Claire

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLAIRA (QLAIRA®)

Composition:

Active substances: estradiol valerate, dienogest;

each calendar pack (28 film-coated tablets) contains:

2 dark yellow tablets, each containing 3 mg estradiol valerate;

5 red tablets, each containing 2 mg estradiol valerate and 2 mg dienogest;

17 light yellow tablets, each containing 2 mg estradiol valerate and 3 mg dienogest;

2 dark red tablets, each containing 1 mg estradiol valerate;

2 white placebo tablets;

Excipients: monohydrate lactose, corn starch, pregelatinized starch, povidone, magnesium stearate, hypromellose, macrogol 6000, talc, titanium dioxide (E 171), yellow iron oxide (E 172) or red iron oxide (E 172);

placebo: monohydrate lactose, corn starch, povidone, magnesium stearate, hypromellose, talc, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets in dark yellow, dark red, light yellow, red, and white colors, with the letters "DD", "DJ", "DH", "DN", or "DT" respectively embossed on one side within a regular hexagon.

Pharmacotherapeutic group.

Sex gland hormones and drugs used in disorders of the genital system. Systemic hormonal contraceptives. ATC code G03A B08.

Pharmacological properties.

Pharmacodynamics.

In clinical studies conducted with the drug Claira in the European Union and the USA/Canada, the following Pearl indices were determined:

Pearl index (patient age 18–50 years):

Method failure: 0.42 (upper limit of 95% confidence interval (CI) 0.77).

Patient failure and method failure: 0.79 (upper limit of 95% CI 1.23).

Pearl index (patient age 18–35 years):

Method failure: 0.51 (upper limit of 95% CI 0.97).

Patient failure and method failure: 1.01 (upper limit of 95% CI 1.59).

The contraceptive effect of combined oral contraceptives (COCs) is based on the interaction of several factors, the most important of which are inhibition of ovulation, changes in cervical secretions, and alterations in the endometrium.

The treatment regimen with Claira (gradual decrease in estrogen dose and gradual increase in progestogen dose) can be used to treat severe menstrual bleeding (SMB) in women without organic pathology, sometimes referred to as dysfunctional uterine bleeding (DUB).

Two multicenter, randomized, double-blind studies with similar designs were conducted to evaluate the efficacy and safety of Claira in women with symptoms of DUB who wish to use oral contraception. A total of 269 women were randomly assigned to the Claira treatment group and 152 women to the placebo group.

After 6 months of therapy, a reduction in mean menstrual blood loss of 88% (from 142 ml to 17 ml) was observed in the Claira group and of 24% (from 154 ml to 117 ml) in the placebo group.

The proportion of women in whom DUB symptoms completely disappeared after 6 months of therapy was 29% in the Claira group and 2% in the placebo group.

The estrogen contained in Claira is estradiol valerate, an ester of 17-beta-estradiol, a natural human hormone (1 mg of estradiol valerate corresponds to 0.76 mg of 17-beta-estradiol). This estrogen differs from estrogens such as ethinylestradiol or its precursor mestranol, which are components of other COCs, by the absence of an ethinyl group at the 17-alpha position.

Dienogest is a derivative of nortestosterone characterized by the absence of androgenic activity and the presence of antiandrogenic activity approximately one-third that of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus, exhibiting only 10% relative affinity compared to progesterone. Despite its low affinity for progesterone receptors, dienogest demonstrates a potent progestogenic effect in vivo. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid properties in vivo.

Histological examination of the endometrium conducted in a subgroup of women (n = 218) after 20 treatment cycles in a clinical study revealed no abnormalities.

Pharmacokinetics.

Dienogest

Absorption. After oral administration, dienogest is rapidly and almost completely absorbed. Following oral intake of a Claira tablet containing 2 mg estradiol valerate + 3 mg dienogest, the maximum serum concentration of 90.5 ng/mL is reached approximately 1 hour later. Bioavailability is approximately 91%. The pharmacokinetics of dienogest administered at doses from 1 to 8 mg is dose-dependent. Concomitant food intake does not have a clinically significant effect on the rate and extent of dienogest absorption.

Distribution. A relatively large portion of circulating dienogest (10%) is in free form, while about 90% is non-specifically bound to albumin. Dienogest does not bind to specific transport proteins—sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). After intravenous administration of 85 µg of 3H-dienogest, the volume of distribution at steady state (Vd,ss) of dienogest is 46 L.

