptoms associated with the menstrual cycle, has been demonstrated.

Drospirenone also has antiandrogenic activity and helps reduce acne, oily skin, and hair. This action of drospirenone is similar to that of natural progesterone produced in the female body. This should be taken into account when choosing a contraceptive drug, especially for women with hormone-dependent fluid retention, as well as for women with acne and seborrhea.

Drospirenone does not possess androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. All this, combined with antimineralocorticoid and antiandrogenic action, gives drospirenone a pharmacological profile similar to that of natural progesterone.

In combination with ethinylestradiol, Drospirenone has a favorable effect on the lipid profile, increasing HDL concentration.

With correct use of the drug, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for one 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, C_max of drospirenone in blood serum is reached in 1-2 hours and is 35 ng/ml. The bioavailability of drospirenone is 76-85%. Food intake does not affect its bioavailability.

Distribution

After oral administration, a biphasic decrease in the concentration of drospirenone in plasma is observed. 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 concentration in plasma does not affect the binding of drospirenone to plasma proteins.

Steady-state concentration. During cyclic treatment, C_ss of drospirenone is reached in the second half of the cycle. A further increase in concentration is noted after approximately 1-6 cycles of taking the drug; 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 plasma in women with mild renal impairment (CrCl 50-80 ml/min) is comparable to that in women with normal renal function. In women with moderate renal impairment (CrCl 30-50 ml/min), the concentration of drospirenone in blood serum 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 that in healthy women with similar C_max values in the absorption and distribution phases. T_1/2 of drospirenone in women with moderate hepatic impairment is 1.8 times higher than in healthy volunteers with normal liver function.

In women with moderate hepatic impairment, a decrease in drospirenone clearance of approximately 50% was noted compared to women with normal liver function, with no differences in plasma potassium concentration observed in the studied groups. No change in potassium concentration was noted even in the presence 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 plasma is reached in 1-2 hours and is 88-100 pg/ml. Ethinylestradiol undergoes first-pass effect through the liver, resulting in an average oral bioavailability of 60%.

Distribution

Binding to plasma proteins (to albumin) is about 98%. Ethinylestradiol induces an increase in SHBG concentration in plasma. The decrease in ethinylestradiol concentration in plasma is biphasic.

Steady-state concentration. C_ss is established during the second half of the first cycle of taking the drug, with the concentration of ethinylestradiol increasing by approximately 1.4-2.1 times.

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;
• Contraception and treatment of moderate acne vulgaris;
• Contraception and treatment of severe PMS.

ICD codes

Dosage Regimen

The tablets are taken orally in the order indicated on the package, every day at approximately the same time, with a small amount of water. One tablet should be taken daily continuously for 28 days. Taking tablets from the next package should be started on the day after taking the last tablet from the previous package.

Withdrawal bleeding usually begins on the 2nd-3rd day after starting the inactive tablets and may not have ended before starting the tablets from the new package.

Starting the drug

If no hormonal contraceptives were taken in the previous month, the use of the drug is started on the 1st day of the menstrual cycle (i.e., on the 1st day of menstrual bleeding). Starting on the 2nd-5th day of the menstrual cycle is allowed, 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 contraceptives (COCs, vaginal ring, or contraceptive patch)

It is preferable to start taking Modelle^® Trend on the day after taking the last active tablet from the previous package, but in no case later than the day after taking the last inactive tablet (for drugs containing 28 tablets per package). Taking Modelle^® Trend 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 progestogen-only contraceptives (“mini-pills”, injectable forms, implant, or intrauterine systems (IUS) with controlled release of progestogen)

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

After a first-trimester abortion

The drug can be started immediately – on the day of the abortion. If this condition is met, the woman does not need additional contraceptive methods.

After childbirth or a second-trimester abortion

It is recommended to start taking the drug on the 21st-28th day after childbirth (in the absence of breastfeeding) or a second-trimester abortion. If started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if the woman has already been sexually active, pregnancy should be excluded before starting Modelle^® Trend or it is necessary to wait for the first menstruation.

