Chloretta^® (Tablets) Instructions for Use

Marketing Authorization Holder

Binnopharm Group LLC (Russia)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

Contact Information

BINNOPHARM GROUP LLC (Russia)

ATC Code

G03AA15 (Chlormadinone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Chlormadinone (Rec.INN registered by WHO)

Dosage Form

Chloretta®

Film-coated tablets, 2 mg+0.03 mg: 21 or 63 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink in color, round, biconvex; on the break of the tablets, a white core is visible, surrounded by one layer of the coating.

Excipients: tablet core lactose monohydrate, corn starch, povidone K30 (polyvinylpyrrolidone), magnesium stearate; film coating hypromellose (E464), titanium dioxide (E171), macrogol, talc (E553b), iron oxide red dye (E172).

21 pcs. – blisters (1) – cardboard packs.
21 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; systemic hormonal contraceptives; progestogens and estrogens, fixed combinations

Pharmacological Action

The drug Chloretta^® is a combined oral low-dose contraceptive drug.

Mechanism of action, pharmacodynamic effects

The contraceptive effect of the combination chlormadinone + ethinylestradiol is achieved through complementary mechanisms: suppression of ovulation, increased viscosity of cervical mucus (thereby hindering the passage of sperm through the cervical canal), proliferation and secretory transformation of the endometrium (preventing the implantation of a fertilized egg). The progestogen included in the drug, chlormadinone, has antiandrogenic properties.

Its action is based on the ability to displace androgens from specific receptors, preventing and weakening the effect of endogenous and exogenous androgens.

With correct use, the Pearl index (an indicator reflecting the pregnancy rate per 100 women during one year of contraceptive use) is less than 1 (0.291-0.698), depending on how carefully the woman adheres to the drug regimen.

Clinical efficacy

During clinical studies of the use of the combination containing 2 mg chlormadinone acetate and 0.03 mg ethinylestradiol for a maximum of 2 years in 1655 women over more than 22000 cycles, 12 pregnancies were registered. In 7 cases, the influence of the following factors during the period of egg fertilization was noted: errors in drug intake; concomitant diseases accompanied by nausea or vomiting; or simultaneous use with drugs known to reduce the contraceptive effect.

Clinical studies have shown that already in the first cycle after discontinuation of chlormadinone and ethinylestradiol, conditions favorable for conception are restored.

Preclinical safety data

Estrogens have low acute toxicity. Due to pronounced differences between species of experimental animals, as well as differences existing between animals and humans, the results of estrogen studies in animals have limited predictive value for humans. Ethinylestradiol is a synthetic estrogen often used in oral contraceptives. Laboratory studies on animals have shown that even at relatively low doses it has an embryolethal effect; in male offspring, anomalies in the development of the genitourinary system organs and signs of feminization were observed. These effects are considered species-specific.

Chlormadinone acetate has been shown to have an embryolethal effect when administered to rabbits, rats, and mice. Teratogenic effects were also observed in rabbits at embryotoxic doses and in mice at the lowest studied doses (1 mg/kg/day). The significance of these data for the use of the drug in humans has not been established.

Standard preclinical safety studies investigating chronic toxicity, genotoxicity, and carcinogenic potential of the drug did not reveal any special risks for humans, except for those already described in other sections of the summary of product characteristics.

Pharmacokinetics

Chlormadinone acetate (CMA)

Absorption

After administration, CMA is rapidly and almost completely absorbed. The systemic bioavailability of CMA is high because it does not undergo first-pass metabolism in the liver. C_max in blood plasma is reached after 1-2 hours.

Distribution

More than 95% of CMA binds to blood plasma proteins, mainly albumin. CMA does not bind to sex hormone-binding globulin or cortisol-binding globulin. CMA accumulates primarily in adipose tissue.

Metabolism

Various reduction, oxidation, and conjugation processes with glucuronides and sulfates lead to the formation of numerous metabolites. The main metabolites in blood plasma are 3-alpha- and 3-beta-hydroxy-CMA with T_1/2 not significantly different from unmetabolized CMA. The 3-hydroxy metabolites have antiandrogenic activity similar to that of CMA itself. In urine, metabolites are found mainly in the form of conjugates. After enzymatic cleavage, the main metabolite is 2-alpha-hydroxy-CMA; 3-hydroxy metabolites and dihydroxymetabolites are also formed.