Metabolism. Dienogest is almost completely metabolized via known pathways of steroid hormone metabolism (hydroxylation, conjugation), primarily by CYP3A4. Pharmacologically inactive metabolites are rapidly eliminated from plasma, resulting in dienogest as the parent compound accounting for approximately 50% of circulating dienogest derivatives. Total clearance after intravenous administration of 3H-dienogest is 5.1 L/h.

Elimination. The plasma elimination half-life of dienogest is approximately 11 hours. Dienogest is extensively metabolized, and only 1% of the active substance is excreted unchanged. After oral administration of dienogest at a dose of 0.1 mg/kg, the drug is excreted via the kidneys and the intestine in a ratio of approximately 3:1. After oral administration, 42% of the dose is excreted within the first 24 hours and 63% within 6 days via renal excretion. Within 6 days, a total of 86% of the administered dose is excreted in urine and feces.

Steady state. The pharmacokinetics of dienogest is independent of SHBG levels. Steady-state concentration of dienogest is achieved after 3 days of administration at a constant dose of 3 mg dienogest in combination with 2 mg estradiol valerate. Minimum, maximum, and mean serum concentrations of dienogest at steady state are 11.8 ng/mL, 82.9 ng/mL, and 33.7 ng/mL, respectively. The mean accumulation ratio, based on AUC (0–24 h) data, is 1.24.

Estradiol valerate

Absorption. After oral administration, estradiol valerate is completely absorbed. Cleavage into estradiol and valeric acid occurs during absorption through the gastrointestinal mucosa or during first-pass metabolism in the liver. As a result, estradiol and its metabolites—estrone and estriol—are formed. After a single dose of a tablet containing 3 mg estradiol valerate on day 1, the maximum serum concentration of estradiol, amounting to 70.6 pg/mL, is reached within 1.5–12 hours.

Metabolism. Valeric acid is very rapidly metabolized. After oral administration, approximately 3% of the dose is directly available as estradiol. Estradiol undergoes extensive first-pass liver metabolism, and a significant portion of the administered dose is metabolized in the gastrointestinal mucosa. Together with presystemic metabolism in the liver, approximately 95% of the oral dose is metabolized before entering systemic circulation. The main metabolites are estrone, estrone sulfate, and estrone glucuronide.

Distribution. In serum, 38% of estradiol is bound to SHBG, 60% to albumin, and 2–3% circulates in free form. Estradiol may cause (depending on the administered dose) a slight increase in serum SHBG levels. On day 21 of treatment, SHBG levels were approximately 148% of baseline, and on day 28, this value decreased to approximately 141% of baseline (end of placebo period). After intravenous administration, the apparent volume of distribution was approximately 1.2 L/kg.

Elimination. The plasma elimination half-life of circulating estradiol is approximately 90 minutes. However, the situation differs slightly after oral administration. Due to the large amount of circulating estrogens as sulfates and glucuronides and enterohepatic recirculation, the terminal elimination half-life of estradiol after oral administration is a complex parameter dependent on all the aforementioned processes and ranges from 13 to 20 hours. Estradiol and its metabolites are primarily excreted in urine, with approximately 10% eliminated in feces.

Steady state. The pharmacokinetics of estradiol is influenced by SHBG levels. In young women, the measured plasma concentration of estradiol consists of endogenous estradiol and estradiol derived from Claira. During the phase of administration of tablets containing 2 mg estradiol valerate + 3 mg dienogest, maximum and mean serum concentrations of estradiol at steady state were 66.0 pg/mL and 51.6 pg/mL, respectively. Stable minimum concentrations of estradiol were maintained throughout the entire 28-day cycle, ranging from 28.7 pg/mL to 64.7 pg/mL.

Special patient populations

The pharmacokinetics of Claira has not been studied in patients with hepatic or renal impairment.

Preclinical safety data

Preclinical data obtained from traditional repeated-dose toxicity, genotoxicity, and reproductive toxicity studies indicate no specific risk for humans. In carcinogenicity studies using dienogest in animals, no increase in tumors was observed. However, it is known that due to their hormonal activity, sex steroid hormones may promote the growth of certain hormone-dependent tissues and tumors.

Clinical characteristics.

Indications.

Oral contraception.

Treatment of severe menstrual bleeding in women without organic pathology who have been prescribed oral contraception.

Contraindications.

Do not use COCs in the presence of any of the following conditions. If any of these conditions first develop during COC use, COC use must be stopped immediately.