Taking missed tablets

Missing inactive tablets can be ignored. However, they should be discarded to avoid accidentally extending the period of taking inactive tablets. The following recommendations apply only to missing active tablets. If the delay in taking the drug is less than 24 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, and the next ones should be taken at the usual time. If the delay in taking the tablets is more than 24 hours, contraceptive protection may be reduced. The more tablets are missed and the closer the missed tablets are to the phase of taking inactive tablets, the higher the likelihood of pregnancy. In this case, the following two basic rules can be followed

• Taking the drug should never be interrupted for more than 7 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 active tablets is more than 24 hours, the following can be recommended.

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 (e.g., a condom) should be used for the next 7 days. If sexual intercourse occurred within 7 days 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 (e.g., a condom) for 7 days.

Third week of drug use

The risk of pregnancy increases due to the upcoming intake of inactive tablets. One of the following two options should be strictly adhered to. In this case, if all tablets were taken correctly during the 7 days preceding the first missed tablet, 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 (e.g., a condom) for 7 days.

1. The last missed tablet should be taken as soon as possible, as soon as the woman remembers (even if this means taking two tablets at the same time). The next tablets are taken at the usual time until the active tablets in the package are finished. The four inactive tablets should be discarded and taking tablets from the next package should be started immediately. Withdrawal bleeding is unlikely until the active tablets in the second package are finished, but spotting and breakthrough bleeding may occur during tablet intake.

2. Taking tablets from the current package can also be interrupted. Then the woman should take a break of no more than 4 days, including the days of missing tablets, and then start taking the drug from a new package.

If a woman missed active tablets and withdrawal bleeding did not occur during the intake of inactive tablets, 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 an active tablet, one should be guided by the recommendations for missed tablets. If a woman does not want to change her usual regimen and shift the start of menstruation to another day of the week, an additional active tablet should be taken from another package.

Changing the day of onset of withdrawal bleeding

To delay the onset of withdrawal bleeding, a woman should continue taking tablets from the next package of Modelle^® Trend, skipping the inactive tablets from the current package. Thus, the cycle can be extended as desired for any period until the active tablets from the second package are finished. While taking the drug from the second package, a woman may experience spotting or breakthrough uterine bleeding. Regular intake of Modelle^® Trend is resumed after the end of the phase of taking inactive tablets.

To shift the start of withdrawal bleeding to another day of the week, a woman should shorten the next phase of taking inactive tablets by the desired number of days. The shorter the interval, the higher the risk that there will be no withdrawal bleeding, and subsequently spotting and breakthrough bleeding will be noted during the intake of the second package (just as in the case when she would like to delay the start of menstruation).

Additional information for special patient categories

Use in children. The efficacy and safety of the drug as a contraceptive have been studied in women of reproductive age. Use of the drug before menarche is not indicated.

Use in the elderly. After the onset of menopause, Modelle^® Trend 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 and for 3 months after these parameters return to normal).

Use in renal impairment.Modelle^® Trend is contraindicated in acute renal failure and severe renal failure.

Adverse Reactions

The following most frequently reported adverse reactions in women using the Drospirenone+Ethinylestradiol combination for the indications “Contraception” and “Contraception and treatment of moderate acne vulgaris” are reported: nausea, breast pain, irregular uterine bleeding, vaginal bleeding of unspecified origin. These adverse reactions occurred in more than 3% of women. In women using Drospirenone+Ethinylestradiol for the indication “Contraception and treatment of severe premenstrual tension syndrome”, the following most common adverse reactions (in more than 10% of women) were reported: nausea, breast pain, irregular uterine bleeding. Serious adverse reactions are arterial and venous thromboembolism.

The frequency of adverse reactions identified during clinical studies of the Drospirenone+Ethinylestradiol combination is defined as follows: common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000). For adverse reactions identified only during post-marketing surveillance, the frequency of which cannot be estimated, “frequency unknown” is indicated.

Infections and infestations rare – oral candidiasis, candidal vulvovaginitis.

Blood and lymphatic system disorders rare – anemia, thrombocytopenia.

Immune system disorders rare – allergic reactions; frequency unknown – hypersensitivity reactions.

Metabolism and nutrition disorders rare – increased appetite, anorexia, hyperkalemia, hyponatremia.

Psychiatric disorders common – emotional lability, depression/depressed mood; uncommon – decreased/loss of libido, somnolence; rare – anorgasmia, insomnia.