Elimination

The mean T_1/2 of CMA from blood plasma is approximately 34 hours after a single dose and about 36-39 hours after multiple administrations. After oral administration, CMA and its metabolites are excreted in approximately equal amounts by the kidneys and through the intestines.

Ethinylestradiol (EE)

Absorption

EE is rapidly and almost completely absorbed after oral administration, reaching C_max in blood plasma after 1.5 hours. Due to presystemic conjugation and metabolism in the liver, the absolute bioavailability is only about 40%, showing strong individual variability (20-65%).

Distribution

Available literature data on EE concentrations in blood plasma vary widely.

About 98% of EE binds to blood plasma proteins, almost exclusively to albumin.

Metabolism

Like natural estrogens, EE is biotransformed via hydroxylation of the aromatic ring (via the cytochrome P450 system). The main metabolite is 2-hydroxy-EE, which is transformed into other metabolites and conjugates. EE undergoes presystemic conjugation both in the small intestinal mucosa and in the liver. Glucuronides are mainly detected in urine, while sulfates are found in bile and blood plasma.

Elimination

The mean T_1/2 of EE from blood plasma is approximately 12-14 hours. EE is excreted by the kidneys and through the intestines in a 2:3 ratio. EE-sulfate, excreted in bile after hydrolysis by intestinal bacteria, undergoes enterohepatic circulation.

Indications

• Oral contraception.

Before prescribing, the presence of individual risk factors for thrombosis and thromboembolism, especially venous thromboembolism (VTE), should be assessed in the woman, and the risk of VTE when taking the drug should be compared with other combined hormonal contraceptives (CHCs).

ICD codes

Dosage Regimen

The drug should be taken orally. The tablet marked with the corresponding day of the week should be removed from the blister pack and swallowed whole, without chewing, with a small amount of water.

One tablet should be taken daily at the same time (preferably in the evening) for 21 consecutive days, followed by a 7-day break. A withdrawal bleeding should begin 2-4 days after taking the last tablet. One tablet should be taken every day at approximately the same time (preferably in the evening) for 21 consecutive days followed by a 7-day break between each pack.

After the end of the 7-day break, the drug from the next pack should be started, regardless of whether the bleeding has stopped or not.

How to start taking Chloretta^®

If no hormonal contraceptive has been used in the last menstrual cycle

Taking the drug should be started on the first day of the menstrual cycle (i.e., on the first day of menstrual bleeding), according to the day of the week indicated on the drug package.

Then the tablets should be taken in order. It is permissible to start taking the drug on days 2-5 of the menstrual cycle, but in this case, during the first 7 days of taking Chloretta^® tablets, it is recommended to additionally use a barrier method of contraception (e.g., a condom).

If menstrual bleeding started 5 days earlier, the woman should be advised to wait for the start of the next menstrual bleeding to begin taking the drug.

When switching from other combined hormonal contraceptive drugs [combined oral contraceptives (COCs), vaginal ring, or transdermal patch]

It is recommended to start taking the drug on the day after taking the last tablet from the previous pack (for drugs containing 21 tablets) or on the day after taking the last active tablet from the previous pack (for drugs containing 28 tablets per pack). Additional contraceptive measures are not required. Taking Chloretta^® should be started on the day of removal of the vaginal ring or patch, but no later than the day when a new ring should be inserted or a new patch should be applied.

Switching from progestogen-only products (“mini-pills”, injectable forms, implant), or from an intrauterine therapeutic system releasing progestogen

Switching from “mini-pills” to Chloretta^® can be done on any day (without a break), from an implant or intrauterine contraceptive with progestogen – on the day of its removal, from an injectable form – from the day the next injection is due. In all cases, during the first 7 days of taking Chloretta^® tablets, it is necessary to additionally use a barrier method of contraception (e.g., a condom).

After spontaneous or medical abortion in the first trimester of pregnancy

Taking Chloretta^® can be started immediately. In this case, the use of additional contraceptive measures is not required.

After childbirth (in the absence of breastfeeding) or termination of pregnancy (including spontaneous) in the second trimester

It is recommended to start taking the drug on day 21-28 after childbirth (in the absence of breastfeeding) or immediately after termination of pregnancy (including spontaneous) in the second trimester. If the drug is started later, it is necessary to use an additional barrier method of contraception during the first 7 days of taking the tablets. If sexual intercourse occurred before starting the drug, pregnancy must first be ruled out.

