Evra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EVRA®

Composition:

Active substances: 1 patch with an area of 20 cm² contains norelgestromin 6.0 mg, ethinylestradiol 0.60 mg; each patch releases 203 μg of norelgestromin and 33.9 μg of ethinylestradiol over 24 hours;

Excipients: adhesive mixture of polyisobutylene and polybutene, lauryl lactate, crospovidone.

Pharmaceutical form. Patch – transdermal therapeutic system (TTS).

Main physicochemical characteristics: square transdermal system with a matte, skin-colored backing, rounded corners, a transparent removable film, and a colorless adhesive (adhesive) layer. The system is packaged in an opaque white pouch with appropriate labeling printed on it.

Pharmacotherapeutic group. Hormonal contraceptives for systemic use.

ATC code G03A A13.

Pharmacological properties.

Pharmacodynamics.

Evara® is a contraceptive that prevents fertilization by inhibiting gonadotropins through the estrogenic and progestogenic effects of ethinylestradiol and norelgestromin. The primary mechanism of action is the inhibition of ovulation, but changes in cervical mucus and the endometrium may also contribute to the drug's effectiveness.

Table 1

Pearl Indices

* Desogestrel 150 mcg + ethinylestradiol (EE) 20 mcg.

** Levonorgestrel 50 mcg + EE 30 mcg days 1–6, levonorgestrel 75 mcg + EE 40 mcg days 7–11, levonorgestrel 125 mcg + EE 30 mcg days 12–21.

To determine whether age, race, and body weight characteristics are associated with pregnancy, exploratory analyses were performed in Phase III studies (n = 3319). The analyses showed no association between patient age or race and pregnancy. Regarding body weight, 5 out of 15 pregnancies reported during use of the Evra® patch occurred in women whose initial body weight was equal to or exceeded 90 kg, representing < 3% of the study population. No association between body weight and pregnancy was observed in women with body weight below 90 kg. Although only 10–20% of the variability in pharmacokinetic data can be explained by body weight (see section "Pharmacokinetics"), the higher proportion of pregnancies in women with body weight of 90 kg or more was statistically significant, indicating that Evra® is less effective in these women.

When higher-dose oral contraceptives (50 mcg ethinylestradiol) are used, the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dose combined hormonal contraceptives remains to be confirmed.

Pharmacokinetics.

Absorption. Steady-state serum concentrations (plateau) of norelgestromin and ethinylestradiol are reached approximately 48 hours after application of the Evra® transdermal patch (TTS). The stable serum concentration of norelgestromin and ethinylestradiol during one week of patch use is approximately 0.8 ng/mL and 50 pg/mL, respectively. In multiple-dose studies of the transdermal patch (TTS) Evra®, serum concentrations (Css) and AUC increased slightly compared to levels during the first week of the first cycle.

The absorption of norelgestromin and ethinylestradiol after application of the Evra® patch (TTS) was studied under conditions of physical activity (sauna, jacuzzi, treadmill, and other aerobic exercises), as well as during cold-water bathing. Results indicated no significant changes in Css and AUC for norelgestromin compared to normal daily activities. For ethinylestradiol, these values increased slightly with physical exertion; however, Css levels remained within reference ranges. Cold water did not affect these parameters.

Results from a study evaluating the use of a single Evra® transdermal contraceptive patch (TTS) for 7 days versus 10 days showed that target Css values of norelgestromin and ethinylestradiol were maintained for 3 days of extended patch use (10 days), indicating that clinical efficacy of the TTS is preserved even if a woman replaces her Evra® patch up to 2 full days later than scheduled.

Distribution. Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin binds to albumin, while norgestrel binds primarily to sex hormone-binding globulin (SHBG). Ethinylestradiol is highly bound to serum albumin.

Biotransformation. Norelgestromin is metabolized in the liver to form the metabolite norgestrel, which primarily binds to sex hormone-binding globulin (SHBG), as well as various hydroxylated and conjugated metabolites. Ethinylestradiol is metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Elimination. After patch removal, the mean elimination half-life of norelgestromin and ethinylestradiol is approximately 28 hours and 17 hours, respectively. Metabolites of norelgestromin and ethinylestradiol are eliminated in urine and feces.