• Presence or risk of venous thromboembolism (VTE):
  • current (during anticoagulant therapy) or history of venous thromboembolism (e.g., deep vein thrombosis (DVT), pulmonary embolism (PE));
  • known hereditary or acquired predisposition to venous thromboembolism, such as activated protein C resistance (including factor V Leiden mutation), antithrombin-III deficiency, protein C deficiency, protein S deficiency;
  • major surgery with prolonged immobilization (see section "Special precautions");
  • high risk of venous thromboembolism due to the presence of multiple risk factors (see section "Special precautions").
• Presence or risk of arterial thromboembolism (ATE):
  • arterial thromboembolism: current or history of arterial thromboembolism (e.g., myocardial infarction) or presence of prodromal symptoms (e.g., angina pectoris);
  • cerebrovascular disorders: current or history of stroke, presence of prodromal symptoms (e.g., transient ischemic attack (TIA));
  • known hereditary or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinemia and antiphospholipid antibodies (anti-cardiolipin antibodies, lupus anticoagulant);
  • history of migraine with focal neurological symptoms;
  • high risk of arterial thromboembolism due to the presence of multiple risk factors (see section "Special precautions") or due to the presence of a single serious risk factor, such as:
    • diabetes mellitus with vascular complications;
    • severe arterial hypertension;
    • severe dyslipoproteinemia;
• Severe liver disease currently or in the past until liver function tests return to normal limits.
• Benign or malignant liver tumor currently or previously.
• Known or suspected hormone-dependent malignant neoplasms (e.g., of the genital organs or breasts).
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Review information on concomitantly administered medicinal products to identify potential interactions.

Interaction studies have been conducted only in adult female patients.

Information on the types of interactions listed below is derived from publications on combined oral contraceptives (COCs) in general or from clinical trial results of the drug Klaira.

Effect of other medicinal products on Klaira.

Interactions with other medicinal products may result in breakthrough bleeding and/or reduced efficacy of the hormonal contraceptive.

Therapy.

Enzyme induction may occur within a few days of starting treatment. Maximum enzyme induction is usually observed only after several weeks, but may persist for 4 weeks or more after discontinuation of the relevant medicinal product.

Short-term therapy.

During short-term treatment with enzyme-inducing medicinal products, women should use a barrier method or another contraceptive method in addition to COCs.

A barrier method should be used throughout the entire period of concomitant therapy and for 28 days after its discontinuation. If therapy extends beyond the active tablet-taking period of the COC, placebo tablets should not be taken; instead, the next pack of COCs should be started immediately.

Long-term therapy.

Women requiring long-term therapy with enzyme-inducing agents are advised to use another reliable non-hormonal contraceptive method.

Medicinal products that increase COC clearance (reducing COC efficacy via enzyme induction): barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin; HIV treatments, including ritonavir, nevirapine, and efavirenz; and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St. John’s wort (Hypericum perforatum).

In a clinical study, rifampicin, a potent inducer of cytochrome P450 CYP3A4, caused a significant reduction in steady-state concentrations and systemic exposure of dienogest and estradiol. Systemic exposure to dienogest and estradiol at steady state, measured as AUC (0–24 hours), decreased by 83% and 44%, respectively.

Medicinal products with variable effects on COC clearance.

Concomitant use of COCs with a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus (HCV) antivirals, may increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, information on the use of concomitant HIV/HCV medicinal products should be reviewed to identify potential interactions and any recommendations. In case of doubt, women should use an additional barrier contraceptive method during therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Medicinal products that decrease COC clearance (enzyme inhibitors).

Dienogest is a substrate of cytochrome CYP3A4.

The clinical significance of potential interactions with enzyme inhibitors is unknown.

Concomitant use of strong CYP3A4 inhibitors may lead to increased plasma concentrations of estrogen, progestin, or both.

Concomitant use of ketoconazole, a potent CYP3A4 inhibitor, resulted in a 2.9-fold and 1.6-fold increase in steady-state AUC (0–24 hours) for dienogest and estradiol, respectively.

Concomitant use of erythromycin, a moderate inhibitor, resulted in a 1.6-fold and 1.3-fold increase in steady-state AUC (0–24 hours) for dienogest and estradiol, respectively. The clinical significance of these interactions is unknown.

Effect of Klaira on other medicinal products.

Oral hormonal contraceptives may affect the metabolism of certain other drugs. Consequently, plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

No effect on the pharmacokinetics of nifedipine was observed when co-administered with 2 mg dienogest and 0.03 mg ethinylestradiol, confirming in vitro study results indicating that CYP enzyme inhibition by Klaira at therapeutic doses is unlikely.