Breastfeeding period (see section “Pregnancy and lactation”)

Women who are breastfeeding are not recommended to take Chloretta^®.

After discontinuation of Chloretta^® the current cycle may lengthen by about one week.

Recommendations in case of a missed dose

If the delay in taking the drug was less than 12 hours, contraceptive protection is not reduced. The missed tablet should be taken as soon as possible, and the next tablet is taken at the usual time.

If the delay in taking the drug was more than 12 hours, contraceptive protection may be reduced.

In case of a missed tablet, it is necessary to remember

1. Taking Chloretta^® should never be interrupted for more than 7 days;
2. 7 days of continuous drug intake are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian system.

Accordingly, if the delay in taking the tablets was more than 12 hours and the interval since taking the last tablet is more than 36 hours, the woman must follow the following recommendations.

The last missed tablet must be taken immediately, even if this means taking two tablets at the same time. The next tablet is taken according to the usual schedule. For the next 7 days, it is necessary to additionally use a barrier method of contraception (e.g., a condom). If sexual intercourse occurred during the week before the missed tablet, the possibility of pregnancy must be considered.

If there are less than 7 tablets left in the current pack, immediately after finishing the Chloretta^® tablets, tablets from a new pack should be started – i.e., without the usual 7-day break. Probably, the usual withdrawal bleeding will not occur until the tablets from the second pack are finished. However, breakthrough bleeding or spotting may occur while taking tablets from the new pack. If withdrawal bleeding does not occur after finishing the tablets from the second pack, a pregnancy test should be performed.

Recommendations in case of gastrointestinal disorders

In severe gastrointestinal disorders, the absorption of the drug may be incomplete, so additional contraceptive methods should be used. If vomiting occurred or there was diarrhea within 3-4 hours after taking the tablet, depending on the week of drug intake, one should refer to the recommendations for missed tablets indicated above.

How to delay the onset of withdrawal bleeding

To delay the onset of withdrawal bleeding, it is necessary to continue further intake of tablets from a new pack of the drug without the usual 7-day break. Tablets from the new pack can be taken for as long as necessary, including until the pack is finished. While taking the drug from the second pack, spotting and/or breakthrough bleeding may be noted. Resumption of the drug from the next pack should be after the usual 7-day break.

How to change the day of onset of withdrawal bleeding

To move the day of onset of withdrawal bleeding to another day of the week, the woman should shorten the nearest 7-day break in taking the tablets by as many days as she wants. The shorter the break in taking the tablets, the higher the likelihood that withdrawal bleeding will not occur and that spotting and/or breakthrough bleeding will be observed while taking tablets from the second pack.

Special patient groups

Elderly women

The drug is not indicated for use in the postmenopausal period.

Children

The drug is intended for use only after menarche.

The efficacy and safety of the chlormadinone + ethinylestradiol combination in adolescent girls under 18 years of age have not been established, data are lacking.

Use of the drug is contraindicated in children.

Adverse Reactions

When taking the drug, the most frequently encountered adverse reactions (more than 20% of cases) are breakthrough bleeding, vaginal spotting, headache, and breast discomfort. The frequency of acyclic bleeding usually decreases with increasing duration of drug use.

Within the framework of a clinical study involving 1629 women, the following adverse reactions that occurred after using the drug were reported. The frequency of occurrence of adverse reactions is indicated according to WHO recommendations.

* – See subsection “Description of selected adverse reactions”

During the post-registration period of use of the chlormadinone and ethinylestradiol combination, the following adverse reactions have been reported: asthenia and allergic skin reactions not associated with immune system disorders.

Description of selected adverse reactions

When using combined oral contraceptives, including the chlormadinone + ethinylestradiol combination, the following adverse reactions have also been reported (see section “Special Precautions”).

• Increased risk of arterial and venous thrombosis and thromboembolism, including myocardial infarction, stroke, TIA, venous thrombosis, pulmonary embolism, was observed in women taking combined oral contraceptives;
• According to some studies, long-term use of combined oral contraceptives increases the risk of developing biliary tract diseases;
• In rare cases, after taking combined oral contraceptives, cases of benign liver tumors have been registered, and even more rarely, malignant tumors have been registered, which can lead to life-threatening intra-abdominal bleeding;
• Exacerbation of chronic inflammatory bowel diseases (Crohn’s disease, ulcerative colitis.