Transdermal versus oral contraceptives. The pharmacokinetic profiles of transdermal and oral combined contraceptives differ, and caution should be exercised when directly comparing pharmacokinetic parameters. In a comparison of the Evra® patch and oral contraceptives containing norgestimate (a prodrug of norelgestromin) 250 mcg/ethinylestradiol 35 mcg, Cmax values were approximately twice as high for NGM and EE in subjects taking oral contraceptives compared to corresponding values in the Evra® group, whereas total exposure (AUC and Css) was similar in subjects using the Evra® patch. Inter-subject variability (% CV) in pharmacokinetic parameters for norelgestromin and ethinylestradiol delivery from the Evra® patch was higher than that observed with oral contraceptives.

Effect of age, body weight, and body surface area

The effects of age, body weight, and body surface area on the pharmacokinetics of norelgestromin and ethinylestradiol were evaluated in 230 women across 9 pharmacokinetic studies of single 7-day use of the Evra® patch (TTS). Css and AUC values of norelgestromin and ethinylestradiol decreased slightly with increasing age, body weight, and body surface area. However, only a small portion (10–20%) of the total variability in the pharmacokinetics of norelgestromin and ethinylestradiol following Evra® patch use can be attributed to any one of these parameters.

Clinical characteristics.

Indications.

Contraception in women.

EVRA® is indicated for use in women of reproductive age. The safety and efficacy of the EVRA® transdermal patch (TTS) have been established only for women aged 18 to 45 years.

The decision to prescribe EVRA® should take into account individual risk factors, particularly regarding venous thromboembolism (VTE), considering the risk of VTE associated with EVRA® compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Contraindications.

Combined hormonal contraceptives (CHCs) must not be used if any of the following conditions are present. If any of these conditions occur during use of EVRA®, treatment must be discontinued immediately.

• Venous thromboembolism (VTE) or risk of its development:
  • venous thromboembolism (on anticoagulant therapy) or history of VTE [deep vein thrombosis (DVT) or pulmonary embolism (PE)];
  • inherited or acquired predisposition to venous thromboembolism, e.g., activated protein C resistance (including factor V Leiden), deficiency of antithrombin III, protein C, or protein S;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • increased risk of venous thromboembolism due to presence of multiple risk factors (see section "Special precautions").
• Arterial thromboembolism (ATE) or risk of its development:
  • arterial thromboembolism, including history (e.g., myocardial infarction), or prodromal stage of thrombosis (e.g., angina pectoris);
  • cerebrovascular disorders: acute cerebrovascular events, history of stroke, or prodromal stage of thrombosis (e.g., transient ischemic attack);
  • inherited or acquired predisposition to arterial thrombosis, e.g., hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • increased risk of arterial thromboembolism due to presence of multiple risk factors (see section "Special precautions") or any of the following serious risk factors:
• diabetes mellitus with vascular complications;
• severe arterial hypertension;
• severe dyslipoproteinemia.
• Hypersensitivity to the active substances of the medicinal product or to any of the excipients.
• Confirmed or suspected carcinoma of the breast.
• Endometrial cancer or other confirmed or suspected estrogen-dependent neoplasms.
• Impaired liver function due to acute or chronic hepatocellular disease.
• Hepatic adenoma or carcinoma.
• Undiagnosed genital bleeding.
• Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, medicinal products containing glecaprevir/pibrentasvir, or sofosbuvir/velpatasvir/voxilaprevir (see section "Interaction with other medicinal products and other types of interactions").

Special precautions.

Immediately after removing the EVRA® transdermal patch (TTS) from its pouch, it should be firmly applied to the skin.

To prevent deterioration of the adhesive properties of the EVRA® TTS, creams, lotions, or powders should not be applied to the area of skin where the patch is to be placed.

After removal, the patch still contains a significant amount of active substances. Residual hormones may harm the environment if released into water; therefore, used EVRA® patches (TTS) must be disposed of carefully. To do this, peel off the adhesive strip from the outer side of the pouch. The used EVRA® patch (TTS) should be placed into the pouch with its adhesive side facing the colored area of the pouch and gently pressed to seal. Any unused materials or waste must be disposed of according to local requirements. Used EVRA® patches (TTS) must not be thrown into the toilet or sewage system.

Interaction with other medicinal products and other types of interactions.

The package leaflet of the concomitant medicinal product should be consulted to determine possible interactions.