Other interactions.

In clinical trials involving patients receiving antiviral hepatitis C treatment with medicinal products containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elevated transaminase levels (ALT) exceeding 5 times the upper limit of normal (ULN) were observed significantly more frequently in women using ethinylestradiol-containing medicinal products, such as combined hormonal contraceptives (CHCs).

The incidence of ALT elevation in women using estrogen-containing medicinal products other than ethinylestradiol, such as estradiol, was similar to that in women not receiving estrogens; however, due to the limited number of women using estrogens other than ethinylestradiol, caution is advised when co-administering with medicinal products containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the combination glecaprevir/pibrentasvir (see section "Special precautions").

Laboratory tests.

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal, and kidney function, plasma levels of binding proteins such as sex hormone-binding globulin, lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Such changes are usually within normal laboratory ranges.

Special precautions.

The decision to prescribe the medication Klaira should be made taking into account individual risk factors, including risk factors for venous thromboembolism (VTE), as well as the VTE risk associated with Klaira compared to other combined hormonal contraceptives (CHCs) (see sections "Contraindications" and "Special precautions").

Warning

If any of the conditions or risk factors listed below are present, the appropriateness of using Klaira should be discussed with the woman.

If any of the conditions or risk factors listed below worsen or occur for the first time, the woman must consult her physician immediately. The physician will then decide whether continued use of Klaira should be discontinued.

If VTE or arterial thromboembolism (ATE) is suspected or confirmed, CHCs should be discontinued. If anticoagulant therapy is initiated, an alternative effective contraceptive method should be provided due to the teratogenic effects of anticoagulants (coumarins).

The precautions and warnings described below are based on clinical and epidemiological data regarding combined oral contraceptives (COCs) containing ethinylestradiol.

Disturbances of circulation

Risk of venous thromboembolism (VTE)

Use of any CHCs increases the risk of VTE in women taking them compared to non-users. Products containing levonorgestrel, norgestimate, or norethisterone are associated with the lowest risk of VTE. Limited data suggest that the risk of VTE with Klaira may be comparable. The decision to use any other product (such as Klaira) instead of one with the lowest VTE risk should only be made after discussion with the woman. It is essential to ensure she understands the VTE risk associated with CHC use, the impact of her individual risk factors, and that the risk of VTE is highest during the first year of use. Some data suggest that the risk of VTE may increase when restarting CHCs after a break of 4 weeks or longer.

In 2 out of 10,000 women who do not use CHCs and are not pregnant, VTE develops within one year. However, for any individual woman, the risk may be significantly higher depending on her individual risk factors (see below).

Epidemiological studies in women using low-dose CHCs (< 50 µg ethinylestradiol) show that 6–12 out of 10,000 women will develop VTE within one year.

It is estimated that approximately 61 out of 10,000 women using CHCs containing levonorgestrel will develop VTE within one year.

1 On average 5–7 cases per 10,000 woman-years, based on relative risk calculations for levonorgestrel-containing CHCs compared to non-CHC users (approximately 2.3–3.6 cases).

Limited epidemiological data suggest that the risk of VTE with Klaira may be similar to that with other CHCs containing levonorgestrel.

The annual incidence of VTE was lower than expected during pregnancy or the postpartum period.

VTE can be fatal in 1–2% of cases.

Very rare cases of thrombosis in other vessels, such as arteries and veins of the liver, kidneys, mesenteric vessels, retinal veins and arteries, have been reported in women using CHCs.

Risk factors for VTE

The risk of venous thromboembolic complications in women using CHCs may be substantially increased in the presence of additional risk factors, especially multiple ones (see Table 1).

Klaira is contraindicated in women with multiple risk factors that may increase the risk of venous thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor, so the overall risk of VTE should be considered. If the benefit-risk ratio is unfavorable, CHCs should not be prescribed (see section "Contraindications").

Table 1

Risk factors for VTE

There is no consensus regarding the possible influence of varicose veins and superficial thrombophlebitis on the occurrence or progression of venous thrombosis.

Particular attention should be paid to the increased risk of thromboembolism during pregnancy and the postpartum period, especially within 6 weeks after delivery (for information on pregnancy and lactation, see section "Use in pregnancy or breastfeeding").

Symptoms of VTE (venous thromboembolism: deep vein thrombosis and pulmonary embolism)

Women should be advised to seek immediate medical attention and inform their physician that they are taking a COC if any of the symptoms listed below occur.

