Evra patch TTS No. 3

Instructions for Evra patch TTS No. 3

Composition

active ingredients: 1 patch with an area of 20 cm2 contains norelgestromin 6.0 mg, ethinyl estradiol 0.60 mg; each patch releases 203 mcg of norelgestromin and 33.9 mcg of ethinyl estradiol over 24 hours;

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

Dosage form

The patch is a transdermal therapeutic system (TTS).

Main physicochemical properties: square transdermal system with a matte flesh-colored base, rounded corners, a transparent removable film and a colorless adhesive layer. The system is packaged in an opaque white bag, which is appropriately labeled.

Pharmacotherapeutic group

Hormonal contraceptives for systemic use.

ATX code G0ZA A13.

Pharmacological properties

Pharmacodynamics.

Evra® is a contraceptive that prevents fertilization by the mechanism of gonadotropin suppression through the estrogenic and progestogenic actions of ethinylestradiol and norelgestromin. The primary mechanism of action is the inhibition of ovulation, but changes in cervical mucus and endometrium may also enhance the effectiveness of the drug.

Table 1

Pearl Indices

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

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

Exploratory analyses were performed in the phase III studies (n = 3319) to determine whether population characteristics of age, race, and body weight were associated with pregnancy. The analyses did not show any association of patient age or race with pregnancy. Regarding body weight, 5 of the 15 pregnancies reported with Evra® were in women with a baseline body weight of 90 kg or more, representing < 3% of the study population. There was no association between body weight and pregnancy for women with a body weight of less than 90 kg. Although only 10–20% of the variability in pharmacokinetic data can be explained by body weight (see Pharmacokinetics), the higher proportion of pregnancies in women with a body weight of 90 kg or more was statistically significant, indicating that Evra® is less effective in these women.

Higher-dose COCs (50 mcg ethinylestradiol) appear to reduce the risk of endometrial and ovarian cancer. Whether this also applies to lower-dose combined hormonal contraceptives remains to be confirmed.

Pharmacokinetics.

Absorption. Steady-state serum concentrations of norelgestromin and ethinyl estradiol are reached approximately 48 hours after application of the Evra® transdermal patch. Steady-state concentrations of norelgestromin and ethinyl estradiol during 1 week of patch application are approximately 0.8 ng/mL and 50 pg/mL, respectively. In multiple-dose studies of the Evra® transdermal patch, serum concentrations (Css) and AUC are slightly increased relative to concentrations at week 1 of the 1st cycle.

The absorption of norelgestromin and ethinylestradiol after application of the Evra® transdermal patch (TTS) was studied in a sports club environment (sauna, jacuzzi, treadmill and other aerobic exercises), as well as in a cold water bath. The results showed that for norelgestromin there were no significant changes in Css and AUC compared to those under normal conditions. For ethinylestradiol, these values increased slightly during exercise; however, Css was within reference values. Cold water did not affect these parameters.

The results of a study of the use of a single contraceptive transdermal patch (TTC) Evra® for 7 days and 10 days showed that the target Css values of norelgestromin and ethinyl estradiol were maintained during 3 days of continued use of the Evra® patch (TTC) (10 days), i.e. the clinical efficacy of the TTC is maintained even if the woman changes the Evra® patch (TTC) 2 full days later than the planned date.

Biotransformation: Norelgestromin is metabolized in the liver to the metabolite norgestrel, which binds primarily 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 removal of the patch, the mean elimination half-lives of norelgestromin and ethinylestradiol are approximately 28 hours and 17 hours, respectively. Metabolites of norelgestromin and ethinylestradiol are eliminated in the urine and feces.

Transdermal and oral contraceptives. The pharmacokinetic profiles of transdermal and oral combined contraceptives are different, and caution should be exercised when directly comparing pharmacokinetic parameters. In a comparison of the Evra® patch (TTC) and an oral contraceptive containing norgestimate (a precursor of norelgestromin) 250 mcg/ethinyl estradiol 35 mcg, Cmax values were 2-fold higher for NMN and EE in subjects taking oral contraceptives compared to those in the Evra® group, while overall exposure (AUC and Css) were similar in subjects using the Evra® patch (TTC). The intersubject variability (%CV) for the pharmacokinetic parameters of norelgestromin and ethinyl estradiol delivery from the Evra® patch (TTC) was higher relative to that observed with oral contraceptives.