Pharmacodynamic interactions

During clinical trials involving patients receiving medications for the treatment of hepatitis C virus (HCV) infection containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, alanine aminotransferase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed. This occurred more frequently in women receiving medications containing ethinylestradiol, including combined hormonal contraceptives (CHCs). Additionally, ALT elevations were also observed in women receiving ethinylestradiol-containing medications, such as CHCs, when treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section "Contraindications"). Therefore, women using EVRA® should start using alternative methods of contraception (e.g., progestogen-only contraceptives or non-hormonal contraceptive methods) before initiating treatment with these regimens. Use of EVRA® may be resumed 2 weeks after completion of such combination therapy.

Effect of other medicinal products on EVRA®

Interactions may occur with medicinal products that induce hepatic enzymes, leading to increased clearance of sex hormones, which in turn may result in breakthrough bleeding and/or loss of contraceptive efficacy. The following interactions have been reported.

Medicinal products that increase CHC clearance (reduced CHC efficacy due to enzyme induction): barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, modafinil, HIV drugs ritonavir, nevirapine, efavirenz, and possibly felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St. John's wort (Hypericum perforatum).

Risk management

Elevated enzyme levels may occur within a few days after starting treatment. Maximum enzyme induction generally occurs within 10 days and persists for up to 4 weeks after discontinuation of therapy.

Short-term treatment

Women undergoing short-term treatment with any of the listed enzyme-inducing medicinal products or individual active substances should temporarily use a barrier method in addition to EVRA® during concomitant use of the medicinal product and for 28 days after its discontinuation.

If concomitant use of the medicinal product continues beyond the end of one week of patch application, the next transdermal patch should be applied without the usual break in patch use.

Long-term treatment

Women undergoing long-term treatment with any of the listed medicinal products should be advised to use another reliable non-hormonal method of contraception.

Medicinal products affecting CHC clearance

When used concomitantly with CHCs, various combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs), including combinations of medications for the treatment of hepatitis C virus (HCV) infection, may increase or decrease plasma concentrations of estrogen and progestins. In some cases, the clinical significance of such concentration changes may be important.

Therefore, before concomitant use, the package leaflets of medications for the treatment of HIV infection should be consulted regarding possible interactions and related recommendations. In case of doubt, women using protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs) should use an additional barrier method of contraception.

Inhibition of ethinylestradiol metabolism

Etoricoxib has been shown to increase plasma levels of EE (by 50–60%) when co-administered with oral triphasic hormonal contraceptives. Etoricoxib is believed to increase EE levels by inhibiting sulfotransferase activity, thereby inhibiting EE metabolism.

Effect of EVRA® on other medicinal products

Hormonal contraceptives may affect the metabolism of certain other active substances. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine). Dose adjustment of the concomitant medicinal product may be necessary.

Lamotrigine: combined hormonal contraceptives significantly reduce lamotrigine plasma concentrations when used concomitantly, due to induction of lamotrigine glucuronidation. This may reduce therapeutic effect; dose adjustment of lamotrigine may be required.

Laboratory parameters

Use of hormonal contraceptives may influence the results of certain laboratory tests, including liver, thyroid, adrenal, and renal function biochemical parameters, plasma protein (carrier) levels such as corticosteroid-binding globulin, lipid/fraction parameters, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes generally remain within normal laboratory ranges.

Special precautions for use.

If any of the conditions/factors listed below are present, the benefits of using the contraceptive patch Evra® and the potential risks for each individual woman should be carefully considered and discussed with the woman before she decides to start using the Evra® patch.

The woman should be informed that if any of these conditions or risk factors worsen, deteriorate, or appear for the first time, she must consult her physician, who will decide whether the use of the product should be discontinued.

There is no clinical evidence that the transdermal patch is safer in any respect compared to combined oral contraceptives.

Evra® is contraindicated during pregnancy (see section "Use during pregnancy or breastfeeding").

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive increases the risk of venous thromboembolism compared to non-use. Contraceptives containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Other contraceptives, such as Evra®, may carry approximately twice the risk of VTE. The decision to use Evra® should only be made after discussing with the woman, ensuring she understands the risk of VTE associated with using the Evra® patch, how her individual risk factors affect this risk, and that the risk of VTE is highest during the first year of using the patch. There is also some evidence that the risk increases when combined oral contraceptives (COCs) are restarted after a break of 4 weeks or more.

Approximately 2 out of 10,000 women who do not use COCs and are not pregnant will develop VTE within one year. However, for individual women, this risk may be significantly higher depending on their individual risk factors (see below).

Among 10,000 women using low-dose COCs containing levonorgestrel, approximately 61 will develop VTE within one year. According to studies, the incidence of VTE in women using the Evra® patch is approximately 6–12 cases per 10,000 women per year, which is about twice the risk compared to women using COCs containing levonorgestrel.