Symptoms of DVT may include:

• Unilateral swelling of the thigh, calf, and/or foot, or swelling along a vein;
• Pain or tenderness in the leg, which may occur only when standing or walking;
• Increased warmth in the affected leg, redness, or skin discoloration of the lower limb.

Symptoms of pulmonary embolism (PE) may include:

• Sudden unexplained shortness of breath or rapid breathing;
• Sudden cough, which may be accompanied by hemoptysis;
• Acute chest pain;
• Dizziness;
• Rapid or irregular heartbeat.

Some of these symptoms (e.g., shortness of breath, cough) are non-specific and may be misinterpreted as more common or less serious conditions (e.g., respiratory tract infections).

Other signs of vascular occlusion may include sudden pain, swelling, and slight bluish discoloration of a limb.

In cases of ocular vessel occlusion, symptoms may include painless blurred vision, which may progress to vision loss. In some cases, vision loss may occur almost instantaneously.

Risk of arterial thromboembolism (ATE)

Epidemiological data indicate that the use of any COC is associated with an increased risk of ATE (myocardial infarction) or cerebrovascular events (transient ischemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or cerebrovascular events increases in women using COCs who have risk factors (see Table 2). The use of Claira is contraindicated in women who have one serious or multiple risk factors for ATE that may increase the risk of arterial thrombosis (see section "Contraindications"). If a woman has more than one risk factor, the increase in risk may be greater than the sum of risks associated with each individual factor, so the overall risk should be considered. If the benefit-risk balance is unfavorable, COCs should not be prescribed (see section "Contraindications").

Table 2

Risk factors for ATE

Arterial Thromboembolic Events (ATE)

Women should be advised to seek immediate medical attention and inform their doctor if they are taking COCs should any of the following symptoms occur.

Symptoms of cerebrovascular disorders may include:

• sudden numbness or weakness of the face, arms, or legs, especially on one side of the body;
• sudden difficulties with walking, dizziness, loss of balance or coordination;
• sudden confusion, speech disturbances, or difficulty understanding speech;
• sudden vision disturbances in one or both eyes, sudden severe or prolonged headache without apparent cause;
• loss of consciousness or syncope, with or without epileptic seizure.

Transient symptoms may indicate a transient ischaemic attack.

Symptoms of myocardial infarction may include:

• pain, discomfort, pressure, heaviness, squeezing, or fullness in the chest, arm, or behind the breastbone;
• pain that may radiate to the back, jaw, throat, arm, or abdomen;
• sensations of fullness, digestive disturbances, or an attack of angina;
• sweating, nausea, vomiting, or dizziness;
• marked weakness, anxiety, shortness of breath, rapid or irregular heartbeat.

Tumours

Some epidemiological studies have suggested that long-term use of COCs (>5 years) may increase the risk of cervical cancer; however, this finding remains controversial, as it has not been definitively established whether the study results adequately accounted for confounding factors such as sexual behaviour or presence of human papillomavirus infection.

A meta-analysis of 54 epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer among women using COCs. This elevated risk gradually disappears within 10 years after discontinuation of COC use. Since breast cancer is rare in women under 40 years of age, the increase in incidence among current or recent users of COCs is small relative to the overall risk of developing breast cancer. These studies do not provide evidence of a causal relationship. The observed increased risk may be due to earlier diagnosis of breast cancer in COC users, a biological effect of COCs, or a combination of both factors. Breast cancers diagnosed in women who have ever used COCs are generally less advanced clinically than those in women who have never used COCs.

Benign, and very rarely malignant, liver tumours have been observed in women taking COCs. In rare cases, such tumours have led to life-threatening intra-abdominal haemorrhage. In women taking COCs who present with severe upper abdominal pain, hepatomegaly, or signs of intra-abdominal bleeding, liver tumour should be considered in the differential diagnosis.

Hepatitis C

In clinical trials involving patients receiving antiviral therapy for hepatitis C with medicinal products containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ALT elevations >5 times the upper limit of normal (ULN) were observed significantly more frequently in women taking ethinylestradiol-containing medicinal products, such as COCs. Additionally, ALT elevations were observed in women taking ethinylestradiol-containing products during treatment with glecaprevir/pibrentasvir.

The incidence of ALT elevation in women taking oestrogen-containing medicinal products other than ethinylestradiol (e.g., estradiol) was similar to that in women not receiving oestrogens; however, due to the limited number of women taking non-ethinylestradiol oestrogens, caution is advised when co-administering such oestrogens with medicinal products containing ombitasvir/paritaprevir/ritonavir with or without dasabuvir, as well as with the combination glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other forms of interaction").