The influence of age, body weight and body surface area

The effects of age, body weight, and body surface area on the pharmacokinetics of norelgestromin and ethinyl estradiol were studied in 230 women in 9 pharmacokinetic studies of a single 7-day application of the Evra® transdermal patch (TTS). The Css and AUC values of norelgestromin and ethinyl estradiol 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 ethinyl estradiol following subsequent application of the Evra® transdermal patch (TTS) can be attributed to one of the above parameters.

Indication

Contraception in women.

Evra® is indicated for use in women of reproductive age. The safety and effectiveness of the Evra® TTC patch have only been established in women aged 18 to 45 years.

The decision to prescribe Evra® should take into account each woman's current risk factors, especially for venous thromboembolism (VTE), taking into account the risk of venous thromboembolism (VTE) with Evra® compared with other combined hormonal contraceptives (CHCs) (see sections "Contraindications", "Special instructions for use").

Contraindication

Combined hormonal contraceptives (CHCs) should not be used if any of the following conditions are present. If any of these conditions occur while using Evra®, its use should be discontinued immediately.

Venous thromboembolism (VTE) or risk of developing it:

history of venous thromboembolism (with anticoagulant treatment) or VTE [deep vein thrombosis (DVT) or pulmonary embolism (PE)];

hereditary or acquired predisposition to venous thromboembolism, for example resistance to activated protein C (including factor V Leiden), antithrombin III, protein C, protein S deficiency;

extensive surgery with prolonged immobilization (see section "Special instructions for use");

increased risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use").

Arterial thromboembolism (ATE) or risk of its development:

arterial thromboembolism, including a history (e.g. myocardial infarction), or prodromal stage of thrombosis (e.g. angina pectoris);

cerebrovascular diseases: acute cerebrovascular disorders, history of stroke or prodromal stage of thrombosis (e.g., transient ischemic attack);

hereditary or acquired predisposition to arterial thrombosis, such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);

migraine with focal neurological symptoms in history;

increased risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special warnings and precautions for use") or one of the serious risk factors listed below:

diabetes mellitus with vascular symptoms;

severe arterial hypertension;

severe dyslipoproteinemia.

Hypersensitivity to the active substances of the drug or to any of the excipients.

Confirmed or suspected breast carcinoma.

Endometrial cancer or other confirmed or suspected estrogen-dependent neoplasms.

Liver dysfunction due to acute or chronic hepatocellular disease.

Adenoma or carcinoma of the liver.

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 safety precautions

To prevent deterioration of the adhesive properties of the Evra® patch (TTS), do not apply creams, lotions or powders to the area of skin where the patch is planned to be applied.

After removal, the patch still contains a significant amount of active ingredients. Residual hormones can be harmful to the environment if they get into water, so used Evra® patches should be disposed of carefully. To do this, peel off the adhesive tape from the outside of the sachet. The used Evra® patch should be placed in the sachet with the sticky side facing the coloured area of the sachet and sealed by pressing lightly. Any unused material or waste should be disposed of in accordance with local requirements. Used Evra® patches should not be flushed down the toilet or into the sewer.

Interaction with other medicinal products and other types of interactions

The Summary of Product Characteristics of the concomitant medicinal product should be consulted to identify possible interactions.

Pharmacodynamic interactions

In clinical trials in patients treated with hepatitis C virus (HCV) medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) have been observed. This occurred at a significantly higher frequency in women taking ethinylestradiol-containing medicinal products, including combined hormonal contraceptives (CHCs). In addition, ALT elevations have also been observed in women taking ethinylestradiol-containing medicinal products, such as CHCs, with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.3). Therefore, women using Evra® should start using alternative methods of contraception (e.g. progestogen-only contraceptives or non-hormonal methods of contraception) before starting treatment with this regimen. Evra® can be restarted 2 weeks after completing treatment with this combination regimen.

Effects of other medicines on Evra®

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

Drugs 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 extract (Hypericum perforatum).

Risk management

Enzyme elevations may occur within a few days of starting treatment. Maximum enzyme activation generally occurs within 10 days and is maintained for up to 4 weeks after cessation of therapy.

Short-term treatment

Women undergoing short-term treatment with any of the above classes of medicinal products or individual active substances that induce hepatic enzymes should temporarily use a barrier method of protection in addition to Evra® during concomitant use of the medicinal product and for 28 days after its discontinuation.

If concomitant medication is continued after one week of patch application, the next transdermal patch should be applied without the usual break in application.

Long-term treatment

Women undergoing long-term treatment with any of these classes of drugs are advised to use another reliable non-hormonal method of contraception.