The number of VTE cases per year with COC use is lower than the number of VTE cases occurring in women during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

1 Median range of 5 to 7 per 10,000 woman-years based on relative risk of COCs containing levonorgestrel compared to non-use – from 2.3 to 3.6.

Very rare cases of thrombosis in other blood vessels, such as hepatic, mesenteric, renal veins, or retinal veins/arteries, have been reported among women using COCs.

Risk factors for VTE

The risk of developing venous thromboembolic complications in women using COCs is substantially increased in the presence of additional risk factors, especially multiple ones (see Table 2).

The use of the Evra® patch is contraindicated in women who have multiple risk factors for venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the total risk may be greater than the sum of individual risks – in such cases, the overall VTE risk in the woman should be carefully evaluated. If the risk-benefit balance is considered unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for VTE

There is no general consensus regarding the possible role of varicose veins and superficial thrombophlebitis in the etiology of venous thromboembolism.

An increased risk of thromboembolism during pregnancy, and particularly during the 6-week period following childbirth, should be taken into account (for additional information, see section "Use in pregnancy or breastfeeding").

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women using combined contraceptives should immediately inform their physician if symptoms of thrombosis occur.

Symptoms of deep vein thrombosis (DVT) include:

• Unilateral swelling of the leg and/or foot, or swelling along a vein in the leg;
• Pain or tenderness in the leg, which may only be felt while standing or walking;
• Increased warmth in the affected leg, redness or paleness of the skin on the leg.

Symptoms of pulmonary embolism (PE) include:

• Sudden onset of breathlessness or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis (coughing up blood);
• Sharp chest pain;
• Pre-syncope or dizziness;
• Rapid or irregular heartbeat.

Some of these symptoms are non-specific (e.g., breathlessness, cough) and may be mistaken for signs of another, more common and less serious condition (e.g., respiratory tract infection).

Other signs of vascular occlusion include: sudden pain, swelling, and mild cyanosis of a limb.

If occlusion occurs in ocular vessels, symptoms may range from painless deterioration of vision to sudden vision loss. Sometimes vision loss occurs almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of combined hormonal contraceptives (CHCs) with an increased risk of arterial thromboembolism (myocardial infarction) or cerebrovascular disorders (e.g., transient ischemic attack, stroke). Arterial thromboembolism can be fatal.

ATE risk factors

The risk of arterial thromboembolic complications or cerebrovascular events in patients using CHCs increases in women with risk factors (see Table 3). The use of the Evra® patch is contraindicated in women who have serious or multiple risk factors for ATE (see section "Contraindications"). If a woman has more than one risk factor, the overall risk may be greater than the sum of individual factors— in such cases, the overall ATE risk in the woman should be carefully considered. If the risk-benefit ratio is considered unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 3

ATE Risk Factors

Arterial Thromboembolism (ATE)

Women using combined oral contraceptives should immediately inform their physician if symptoms of ATE occur.

Symptoms of cerebrovascular accident include:

• sudden weakness or numbness of the face, arm, or leg, especially on one side of the body;
• sudden difficulty walking, dizziness, loss of balance or coordination;
• sudden confusion, trouble speaking or understanding speech;
• sudden vision problems in one or both eyes;
• sudden, severe, or prolonged headache without a known cause;
• loss of consciousness or syncope with or without seizures.

Transient symptoms may indicate a transient ischemic attack.

Symptoms of myocardial infarction include:

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

Women using combined oral contraceptives should immediately report possible symptoms of thrombosis to their physician. In case of suspected or confirmed thrombosis, hormonal contraceptives should be discontinued. An adequate alternative contraception should be initiated, considering the teratogenicity of anticoagulant therapy (e.g., coumarins).

Tumors

Some epidemiological studies have reported an increased risk of cervical cancer with long-term use of COCs, but it has not been established to what extent this finding is influenced by a combination of sexual behavior and other factors such as human papillomavirus (HPV).

A meta-analysis of 54 epidemiological studies showed a slightly increased risk (relative risk = 1.24) of developing breast cancer in women using COCs. The risk gradually decreases over 10 years after discontinuation of COCs. Since breast cancer is rare among women under 40 years of age, the number of breast cancer diagnoses among current or former COC users is low compared to the overall risk of breast cancer. Breast cancers diagnosed in long-term COC users are generally less clinically advanced than those in women who have never used contraceptives.