Nervous system disorders common – headache; uncommon – dizziness, paresthesia; rare – vestibular dizziness, tremor.

Eye disorders rare – conjunctivitis, dry eye, visual impairment.

Cardiac disorders uncommon – migraine, varicose veins, increased blood pressure; rare – tachycardia, phlebitis, vascular disease, epistaxis, syncope, venous or arterial thromboembolism*.

Gastrointestinal disorders common – nausea; uncommon – abdominal pain, vomiting, dyspepsia, flatulence, gastritis, diarrhea; rare – abdominal distension, gastrointestinal disorder, feeling of abdominal fullness, hiatal hernia, constipation, dry mouth, biliary colic, cholecystitis.

Skin and subcutaneous tissue disorders uncommon – acne, pruritus, rash; rare – chloasma, eczema, alopecia, acneiform dermatitis, dry skin, erythema nodosum, hypertrichosis, striae, contact dermatitis, photodermatitis; frequency unknown – erythema multiforme.

Musculoskeletal and connective tissue disorders uncommon – back pain, pain in extremity, muscle spasms.

Reproductive system and breast disorders common – breast tenderness, acyclic bleeding**, absence of withdrawal bleeding; uncommon – pelvic pain, breast enlargement, fibrocystic breast disease, genital discharge, “hot flushes”, vaginitis, painful withdrawal bleeding, scanty withdrawal bleeding, vaginal dryness, abnormal Pap smear; rare – dyspareunia, vulvovaginitis, postcoital bleeding, breast cyst, breast hyperplasia, breast neoplasm, cervical polyp, endometrial atrophy, ovarian cyst, uterine enlargement.

Investigations uncommon – weight increased; rare – weight decreased.

General disorders and administration site conditions uncommon – asthenia, hyperhidrosis, edema (generalized edema, peripheral edema, facial edema); rare – malaise.

* venous or arterial thromboembolism includes occlusion of peripheral deep veins; thrombosis and thromboembolism/occlusion of pulmonary vessels; myocardial infarction, cerebral infarction and hemorrhagic stroke.

** during continuous treatment, the irregularity of bleeding usually decreases.

The following adverse reactions have been reported in women using COCs with very rare frequency or with delayed symptoms, which are believed to be possibly associated with COC use:

• Breast cancer;
• Liver tumors (benign and malignant);
• Erythema nodosum;
• Increased blood pressure;
• Pancreatitis in women with hypertriglyceridemia;
• Onset or worsening of conditions whose association with COC use is not definitively established: porphyria, SLE, herpes gestationis, Sydenham’s chorea, hemolytic-uremic syndrome, cholestatic jaundice and/or pruritus associated with cholestasis; cholelithiasis; otosclerosis with hearing impairment;
• Impaired liver function;
• Changes in glucose tolerance and development of insulin resistance;
• Chloasma;
• Crohn’s disease, ulcerative colitis;
• Hypersensitivity reactions (including skin rash, urticaria).

In women with hereditary angioedema, estrogen administration may induce or exacerbate its symptoms.

Contraindications

• Current or history of thrombosis (venous and arterial) (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular events);
• Current or history of prothrombotic conditions (including transient ischemic attacks, atrial fibrillation, angina pectoris);
• Identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Current or history of migraine with focal neurological symptoms;
• Diabetes mellitus with vascular complications;
• Multiple or pronounced risk factors for venous or arterial thrombosis (including complicated valvular heart disease, atrial fibrillation, cerebrovascular or coronary artery disease; uncontrolled arterial hypertension, prolonged immobilization, major surgery, surgery on lower limbs, extensive trauma, smoking at age over 35 years, obesity with BMI >30 kg/m²);
• Current or history of pancreatitis with severe hypertriglyceridemia;
• Hepatic failure and severe liver diseases (until liver function tests normalize and for 3 months after these parameters return to normal);
• Current or history of liver tumors (benign or malignant);
• Acute renal failure or severe renal failure;
• Identified hormone-dependent malignant diseases (including of the genital organs or breasts) or suspicion thereof;
• Vaginal bleeding of unknown origin;
• Pregnancy or suspected pregnancy;
• Period of lactation (breastfeeding);
• Hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome;
• Hypersensitivity to drug components.