Other Conditions

Women with hypertriglyceridaemia or a family history of this condition may have an increased risk of pancreatitis when using COCs.

Although a slight increase in blood pressure has been reported in many women using COCs, clinically significant elevations are rare. However, if sustained clinically significant hypertension develops during COC use, the physician should discontinue the COC and initiate antihypertensive treatment. If normal blood pressure is achieved with antihypertensive therapy, COC use may be resumed if considered appropriate.

The following conditions have been reported to occur or worsen during pregnancy or COC use, although a definitive causal relationship with COC use has not been established: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic-uraemic syndrome; Sydenham's chorea; herpes gestationis; hearing loss associated with otosclerosis.

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

Acute or chronic liver function disorders may require discontinuation of COC use until liver function tests normalize. Recurrence of cholestatic jaundice, which first appeared during pregnancy or previous use of sex steroids, necessitates discontinuation of COC use.

COCs may also affect peripheral insulin resistance and glucose tolerance. However, there are currently no data indicating the need to alter therapeutic regimens in diabetic patients using low-dose COCs (containing < 0.05 mg ethinylestradiol). Nevertheless, diabetic patients should be closely monitored during COC use, particularly at the beginning of treatment.

Worsening of endogenous depression, epilepsy, Crohn's disease, and ulcerative colitis has been observed during COC use.

Depressed mood and depression are well-known adverse reactions that may occur during use of hormonal contraceptives (see section "Adverse Reactions"). Depression can be a serious condition and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their doctor if they experience mood changes or symptoms of depression, including shortly after starting treatment.

Chloasma may occasionally occur, particularly in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid sun exposure or ultraviolet radiation during COC use.

Oestrogens may cause fluid retention; therefore, patients with cardiac disorders or renal dysfunction should be closely monitored. Particular attention is required in patients with end-stage renal disease due to the potential for increased plasma oestrogen concentrations following administration of Claira.

One tablet of Claira contains no more than 50 mg of lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Medical Examination/Consultation

Before initiating or resuming use of Claira, a complete medical and family history should be taken, and pregnancy should be ruled out in the patient. Blood pressure should be measured, and a physical examination should be performed, considering contraindications (see section "Contraindications") and warnings (see section "Special Warnings and Precautions for Use"). The woman should be informed about venous and arterial thrombosis, including the risk associated with use of Claira compared to other COCs, symptoms of VTE and ATE, known risk factors, and actions to take if thrombosis is suspected.

The woman should also be informed that she should carefully read the package leaflet and follow the instructions provided. The frequency and nature of follow-up examinations should be based on current medical practice guidelines and individual patient characteristics.

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

Reduced Efficacy

The efficacy of COCs may be reduced, for example, if a hormone-containing tablet is missed (see section "Dosage and Administration"), due to gastrointestinal disturbances during active tablet intake (see section "Dosage and Administration"), or due to concomitant medication (see section "Interaction with other medicinal products and other forms of interaction").

Cycle Control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use.

Therefore, evaluation of any irregular bleeding is important after an adaptation period of approximately three cycles.

Based on data from patient diaries in a comparative clinical study, the proportion of women experiencing intermenstrual bleeding during a cycle while taking Claira was 10–18%.

Amenorrhoea may occur in women taking Claira, even if they are not pregnant. According to patient diaries, approximately 15% of cycles were amenorrhoeic.

If Claira has been taken according to the recommendations described in the section "Dos游戏副本 and Administration", it is unlikely that the woman is pregnant. However, if there was non-adherence to the recommended regimen before the first missed withdrawal bleed, or if withdrawal bleeds are absent for two consecutive cycles, pregnancy must be ruled out before continuing Claira.

In cases of persistent irregular bleeding or if irregular bleeding occurs in women who previously had regular cycles, non-hormonal causes should be considered, and appropriate diagnostic measures should be taken to exclude malignancy or pregnancy. Diagnostic measures may also include curettage.

Use during Pregnancy or Breastfeeding

Pregnancy

The drug must not be used during pregnancy.

If a woman becomes pregnant while taking Claira, further use of the drug should be discontinued. Extensive epidemiological studies on combined oral contraceptives containing ethinylestradiol have not shown an increased risk of congenital malformations in children of mothers who used COCs before pregnancy, nor a teratogenic effect after accidental use of COCs during pregnancy. Animal studies have not revealed any risk of reproductive toxicity (see section "Pharmacological Properties").