The increased risk may be related to earlier diagnosis of breast cancer among COC users, the biological effects of COCs, or a combination of both factors.

Rare cases of benign liver tumors and even rarer cases of malignant liver tumors have been reported in patients using COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhage. Therefore, liver tumor should be included in the differential diagnosis in women using the medicinal product Evra® who present with acute abdominal pain, hepatomegaly, or signs of intra-abdominal bleeding.

Psychiatric Disorders

Mood depression and depression are known side effects of hormonal contraceptive use (see section "Adverse Reactions"). Depression can be severe and is a well-known risk factor for suicidal behavior and suicide. Women should be instructed to consult their physician if mood changes or symptoms of depression occur, including those emerging shortly after starting COC use.

Other Conditions

Contraceptive efficacy may be reduced in women with body weight equal to or exceeding 90 kg (see sections "Dosage and Administration" and "Pharmacodynamics").

Women with hypertriglyceridemia or a family history of this condition have an increased risk of pancreatitis when using combined hormonal contraceptives.

Although a slight increase in blood pressure has been observed in many women using hormonal contraceptives, clinically significant hypertension is rare. A causal relationship between hormonal contraceptive use and clinical arterial hypertension has not been established. If during the use of combined hormonal contraceptives, a persistent or marked increase in blood pressure occurs in women with pre-existing hypertension and does not respond to antihypertensive treatment, combined hormonal contraceptives should be discontinued. Combined hormonal contraceptives may be resumed if antihypertensive therapy successfully controls blood pressure to normal levels.

The following conditions have been reported to occur or worsen either during pregnancy or with COC use, but evidence of a causal relationship with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallbladder disease, including cholecystitis and cholelithiasis; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

Acute or chronic liver function disorders may require discontinuation of combined hormonal contraception until liver markers return to normal. Recurrence of pruritus related to cholestasis, previously experienced during pregnancy or prior use of sex steroids, requires discontinuation of combined hormonal contraceptives.

Although combined hormonal contraceptives may affect peripheral insulin resistance and glucose tolerance, there is no evidence to suggest a need for changes in therapeutic regimen for diabetes during use of hormonal contraceptives. However, women with diabetes should be closely monitored, especially during the initial stages of using Evra®.

Exacerbations of endogenous depression, epilepsy, Crohn's disease, or ulcerative colitis have been reported during COC use.

Exogenous estrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

Chloasma may occur during hormonal contraceptive use, particularly in women with a history of chloasma during pregnancy. Patients with a predisposition to chloasma should avoid sun exposure or UV radiation while using Evra®. Chloasma is often irreversible.

Medical Examination/Consultation

Before initiating or resuming use of Evra®, a complete medical and family history should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination performed to identify contraindications (see section "Contraindications") and precautions (see section "Special Warnings and Precautions for Use"). It is important to inform women about venous and arterial thrombosis, including the risk associated with using the Evra® patch compared to other CHCs, symptoms of VTE and ATE, known risk factors, and actions to take in case of suspected thrombosis.

Women should be instructed to carefully read the patient information leaflet and follow the provided recommendations. The frequency and extent of follow-up examinations should be determined according to established clinical practice and the woman’s clinical condition.

Women should be informed that hormonal contraceptives do not protect against HIV infection (AIDS) or other sexually transmitted diseases.

Changes in Bleeding Pattern

As with other combined hormonal contraceptives, irregular bleeding (spotting or breakthrough bleeding) may occur during the first months of use. Therefore, specialist consultation may only be useful after an adaptation period of approximately three cycles. If breakthrough bleeding persists or occurs after previously regular cycles while using Evra® according to instructions, other causes should be considered. Non-hormonal causes should be considered, and if necessary, diagnostic measures should be taken to exclude organic disease or pregnancy. These measures may include curettage. In some women, menstruation may not occur during the patch-free interval. If Evra® has been used according to the instructions in section "Dosage and Administration," pregnancy is unlikely. Pregnancy cannot be excluded if Evra® has not been used according to instructions before the first or second missed period.

Amenorrhea or oligomenorrhea may occur in some women after discontinuation of hormonal contraception, particularly if these conditions were present in the past.

Use during Pregnancy or Breastfeeding

Pregnancy

The Evra® patch is not indicated for use during pregnancy.