Information about other serious adverse reactions, such as cervical cancer or breast cancer, is presented in the “Special Precautions” section.

Interactions

Breakthrough bleeding and/or contraceptive failure may be the result of interaction of other medicinal products (hepatic enzyme inducers) with combined oral contraceptives (see section “Drug Interactions”).

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

The use of the chlormadinone + ethinylestradiol combination is contraindicated in the presence of any of the following diseases/conditions or risk factors.

• Hypersensitivity to chlormadinone, and/or ethinylestradiol, or to any of the excipients of the drug;
• Venous thrombosis or thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE) currently or in history;
• Arterial thrombosis or thromboembolism (ATE), including myocardial infarction, stroke or prodromal conditions [including transient ischemic attack (TIA), angina pectoris] currently or in history;
• Identified hereditary or acquired predisposition to VTE or ATE, including activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Presence of multiple high-risk factors for the development of VTE or ATE (see section “Special Precautions”) or one serious risk factor, such as:
  • Diabetes mellitus with diabetic angiopathy;
  • Severe dyslipoproteinemia;
  • Uncontrolled arterial hypertension (BP 160/100 mm Hg and above);
• Migraine with focal neurological symptoms in history; newly occurring migraine attacks or the appearance of unusually severe headache;
• Major surgical intervention with prolonged immobilization;
• Pancreatitis currently or in history, accompanied by severe hypertriglyceridemia;
• Uncontrolled diabetes mellitus;
• Severe lipid metabolism disorders;
• Acute or chronic severe liver diseases (until liver function tests normalize), including in history;
• Generalized pruritus, cholestasis, especially during previous pregnancy or use of sex hormones in history;
• Impaired liver excretory function, including Dubin-Johnson syndrome, Rotor syndrome;
• Meningioma currently or in history;
• Liver tumors (benign and malignant), including in history;
• Severe epigastric pain, liver enlargement or symptoms of intra-abdominal bleeding;
• Hormone-dependent malignant neoplasms of the genital organs or breast (including suspected);
• Acute sensory disturbances, for example, visual or hearing impairments;
• Motor disorders (in particular, paresis);
• Porphyria, occurring for the first time or recurrent (all 3 forms, especially acquired);
• Otosclerosis, which progressed during previous pregnancies;
• Severe depression;
• Epilepsy (increase in the frequency of seizures in epilepsy);
• Endometrial hyperplasia;
• Amenorrhea of unclear etiology;
• Genital bleeding of unclear etiology;
• Pregnancy (including suspected);
• Breastfeeding period;
• Age under 18 years (due to the lack of data on the efficacy and safety of the use of the chlormadinone + ethinylestradiol combination in adolescent girls under 18 years of age);
• Concomitant use with direct-acting antiviral drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, or with drugs containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Drug Interactions”).

If any of these diseases/conditions or risk factors occur during the use of the contraceptive, the drug should be discontinued immediately.

Use in Pregnancy and Lactation

Pregnancy

The use of the chlormadinone + ethinylestradiol combination during pregnancy is contraindicated. In case of use of chlormadinone and ethinylestradiol, their administration should be discontinued immediately. Numerous epidemiological studies have not revealed an increased risk of developmental defects in children born to women who received sex hormones before pregnancy, nor the presence of a teratogenic effect when sex hormones were taken inadvertently in early pregnancy.

Breastfeeding

The use of the drug, like other combined oral contraceptives, may reduce the amount of breast milk and change its composition, therefore, the use of the drug is contraindicated until breastfeeding is discontinued. A small amount of the hormones contained in the contraceptive and/or their metabolites can pass into breast milk and affect the child’s health.

Fertility

Chlormadinone and ethinylestradiol are indicated for oral contraception. Clinical studies have shown that conditions favorable for conception are restored already in the first cycle after discontinuation of chlormadinone and ethinylestradiol.

Special Precautions

Smoking

Smoking increases the risk of serious cardiovascular complications associated with the use of combined oral contraceptives. The risk increases with age, with an increase in the number of cigarettes smoked and is high in women over 35 years of age. Women over 35 years of age who smoke should use other methods of contraception.