When resuming use of Claira, the increased risk of VTE in the postpartum period should be considered (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use").

Breastfeeding

Use of COCs may affect lactation by reducing the quantity and altering the composition of breast milk. Therefore, COCs are generally not recommended while breastfeeding continues. A small amount of contraceptive steroids and/or their metabolites may pass into breast milk and may adversely affect the infant's health.

Fertility

Claira is indicated for the prevention of pregnancy. Information on the return of fertility can be found in the section "Pharmacodynamics".

Effect on Ability to Drive and Use Machines

No effect on the ability to drive or use machines has been observed in patients taking Claira.

Method of Administration and Dosage

Method of Administration

Oral use.

How to take the medication Klaira

Tablets should be taken in the order indicated on the packaging, daily at approximately the same time, swallowing with liquid if needed. The tablets must be taken continuously. Take 1 tablet daily for 28 consecutive days. Each new pack should be started the day after taking the last tablet from the previous pack. Withdrawal bleeding usually begins during the intake of the last tablets in the pack and may not have finished by the time the next pack is started. In some women, bleeding may start shortly after beginning tablets from a new pack.

How to start taking Klaira

If no hormonal contraceptive has been used (in the previous month)

Begin taking tablets on day 1 of the woman’s natural cycle (i.e., the first day of her menstrual bleeding).

When switching from another combined hormonal oral contraceptive, vaginal ring, or transdermal patch

Start taking Klaira the day after taking the last hormonally active tablet of the previous combined oral contraceptive (COC). If using a vaginal ring or transdermal patch, start taking Klaira on the day of device removal.

When switching from a progestogen-only method (progestogen-only oral contraceptive, injectable contraceptive, implant) or an intrauterine system (IUS) containing progestogen

A woman may switch to Klaira from a progestogen-only oral contraceptive at any day (from an implant or IUS—on the day of removal, from an injectable—on the day the next injection would have been due); however, additional barrier contraceptive methods must be used during the first 9 days of taking Klaira.

After a first-trimester abortion

Klaira may be started immediately. If the medication is started promptly, the woman does not require additional contraceptive methods.

After childbirth or second-trimester abortion

For women who are breastfeeding, see section "Use during pregnancy or breastfeeding".

It is recommended to start taking Klaira on days 21–28 after childbirth or second-trimester abortion. If started later, additional barrier contraceptive methods should be used for the first 9 days of taking the medication. However, if sexual intercourse has already occurred, pregnancy must be ruled out before starting the COC, or the woman should wait for the onset of the first menstrual period.

Taking Klaira if a tablet has been missed

A missed white tablet (non-hormonal tablet) can be disregarded. However, such tablets should be removed to prevent unintentional prolongation of the hormone-free interval.

The following advice applies to missed hormonally active tablets

If a tablet is taken less than 12 hours late, the contraceptive effect of Klaira is not reduced. The woman should take the missed tablet as soon as she remembers. The next tablet should be taken at the usual time.

If a tablet is taken more than 12 hours late, contraceptive protection may be reduced. The woman should take the missed tablet as soon as possible, even if this means taking two tablets at the same time. She should then continue taking tablets at her usual time.

Depending on the day of the cycle when the tablet was missed (see table below), additional contraceptive methods (e.g., barrier methods such as condoms) may be required, according to the recommendations below.

Table 3

Guidelines for managing a missed tablet

Do not take more than 2 tablets in one day.

If a woman forgets to start a new pack or misses taking 1 or more tablets on days 3–9 of the current pack, there is a risk that she may already be pregnant (if she had sexual intercourse during the 7 days prior to the missed tablet). The greater the number of tablets missed (especially those containing the combination of two hormones, on days 3–24) and the closer they are to the inactive tablet phase, the higher the risk of pregnancy.

If withdrawal bleeding does not occur during the intake of the last tablets of the pack/start of a new pack after missed tablets, pregnancy should be considered.

Recommendations in case of gastrointestinal disturbances

In case of severe gastrointestinal disorders (e.g., vomiting or diarrhea), absorption may be incomplete; therefore, additional contraceptive methods should be used.

If vomiting occurs within 3–4 hours after taking the hormonal tablet, the next tablet should be taken as soon as possible. A new tablet should be taken within 12 hours of the usual intake time, if possible. If more than 12 hours have passed since the last tablet was taken, follow the recommendations for missed tablets described above in this section "Taking Claira after missing tablets". If a woman does not wish to alter her usual dosing schedule, she should take tablet(s) from another pack.