Epidemiological studies have shown no increased risk of congenital malformations in children born to women who used hormonal contraceptives prior to pregnancy. Most recent studies have also not shown teratogenic effects with inadvertent use of oral hormonal contraceptives in early pregnancy.

Limited data on the use of Evra® in pregnant women do not allow conclusions regarding the safety of this product during pregnancy.

Animal studies have shown adverse effects during pregnancy or lactation. Therefore, the risk of adverse reactions due to hormonal disturbance with Evra® should not be excluded, although the overall experience with combined oral contraceptives during pregnancy has not shown any signs of adverse effects in humans.

If pregnancy occurs during use of the Evra® patch, treatment should be discontinued immediately.

The increased risk of VTE in the postpartum period should be considered when deciding on resuming use of the Evra® patch (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Breastfeeding

The use of combined hormonal contraceptives in the postpartum period may negatively affect the quantity and quality of breast milk. Mothers who are breastfeeding should not use the Evra® patch (TTS) until breastfeeding has ended.

Fertility

After discontinuation of Evra®, a delay in fertility may occur.

Ability to Influence Reaction Speed in Driving and Operating Machinery

The Evra® patch (TTS) has no effect or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Doses

To achieve maximum contraceptive effectiveness, a woman must use the Evra® transdermal patch (TTS) strictly following the instructions provided below in the section "How to Start Using the Evra® Transdermal Patch (TTS)".

Only one Evra® transdermal patch (TTS) may be used at a time.

Each used Evra® transdermal patch (TTS) must be removed and immediately replaced with a new one on the same day of the week—the "patch change day"—on days 8 and 15 of the menstrual cycle. The used patch may be replaced at any time during the "patch change day." During the 4th week, starting from day 22 of the cycle, the Evra® transdermal patch (TTS) is not used.

A new contraceptive cycle begins the day after the end of the 4th week; the next Evra® transdermal patch (TTS) should be applied even if withdrawal bleeding has not occurred or has not yet ended.

The break in using the Evra® transdermal patch (TTS) must not exceed 7 days. If the break lasts longer than 7 days, a woman may not be protected against pregnancy. In such cases, a barrier method of contraception must be used additionally for 7 days, as the risk of ovulation increases with each day exceeding the recommended duration of the patch-free interval. Pregnancy should be considered possible if intercourse occurs during such a period.

Special Patient Categories

Body weight 90 kg or more: In women with body weight of 90 kg or more, contraceptive effectiveness may be reduced.

Renal impairment: The use of Evra® in women with renal impairment has not been studied. There is no need to reduce the dose; however, data indicate a higher level of unbound fraction of ethinylestradiol, so Evra® should be used under medical supervision in this patient group.

Hepatic impairment: The use of Evra® in women with hepatic impairment has not been studied. Evra® is contraindicated in women with hepatic impairment (see section "Contraindications").

Elderly patients: Evra® is not intended for use as hormone replacement therapy in postmenopausal women.

Children: The safety and efficacy of the Evra® transdermal patch (TTS) have been established in women aged 18 years and older. Evra® is not recommended for use before the onset of first menstruation.

Method of Administration

The Evra® transdermal patch (TTS) should be applied to clean, dry, intact, and healthy skin on the buttocks, abdomen, outer surface of the upper arm, or upper torso, avoiding hairy areas, and on sites where it will not be irritated by tight-fitting clothing. The Evra® transdermal patch (TTS) must not be applied to the breasts or to areas of skin with redness, irritation, or cuts. To avoid possible skin irritation, each subsequent Evra® transdermal patch (TTS) should be applied to a different skin area, although this may be within the same anatomical region.

The Evra® transdermal patch (TTS) must be firmly pressed so that its edges adhere well to the skin.

To prevent reduced adhesive properties, cosmetics, creams, lotions, powders, or other topical products must not be applied to areas of skin where the patch is applied or will be applied.

A woman should inspect the transdermal patch daily to ensure it remains securely attached.

The Evra® transdermal patch (TTS) must not be cut, damaged, or altered in any way, as this may compromise contraceptive effectiveness.

Used transdermal patches must be disposed of according to the instructions provided in the section "Special Precautions."

How to Start Using the Evra® Transdermal Patch (TTS)?

If the woman has not used hormonal contraceptives during the previous menstrual cycle

Contraception with the Evra® transdermal patch (TTS) should be started on the first day of menstruation. Apply one Evra® transdermal patch (TTS) to the skin and wear it for one week (7 days). The day of applying the first Evra® transdermal patch (TTS) (Day 1/start day) determines the subsequent patch change days. Patch changes will occur on the same day each week (days 8, 15, 22 of the cycle, and day 1 of the next cycle). On day 22 of the cycle, remove the Evra® patch, and during the fourth week of the cycle, the woman does not use the Evra® transdermal patch (TTS).