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

With caution

The potential risk and expected benefit of using MODELL^® TREND 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 first-degree relative), age over 35 years in non-smoking women;
• Other diseases in which peripheral circulation disorders may be noted: diabetes mellitus without diabetic angiopathy, systemic lupus erythematosus (SLE), hemolytic-uremic syndrome, Crohn’s disease or ulcerative colitis, sickle cell anemia, superficial phlebitis;
• Hereditary angioedema;
• Hypertriglyceridemia;
• Liver diseases not classified as contraindications (see section “Contraindications”);
• Diseases that first occurred or worsened during pregnancy or during previous use of sex hormones (e.g., cholestasis-associated jaundice and/or pruritus, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes gestationis, Sydenham’s chorea);
• Postpartum period.

Use in Pregnancy and Lactation

Pregnancy. The use of MODELL^® TREND is contraindicated during pregnancy. If pregnancy is detected while using MODELL^® TREND, 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 related to their pharmacological action. In particular, reproductive toxicity studies in animals revealed embryotoxic and fetotoxic effects, but these effects were considered species-specific. At animal exposure levels exceeding the corresponding levels in patients taking Drospirenone and Ethinylestradiol, an effect on sex differentiation of rat embryos was observed, which was absent in small monkeys. Based on data from 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 COC use during pregnancy has not provided evidence of adverse effects in humans. Data on the outcomes of MODELL^® TREND use 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 available.

Breastfeeding period. The use of MODELL^® TREND is contraindicated during breastfeeding. COCs may reduce the amount of breast milk and change its composition, so their use is not recommended until breastfeeding is discontinued. A small amount of sex hormones and/or their metabolites may be excreted in milk.

Use in Hepatic Impairment

The use of the drug is contraindicated in hepatic failure and severe liver diseases (until liver function tests normalize and for 3 months after these parameters return to normal), current or history of liver tumors (benign or malignant).

The drug should be prescribed with caution in liver diseases not classified as contraindications.

Use in Renal Impairment

The drug is contraindicated in acute renal failure and severe renal failure.

Pediatric Use

The use of the drug before menarche is not indicated.

Geriatric Use

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

Special Precautions

Medical examinations

Before starting or resuming the use of MODELL^® TREND, it is necessary to review the woman’s personal and family history, conduct a thorough general medical examination (including measurement of blood pressure, heart rate, determination of BMI) and a gynecological examination, including breast examination and cytological examination of a cervical smear (Pap 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 conducted at least once every 6 months.

The woman should be informed that MODELL^® TREND 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, the potential risk and expected benefit of COC use 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 system diseases

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. The risk is especially high during initial use of COCs or resumption of use of the same or different COCs (after a break in drug use of 4 weeks or more). Data from a large prospective study involving 3 patient groups show that the risk is highest mainly during the first 3 months.

The overall risk of VTE in women taking low-dose COCs (containing less than 50 mcg ethinylestradiol) is 2-3 times higher than in non-pregnant women 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, manifesting as deep vein thrombosis or pulmonary embolism (PE), 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 relationship 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 PE are as follows: 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 unilateral or bilateral 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 bluish discoloration of the limbs, “acute abdomen” symptom complex.

Symptoms of myocardial infarction include: pain; discomfort; feeling of pressure, heaviness, squeezing, or fullness in the chest, in the arm or behind the breastbone; discomfort in the left half of the chest radiating to the back, jaw, larynx, arm, epigastric region; cold sweat, nausea, vomiting, or dizziness, severe weakness, feeling of anxiety, or shortness of breath; sensation of rapid or irregular heartbeat. Arterial thromboembolism can be life-threatening or fatal.

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

• With age;
• In smokers (with increasing number of cigarettes or increasing age, the risk increases, especially in women over 35 years old);

In the presence of

• Obesity (BMI > 30 kg/m²);
• 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 COC use;
• Prolonged immobilization, major surgery, any surgery on the lower limbs, or extensive trauma. In these situations, it is necessary to discontinue COC use (in case of planned surgery, at least 4 weeks before it) and not resume intake until 2 weeks after the end of immobilization;
• Dyslipoproteinemia;
• Arterial hypertension;
• Migraine;
• Heart valve diseases;
• 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 may also be noted 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 COC use (which may precede cerebrovascular events) should be grounds 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, 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 may 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 oral contraceptives (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 MODELL^® TREND.