The use of combined oral contraceptives is associated with an increased risk of developing serious complications, such as myocardial infarction, thromboembolism, stroke or liver neoplasms. Other risk factors, such as arterial hypertension, hyperlipidemia, obesity and diabetes mellitus, significantly increase the risk of complications and mortality. In the presence of one of the following diseases/conditions or risk factors, the potential risk and expected benefit of using the chlormadinone + ethinylestradiol combination should be weighed and discussed with the woman before she starts taking this drug.

In case of exacerbation of diseases, worsening of the condition or the appearance of the first symptoms of conditions/diseases or risk factors, the woman should immediately consult a doctor to decide on discontinuing the drug.

Thromboembolism or other vascular diseases

Results of epidemiological studies show that there is a relationship between the use of combined oral contraceptives and an increased risk of venous and arterial thromboembolic diseases, for example: myocardial infarction, cerebral hemorrhage, DVT and PE. These diseases develop rarely. Very rarely, thrombosis of other blood vessels has been reported in patients taking combined oral contraceptives, for example: hepatic, mesenteric, renal, or retinal veins and arteries.

Risk of developing VTE and ATE

Results of epidemiological studies indicate a relationship between the use of combined oral contraceptives and an increased incidence of venous and arterial thrombosis and thromboembolism (such as DVT and PE, myocardial infarction, cerebrovascular disorders). These diseases are rare. The risk of developing VTE is highest in the first year of taking such drugs. An increased risk is present after initial use of combined oral contraceptives or resumption of use after a break in taking the drug of 4 weeks or more. Data from a large prospective study involving 3 patient groups show that this increased risk is present mainly during the first 3 months. Drugs containing levonorgestrel, norgestimate or norethisterone as the progestogenic component have the lowest risk of developing VTE. It is unknown to what extent the risk of developing VTE when taking the chlormadinone + ethinylestradiol combination exceeds the risk of this complication when taking drugs containing levonorgestrel, norgestimate or norethisterone.

VTE can be life-threatening or fatal (in 1-2% of cases).

VTE, manifested as DVT or PE, can occur with the use of any combined oral contraceptives.

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

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

ATE can lead to stroke, vascular occlusion or myocardial infarction.

Symptoms of stroke: sudden weakness or loss of sensation in the face, limbs, especially on one side of the body, sudden confusion, unilateral or bilateral loss of vision, gait disturbance, dizziness, loss of balance or coordination, severe or prolonged headache for no apparent reason; problems with speech and understanding, loss of consciousness or fainting with or without a seizure.

Other signs of vascular occlusion sudden pain, swelling and slight cyanosis of the extremities, acute abdomen.

Symptoms of myocardial infarction: pain, discomfort, pressure, heaviness, feeling of squeezing or fullness in the chest or behind the breastbone, with radiation to the back, jaw, upper limb, epigastric region; cold sweat, nausea, vomiting or dizziness, severe weakness, anxiety or shortness of breath; rapid or irregular heartbeat. ATE can be life-threatening or fatal. In women with a combination of several risk factors or a high severity of one of them, the possibility of their mutual enhancement should be considered. In such cases, the degree of risk increase may be higher than with simple summation of factors.

In this case, the use of the chlormadinone + ethinylestradiol combination is contraindicated.

The risk of developing venous and/or arterial thrombosis, thromboembolism or cerebrovascular disorders increases

• With age;
• In smokers (the risk increases to a greater extent in women over 35 years of age);
• In the presence of a family history of venous or arterial thrombosis or thromboembolism in siblings or parents under the age of 50 years (in case of a suspected hereditary predisposition, consultation with a specialist should be obtained before starting combined oral contraceptives);
• With obesity (BMI over 30 kg/m²);
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation;
• In case of prolonged immobilization, major surgery, any surgery on the lower limbs, pelvic area or neurosurgical intervention, extensive severe trauma. In these situations, the use of combined oral contraceptives should be discontinued (in case of planned surgery at least four weeks before it) and not resumed for two weeks after the end of immobilization.

Temporary immobilization (for example, air travel lasting more than 4 hours) may also be a risk factor for the development of VTE, especially in the presence of other risk factors.

The question of the possible role of varicose veins and superficial thrombophlebitis in the development of VTE remains controversial.