If a woman starts using the transdermal patch (TTS) Evra® not on the first day of the cycle, a barrier method of contraception should be used simultaneously for the first 7 days of the first contraceptive cycle.

If switching from a combined oral contraceptive to the Evra® transdermal patch (TTS)

The Evra® transdermal patch (TTS) should be applied to the skin on the first day of menstruation that begins after stopping the combined oral contraceptive. If menstruation does not begin within 5 days after taking the last contraceptive tablet, pregnancy must be ruled out before starting Evra®. If Evra® is started later than the first day of menstruation, a barrier method of contraception must be used simultaneously for 7 days.

If more than 7 days have passed since the last contraceptive tablet was taken, ovulation may occur, and the woman should consult a physician before starting the Evra® transdermal patch (TTS). Sexual intercourse during this extended tablet-free interval may result in pregnancy.

If switching from a progestogen-only contraceptive to the Evra® transdermal patch (TTS)

A woman may switch from a progestogen-only contraceptive (on the day of implant removal or on the day of the next scheduled injection) to the Evra® transdermal patch (TTS) on any day, but a barrier method should be used during the first 7 days of Evra® use to enhance contraceptive effectiveness.

After abortion or miscarriage

The Evra® transdermal patch (TTS) may be started immediately after an abortion or miscarriage up to the 20th week of pregnancy. If a woman starts using the Evra® transdermal patch (TTS) immediately after an abortion or miscarriage, no additional contraceptive method is required. The woman should be aware that ovulation may occur within 10 days after an abortion or miscarriage.

After an abortion or miscarriage at or after the 20th week of pregnancy, the Evra® transdermal patch (TTS) may be started on day 21 after the abortion or miscarriage or on the first day of the first menstruation. The frequency of ovulation on day 21 after an abortion (at the 20th week of pregnancy) is unknown.

After childbirth

Women who are not breastfeeding may start using the Evra® transdermal patch (TTS) no earlier than 4 weeks after childbirth. If a woman starts using the Evra® transdermal patch (TTS) later, a barrier method of contraception should be used additionally during the first 7 days. If there has been sexual intercourse, the possibility of pregnancy must be ruled out before starting the Evra® transdermal patch (TTS), or the woman should wait for the first menstruation.

For information on use of the patch in breastfeeding women, see section "Use During Pregnancy or Breastfeeding."

In Case of Complete or Partial Detachment of the Evra® Transdermal Patch (TTS)

If the Evra® transdermal patch (TTS) becomes completely or partially detached, an insufficient amount of its active ingredients may enter the bloodstream.

Even in case of partial detachment of the Evra® transdermal patch (TTS):

• For less than 24 hours: The Evra® transdermal patch (TTS) should be reapplied to the same skin area or immediately replaced with a new Evra® transdermal patch (TTS). No additional contraception is needed. The next Evra® patch should be applied on the usual "patch change day";
• For more than 24 hours, or if the woman is unsure when the Evra® transdermal patch (TTS) became partially or completely detached: Pregnancy may occur. The woman should immediately start a new cycle by applying a new Evra® transdermal patch (TTS), considering this day as the first day of the new contraceptive cycle. A barrier method of contraception should be used simultaneously only during the first 7 days of the new cycle.

Do not attempt to reattach an Evra® transdermal patch (TTS) if it has lost its adhesive properties; instead, immediately apply a new Evra® transdermal patch (TTS). Additional adhesive tapes or dressings must not be used to secure the Evra® transdermal patch (TTS) in place.