Drugs affecting the clearance of CHC

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

Therefore, before concomitant use, the Summary of Product Characteristics of HIV-infection drugs should be consulted for possible interactions and related recommendations for use. In case of doubt, women taking 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 EE levels (by 50-60%) when co-administered with oral triphasic hormonal contraceptives. Etoricoxib is thought to increase EE levels by inhibiting sulfotransferase activity, thereby inhibiting EE metabolism.

Effect of Evra® on other medicines

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

Laboratory indicators

The use of hormonal contraceptives may affect the results of some laboratory tests, including biochemical parameters of the liver, thyroid, adrenal and renal systems, the level of plasma proteins (carriers), for example, corticosteroid-binding globulin and fat/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the limits of laboratory norms.

Application features

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

The woman should be explained that in the event of worsening, exacerbation, or the appearance of one of these conditions or risk factors, she should consult a doctor who will decide whether to discontinue use of the drug.

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

The drug Evra® is not indicated 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 with not using such drugs. Products containing levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Evra® may have a twofold higher risk of VTE. The decision to use the drug should only be made after a discussion with the woman, ensuring that she is aware of the risk of VTE with Evra® and understands how her risk factors affect this risk and that the risk of VTE is highest during the first year of use of the patch. There is also some evidence that the risk is increased when combined oral contraceptives (COCs) are restarted after a break of 4 weeks or more.

About 2 in 10,000 women who are not using CHCs and are not pregnant will develop a VTE in 1 year. However, the risk may be much higher for each woman depending on the risk factors she has (see below).

It has been found that out of 10,000 women using low-dose CHCs containing levonorgestrel, about 61 will develop VTE within 1 year. According to studies, the incidence of VTE in women using the Evra® patch is about 6-12 cases per 10,000 women per year, which is twice as high as in women using CHCs containing levonorgestrel.

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

VTE can be fatal in 1-2% of cases.

1 The median range of 5 to 7 per 10,000 women-years is based on a relative risk of 2.3 to 3.6 for use of levonorgestrel-containing CHCs compared to no use.

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

Risk factors for VTE

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

The use of the Evra® patch is contraindicated in women with multiple risk factors for venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the total risk is greater than the sum of the individual factors - in this case, the woman's overall risk of VTE should be considered. If the risk-benefit ratio is considered negative, CHCs should not be prescribed (see section 4.3).

Table 2

Risk factors for VTE

There is no generally accepted opinion regarding the possible role of varicose veins and disseminated thrombophlebitis in the etiology of venous thromboembolism.

The increased risk of thromboembolism during pregnancy, and especially during the 6-week period after delivery, should be taken into account (for further information, see section “Use during pregnancy or lactation”).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

Women using combined contraceptives should immediately inform their doctor about the appearance of symptoms of thrombosis.

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 aching sensations in the leg that are felt only when standing and walking;

increased temperature of the affected leg, redness or paleness of the skin of the leg.

Symptoms of pulmonary embolism (PE) include:

sudden shortness of breath or rapid breathing;

sudden cough, which may be accompanied by hemoptysis;

sharp chest pain;

fainting or dizziness;

fast or irregular heartbeat.

Some of these symptoms are nonspecific (e.g., shortness of breath, cough) and may be mistaken for signs of another more common and less severe condition (e.g., respiratory tract infection).

Other signs of vascular occlusion include: sudden pain, swelling, and slight blueness of the limb.

If the occlusion occurs in the vessels of the eye, symptoms can range from painless vision loss to complete vision loss. Sometimes vision loss occurs almost instantly.

Risk of arterial thromboembolism (ATE)

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

ATE risk factors

The risk of arterial thromboembolic complications or cerebrovascular accidents in patients using CHCs is increased in women with risk factors (see Table 3). The use of the Evra® patch is contraindicated in women with serious or multiple risk factors for ATE (see section "Contraindications"). If a woman has more than one risk factor, it is possible that the total risk is greater than the sum of the individual factors - in this case, the woman's overall risk of ATE should be considered. If the risk-benefit ratio is considered negative, CHCs should not be prescribed (see section "Contraindications").

Table 3

ATE risk factors

Symptoms of ATE

Women using combined contraceptives should immediately notify their doctor if symptoms of ATE appear.

Symptoms of stroke 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, problems with speech or understanding;

sudden vision problems in one or both eyes;

sudden, severe, or prolonged headache without a specific cause;

loss of consciousness or fainting with or without convulsions.

Temporary symptoms suggest a transient ischemic attack.