Additional information for specific patient groups

Elderly patients. The medicinal product Claira is not indicated for use after menopause.

Patients with hepatic impairment. The medicinal product Claira is contraindicated in women with severe liver disease (see also section "Contraindications").

Patients with renal impairment. The use of the medicinal product Claira in patients with renal dysfunction has not been specifically studied.

Children.

There are no data on the use of the drug in children (under 18 years of age).

Overdose.

There are no reports of serious consequences of overdose with Claira.

Symptoms that may occur in case of overdose of hormonal tablets: nausea, vomiting, and in young girls – slight vaginal bleeding. There are no specific antidotes, and further treatment should be symptomatic.

Adverse reactions

The most common adverse reactions observed during the use of the drug Claira as an oral contraceptive or for the treatment of heavy menstrual bleeding in women without organic pathology who were prescribed oral contraception were acne, breast discomfort, headache, intermenstrual bleeding, nausea, and weight gain.

Serious adverse reactions include arterial and venous thromboembolism, which are described in the section "Special precautions".

Table 4 lists adverse reactions according to the MedDRA System Organ Class (MedDRA SOCs) classification. The most appropriate MedDRA term (version 12.0) is used to describe each adverse reaction. Synonyms or related conditions are not listed but should also be considered. The frequency is based on data from clinical studies. Information on adverse reactions was obtained from five phase III clinical trials (N=2,266 women receiving Claira as an oral contraceptive; N=264 women with heavy menstrual bleeding without organic pathology who were prescribed oral contraceptives), and refers to events potentially causally related to the use of Claira. All adverse reactions with a frequency of "rare" occurred in one or two patients, equivalent to <0.1%. N=2,530 women (100%).

Table 4

1 including vulvovaginal candidiasis and fungal infection of the cervix

2 including crying and affective lability

3 including loss of libido

4 including mood changes and mood lability

5 including tension headache and sinus headache

6 including migraine with aura and without aura

7 including abdominal distension, pain in the upper and lower abdomen

8 including increased levels of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase

9 including pustular acne

10 including generalized pruritus and rash accompanied by pruritus

11 including macular rash

12 including allergic dermatitis and urticaria

13 including skin tightness sensation

14 including breast tenderness and breast pain, nipple disorders and nipple tenderness

15 including irregular menstruation

16 including breast swelling

17 including vaginal, genital, and uterine bleeding

18 including peripheral edema

19 including increased and decreased blood pressure

Description of selected adverse reactions

Women using COCs have been observed to have an increased risk of arterial and venous thromboembolism and thromboembolic events, including myocardial infarction, stroke, transient ischemic attack, venous thromboembolism, and pulmonary embolism, as described in detail in the section "Special precautions for use".

General information on the frequency of amenorrhea and intermenstrual bleeding is calculated from patient diaries and presented in the section "Cycle control" under "Special precautions for use".

The serious adverse reactions listed below have been observed in women using COCs. They are also described in the section "Special precautions for use".

Tumors

• Slightly increased frequency of breast cancer diagnosis has been observed in women using COCs. Since breast cancer is rare in women under 40 years of age, the increase in breast cancer incidence is small compared to the overall risk of developing breast cancer. A causal relationship with COC use has not been established. See also sections "Contraindications" and "Special precautions for use".
• Liver tumors.

Other conditions:

• Nodular erythema, polymorphic erythema;
• Galactorrhea;
• Arterial hypertension;
• Development or exacerbation of disorders for which a causal relationship with COC use has not been definitively established: Crohn's disease, ulcerative colitis, epilepsy, migraine, uterine fibroids, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema;
• Acute or chronic liver function disorders may require discontinuation of COCs until liver function parameters normalize;
• Chloasma;
• Hypersensitivity (including symptoms such as rash, urticaria).

Interactions

The interaction of other medicinal products (enzyme inducers) with oral contraceptives may result in breakthrough bleeding and/or contraceptive failure (see section "Interaction with other medicinal products and other forms of interaction").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after product authorization is very important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report suspected adverse reactions.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

28 film-coated tablets (2 dark yellow tablets, 5 red tablets, 17 light yellow tablets, 2 dark red tablets, 2 white placebo tablets) in a blister pack, 1 blister pack in a cardboard carton.

Prescription category.

Prescription only.

Manufacturer.

Bayer Weimar GmbH & Co. KG.

Manufacturer's address.

Doblerstrasse 20, 99427 Weimar, Germany.