If Scheduled Patch Change Days Are Missed

• At the beginning of any contraceptive cycle (Week 1/Day 1): The woman may not be protected against pregnancy: she should immediately apply the first Evra® transdermal patch (TTS) of the new cycle as soon as she remembers. This day is considered the new "Day 1," and the new "patch change day" is counted from this day. A non-hormonal contraceptive method should be used simultaneously during the first 7 days of the new cycle. If intercourse occurs during this prolonged period without using the Evra® transdermal patch (TTS), fertilization may occur.
• In the middle of the cycle (Week 2/Day 8 or Week 3/Day 15):
  • If 1 or 2 days (up to 48 hours) have passed since the scheduled patch change day, the woman should immediately apply a new Evra® transdermal patch (TTS). The next Evra® transdermal patch (TTS) should be applied on the usual "patch change day." If the woman has used the patch correctly during the 7 days preceding the first missed patch application day, no additional contraception is needed;
  • If more than 2 days (48 hours or more) have passed since the scheduled patch change day, the woman may not be protected against pregnancy. She should discontinue the current contraceptive cycle and immediately start a new 4-week cycle by applying a new Evra® transdermal patch (TTS). This day is considered the new "Day 1," and the "patch change day" is counted from this day. A barrier method of contraception should be used simultaneously during the first 7 days of the new cycle.
• At the end of the cycle (Week 4/Day 22): If the Evra® transdermal patch (TTS) has not been removed at the end of the 4th week (day 22), it should be removed as soon as possible. The next contraceptive cycle should start on the usual "patch change day," which is the day following day 28. No additional contraception is needed.

Changing the "Patch Change Day"

To delay menstruation by one cycle, the woman should apply a new Evra® patch at the beginning of the 4th week (day 22), thereby skipping the patch-free interval. Intermenstrual bleeding or spotting may occur. After 6 consecutive weeks of using the Evra® transdermal patch (TTS), a 7-day interval free from the Evra® transdermal patch (TTS) must be taken. After this interval, regular use of the product should be resumed.

If a woman wishes to change her patch change day, she should complete the current cycle and remove the third Evra® transdermal patch (TTS) on the scheduled day. During the patch-free week, she may choose a new patch change day by applying the first Evra® transdermal patch (TTS) of the next cycle on the desired day. The patch-free interval must in no case exceed 7 days. The shorter this interval, the higher the likelihood that the woman will not have the next menstruation, and intermenstrual bleeding or spotting may occur during the next contraceptive cycle.

In Case of Mild Skin Irritation

If the use of the Evra® transdermal patch (TTS) causes skin irritation, a new Evra® patch may be applied to another skin area and worn until the next "patch change day." Only one Evra® patch may be used at a time.

Children

The Evra® transdermal patch (TTS) is not recommended for use in children (under 18 years) due to insufficient data on safety and efficacy. The medicinal product Evra® is not recommended for use before the onset of first menstruation.

Overdose

No serious adverse reactions have been reported following accidental ingestion of large doses of oral contraceptives. Overdose may cause nausea or vomiting. Vaginal bleeding may occur in some women. In case of suspected overdose, the Evra® transdermal patch (TTS) should be removed and symptomatic treatment administered.

Adverse reactions.

The most common adverse reactions observed during clinical studies were headache, nausea, and breast tenderness, occurring in approximately 21%, 16.6%, and 15.9% of cases, respectively. Adverse reactions that may occur at the beginning of treatment but usually resolve after the first three cycles include spotting, breast tenderness, and nausea.

Women using COCs have an increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis, and pulmonary embolism (see section "Special precautions").

The safety of the Evra® patch (TTS) was evaluated in 3322 women who were sexually active and participated in phase III clinical studies assessing contraceptive efficacy. These women used contraception for 6 or 13 cycles (Evra® patch or an oral contraceptive for comparison), received at least one dose of the investigational drug, and provided information on adverse reactions. The adverse reactions observed during clinical studies and in the post-marketing period are listed in Table 3 below. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (frequency cannot be estimated from available data).

Table 4

Frequency of adverse reactions

*Adverse reactions identified during the post-marketing period.

**Including adverse reactions identified during clinical trials and the post-marketing period.

†See section "Special precautions".

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children. Do not store in a refrigerator or freezer.

Packaging.

1 patch in a pouch made of laminated paper and aluminum foil; 3 pouches in a transparent polymer film bag; 1 or 3 transparent bags (3 or 9 patches) together with special stickers for a calendar to mark the use of the patch (TTS) in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

Manufacture of the unpackaged product and primary packaging:

LTS Lohmann Therapie – Systeme AG / LTS Lohmann Therapie – Systeme AG.

Secondary packaging and batch release:

JSC "Gedeon Richter" / Gedeon Richter Plc.

Manufacturer's location and address of the place of business.

Lohmannstrasse 2, D-56626 Andernach, Germany / Lohmannstrasse 2, D-56626 Andernach, Germany.

H-1103, Budapest, Gyomroi ut. 19-21, Hungary / H-1103, Budapest, Gyomroi ut. 19-21, Hungary.