The increased risk of thromboembolic complications in the postpartum period should be taken into account.

Peripheral circulatory disorders may also be noted in diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine while taking the chlormadinone + ethinylestradiol combination (which may precede cerebrovascular disorders) is grounds for immediate discontinuation of these drugs.

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

When assessing the benefit-risk ratio, it should be taken into account that therapy for these conditions/diseases may reduce the associated risk of developing thromboembolic complications.

Women taking the chlormadinone + ethinylestradiol drug should be informed that in case of possible symptoms of thrombosis, they should immediately consult a doctor and discontinue the drug.

Tumors

The most significant risk factor for cervical cancer (CC) is persistent human papillomavirus infection. There are reports of a slight increase in the risk of developing CC with long-term use of combined oral contraceptives. The connection with the use of combined oral contraceptives has not been proven. However, to date, there are controversies regarding the degree of influence of various factors on these data, in particular, cervical screening examinations or features of a woman’s sexual behavior (number of sexual partners or use of barrier contraceptive methods), as well as the cause-and-effect relationship of these factors.

According to a meta-analysis of the results of 54 epidemiological studies, a slight increase (1.24) in the risk of developing breast cancer (BC) was identified in women using combined oral contraceptives. The increased risk gradually decreases over 10 years after discontinuation of combined oral contraceptives. Since BC is rare in women under 40 years of age, the increase in the number of BC cases in women currently taking or recently taking combined oral contraceptives is insignificant relative to the overall risk of this disease. Its connection with the use of combined oral contraceptives has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of BC in women taking combined oral contraceptives (they are diagnosed with earlier clinical forms of BC than women who have not taken combined oral contraceptives), the biological effect of combined oral contraceptives, or a combination of both factors.

Very rarely, cases of benign and even more rarely malignant liver tumors have been observed with the use of combined oral contraceptives. In some cases, these tumors led to life-threatening intra-abdominal bleeding.

In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when conducting a differential diagnosis.

Meningioma

Cases of meningioma (single and multiple) have been reported with the use of chlormadinone acetate, especially when taken in high doses and for a long time (several years). Patients should be monitored for signs and symptoms of meningioma in accordance with clinical practice standards. If a patient is diagnosed with meningioma, as a precautionary measure, therapy with any drugs containing Chlormadinone acetate should be discontinued.

There is evidence that the risk of developing meningioma may decrease after discontinuation of chlormadinone acetate therapy.

Other conditions

Women with hypertriglyceridemia or a corresponding family history have an increased risk of developing pancreatitis when taking combined oral contraceptives.

Although a slight increase in blood pressure has been described in many women taking combined oral contraceptives, clinically significant increases have been rare. However, if a persistent clinically significant increase in blood pressure develops while taking combined oral contraceptives, the use of the chlormadinone + ethinylestradiol combination must be discontinued and antihypertensive therapy started. After normalization of blood pressure, the contraceptive can be continued.

In women with a history of gestational herpes, a relapse of this disease is possible while taking combined oral contraceptives.

In acute or chronic liver diseases, it may be necessary to discontinue the drug until liver function tests normalize.

Recurrence of cholestatic jaundice, which first developed during a previous pregnancy or previous use of sex hormones, requires discontinuation of COCs.

The use of the chlormadinone + ethinylestradiol combination may affect peripheral insulin resistance and glucose tolerance; women with diabetes mellitus should be under close medical supervision while taking the drug.

In rare cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma while taking COCs should avoid prolonged sun exposure and ultraviolet radiation.

Exacerbation of endogenous depression, epilepsy, Crohn’s disease, and ulcerative colitis has been reported during COC use.

Depressed mood and depression are well-known adverse reactions to hormonal contraceptives (see section “Adverse Reactions”). Depression can be serious and is a well-known risk factor for suicidal behavior and suicide. Women should consult their doctor if mood swings and depressive symptoms occur, including shortly after starting COCs.