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 association with COC use has not been proven. There are conflicting data regarding the extent to which these findings are related to screening for cervical pathology or to sexual behavior characteristics (less frequent use of barrier contraceptive 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 discontinuation of 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 COC use has not been proven. The observed increase in risk may also be a consequence of close 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 in the differential diagnosis. Tumors can be life-threatening or fatal.

Other Conditions

Clinical studies have shown no effect of drospirenone on plasma potassium concentration in women with mild to moderate renal insufficiency. Theoretically, there is a risk of hyperkalemia in women with impaired renal function and baseline potassium levels at the upper limit of normal or while taking medications that cause potassium retention in the body.

In women with hypertriglyceridemia (or a family history of this condition), the risk of pancreatitis may increase while taking combined oral contraceptives (COCs).

Although a slight increase in blood pressure (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 initiated. COC use 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 with the use of COCs, but their association with COC use has not been proven: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus (SLE); hemolytic-uremic syndrome; Sydenham’s chorea; herpes gestationis; 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 disorders, it may be necessary to discontinue the drug until liver function tests return to normal. Recurrent cholestatic jaundice, which first developed during pregnancy or during previous use of sex hormones, requires discontinuation of COCs.

Although COCs can affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in women with diabetes using low-dose COCs (containing <50 mcg ethinylestradiol). Nevertheless, women with diabetes 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 should avoid prolonged sun exposure and ultraviolet radiation while using COCs.

Reduced Efficacy

The efficacy of COCs may be reduced if active tablets are missed, or as a result of vomiting, diarrhea, or 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 evaluation of any irregular bleeding should be performed only after an adaptation period of approximately 3 cycles. If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be performed to rule out malignant neoplasms or pregnancy.

In some women, withdrawal bleeding may not occur during the break in taking active tablets. If the COC was taken as directed, pregnancy is unlikely. However, if the COC was taken irregularly before, or if two consecutive withdrawal bleeds are absent, pregnancy must be ruled out before continuing the drug.

Effect on Laboratory Test Results

Taking COCs may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, and adrenal function, the content of transport proteins in plasma, parameters of carbohydrate metabolism, and coagulation and fibrinolysis parameters. The changes usually remain within the normal range.

Drospirenone increases plasma renin and aldosterone concentrations, which is associated with its antimineralocorticoid effect.

Effect on the Ability to Drive and Operate Machinery

No effect on the ability to drive vehicles and operate machinery has been identified.

Overdose

No serious adverse effects from overdose have been reported.

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

Treatment symptomatic therapy should be administered; there is no specific antidote.

Drug Interactions

Interactions of oral contraceptives with other medicinal products may lead to breakthrough bleeding and/or reduced contraceptive reliability. Women taking these drugs should temporarily use barrier methods of contraception in addition to MODELL^® TREND or choose another method of contraception.

Medicinal Products that Reduce the Efficacy of MODELL^® TREND

The use of drugs that induce hepatic microsomal enzymes may lead to an increase in the clearance of sex hormones, which in turn can 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.

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

During the use of drugs that affect hepatic microsomal enzymes and for 28 days after their discontinuation, an additional barrier method of contraception should be used.

Some antibiotics (e.g., penicillins and tetracyclines) 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, an additional barrier method of contraception should be used. If during these 7 days of using a barrier method the active tablets run out, the inactive tablets from the current pack should be skipped and the active tablets from the next pack of MODELL^® TREND should be started.

Other Interactions

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

COCs may affect the metabolism of other medicinal products, 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 an 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 plasma potassium concentration in women receiving MODELL^® TREND concurrently with other drugs that may increase plasma potassium concentration. These drugs include ACE inhibitors, angiotensin II receptor antagonists, some anti-inflammatory drugs, potassium-sparing diuretics, and aldosterone antagonists. However, in studies investigating the interaction of drospirenone with ACE inhibitors or indomethacin, no significant difference in plasma 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 – 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.