Symptoms of myocardial infarction include:

pain, discomfort, pressure, heaviness, a feeling of squeezing or bursting in the chest, arm, or below the breastbone;

discomfort with irradiation to the back, jaw, throat, arms, abdomen;

feeling of fullness, indigestion, or suffocation;

sweating, nausea, vomiting and dizziness;

fast or irregular heartbeat.

Women using combined contraceptives should immediately inform their doctor about possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, hormonal contraceptives should be discontinued. Adequate contraception should be initiated due to the teratogenicity of anticoagulant therapy (coumarins).

Tumors

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

A meta-analysis of 54 epidemiological studies has shown that there is a slightly increased risk (relative risk = 1.24) of breast cancer in women who use COCs. The risk gradually decreases within 10 years after stopping COC use. Since breast cancer is rare in women under 40 years of age, the number of breast cancer diagnoses in current or past COC users is small compared with the overall risk of breast cancer. Breast cancer diagnosed in current COC users is generally less common than in women who have never used COCs.

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

Benign liver tumors and even more rarely malignant liver tumors have been reported in patients using COCs. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. Therefore, a liver tumor should be considered in the differential diagnosis of acute abdominal pain, liver enlargement, and signs of intra-abdominal bleeding in women using Evra®.

Mental disorders

Known side effects of hormonal contraceptives are depressed mood and depression (see section 4.8). Depression can be severe and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to seek medical advice if they experience mood changes and symptoms of depression, including those that occur shortly after starting COC use.

Other states

Contraceptive efficacy may be reduced in women weighing 90 kg or more (see sections 4.2 and 5.1).

Women with hypertriglyceridemia or a family history of it are at increased risk of developing pancreatitis when using combined hormonal contraceptives.

Although a slight increase in blood pressure has been observed in many women taking hormonal contraceptives, clinically significant increases have been rare. The relationship between the use of hormonal contraceptives and clinical hypertension has not been established. If, during the use of combined hormonal contraceptives, a persistent or significant increase in blood pressure occurs in the presence of existing hypertension, which does not respond to antihypertensive treatment, the use of combined hormonal contraceptives should be discontinued. Combined hormonal contraceptives can be restarted if antihypertensive therapy provides control of the normal level of blood pressure.

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

Acute and chronic liver function disorders may require discontinuation of combined hormonal contraceptives until liver markers return to normal. Recurrence of pruritus associated with cholestasis, which occurred during a previous pregnancy or previous 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 that diabetic patients should be treated with hormonal contraceptives. However, women with diabetes should be closely monitored, especially in the early stages of Evra® use.

Complications of endogenous depression, epilepsy, Crohn's disease or ulcerative colitis have been reported during the use of COCs.

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

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

Before initiating or reinstituting Evra®, a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed to identify contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw the woman's attention to information on venous and arterial thrombosis, including the risk of Evra® compared with other CHCs, the symptoms of VTE and ATE, known risk factors and what to do if thrombosis is suspected.

The woman should be instructed to carefully read the instructions for use of the medicinal product and to follow the recommendations provided. The frequency and extent of subsequent medical examinations should be established in accordance with existing clinical practice and the clinical condition of the woman.

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

Bleeding disorders

As with other combined hormonal contraceptives, irregular bleeding (spotting or breakthrough bleeding) may occur during the first months of use. Therefore, specialist advice may only be useful after a habituation period of approximately 3 cycles. If breakthrough bleeding persists or occurs after regular bleeding in previous cycles when using Evra® according to the recommendations, another cause 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 period. If Evra® has been used according to the recommendations in the section “Method of administration and dosage”, it is unlikely that the woman is pregnant. Pregnancy cannot be excluded if the Evra® patch was not used according to the instructions before the first or second missed menstruation.

Some women may experience amenorrhea or oligomenorrhea after stopping hormonal contraception, especially if there is a history of these conditions.

Use during pregnancy or breastfeeding

Pregnancy

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

Epidemiological studies have shown no increased risk of birth defects in children born to women who used hormonal contraceptives before pregnancy. Most recent studies have also shown no teratogenic effects from inadvertent use of oral hormonal contraceptives early in pregnancy.

Limited data on the use of Evra® in pregnant women do not allow a conclusion to be drawn regarding the safety of this product during pregnancy.

In animal studies, there have been cases of adverse reactions during pregnancy or lactation. Therefore, the risk of adverse reactions due to hormonal disruption when using the drug Evra® cannot be excluded, although the general experience with the use of combined oral contraceptives during pregnancy has not shown any signs of undesirable effects in humans.

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

The increased risk of VTE in the postpartum period should be considered.