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

Use with caution

The use of drugs containing estrogen or estrogen + progestogen may adversely affect some diseases and conditions, in which case careful medical supervision is required

• Multiple sclerosis
• Tetany
• Bronchial asthma
• Chronic heart or renal failure
• Chorea
• Diabetes mellitus
• Liver diseases
• Dyslipoproteinemia
• Arterial hypertension
• Endometriosis
• Porphyria
• Varicose veins
• Thrombophlebitis
• Blood clotting disorders
• Mastopathy
• Autoimmune diseases, including systemic lupus erythematosus
• Gestational herpes
• Uterine fibroids

Medical examinations, check-up

Before starting or resuming the use of the chlormadinone + ethinylestradiol combination, it is necessary to review the woman’s personal and family history, perform a general medical (including blood pressure measurement, BMI determination) and gynecological examination (including breast examination and cervical cytology), and rule out pregnancy. The scope of additional tests and the frequency of follow-up examinations are determined individually, at least once every 6 months.

Women should be informed that the drug does not protect against HIV infection (AIDS) and other sexually transmitted infections!

Reduced effectiveness

A missed tablet (see section “Dosage and Administration”, subsection “Recommendations in case of a missed dose”), vomiting or intestinal disorders, including diarrhea, long-term concomitant use of certain drugs (see section “Drug Interactions”) or, in very rare cases, metabolic disorders may reduce the contraceptive effectiveness of the drug.

Effect on menstrual cycle control

Breakthrough bleeding and spotting

The use of COCs may lead to vaginal bleeding (breakthrough bleeding and minor spotting), especially during the first cycles of drug use. Therefore, medical evaluation of irregular cycles should be performed only after an adaptation period of about three cycles. If breakthrough bleeding persists or reappears during the use of the chlormadinone + ethinylestradiol combination, although the cycle was previously regular, an examination should be performed to rule out pregnancy or organic diseases. After excluding pregnancy or an organic disease, the use of the chlormadinone + ethinylestradiol combination can be continued or the patient can be switched to another contraceptive.

Intermenstrual bleeding may be a sign of reduced contraceptive effectiveness (see section “Dosage and Administration”, subsections “Recommendations in case of a missed dose”, “Recommendations in case of gastrointestinal disorders”, and section “Drug Interactions”).

Absence of withdrawal bleeding

As a rule, withdrawal bleeding occurs after 21 days of drug use. Sometimes, especially during the first months of drug use, withdrawal bleeding may be absent. However, this does not necessarily indicate a reduction in contraceptive effect.

If bleeding was absent after one cycle of use, during which the woman did not violate the dosing regimen (did not miss a tablet, did not exceed a 7-day break in use), did not take other drugs, and the patient did not have vomiting or diarrhea, then fertilization of the egg is unlikely and the use of the chlormadinone + ethinylestradiol combination can be continued.

If before the first absence of withdrawal bleeding the use of the chlormadinone + ethinylestradiol combination occurred in violation of the instructions or withdrawal bleeding is absent for two cycles, pregnancy should be ruled out before continuing the drug use.

Herbal preparations containing St. John’s wort (Hypericum perforatum) should not be taken concomitantly with the chlormadinone + ethinylestradiol combination (see section “Drug Interactions”).

Effect of chlormadinone and ethinylestradiol on laboratory tests

Some laboratory test parameters may change during COC use, for example: biochemical parameters of liver, thyroid, adrenal, and kidney function, the content of transport proteins in blood plasma (e.g., corticosteroid-binding globulin, lipid and lipoprotein fractions), as well as parameters of carbohydrate metabolism, coagulation, and fibrinolysis. Usually, the changes remain within normal limits.

Excipients

This drug contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and machinery

There are no data on the negative effect of COC use on the ability to drive vehicles and machinery.

Overdose

There are no data on serious toxic effects of the drug in case of overdose.

Symptoms nausea, vomiting, and minor vaginal bleeding may occur, especially in young girls.

Treatment there is no specific antidote; symptomatic therapy is administered. In rare cases, monitoring of water-electrolyte balance and liver function parameters may be necessary.

Drug Interactions

Note: in case of simultaneous use of the chlormadinone + ethinylestradiol combination and other drugs, information presented in the medical instructions for use of these drugs should also be analyzed to identify possible drug interactions.

Pharmacodynamic interaction

In clinical studies involving patients receiving drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, for the treatment of viral hepatitis C (HCV), women using drugs containing ethinylestradiol, such as combined hormonal contraceptives, had a significantly higher frequency of ALT activity increase of more than 5 times the upper limit of normal.

Furthermore, an increase in ALT activity was observed in women using drugs containing ethinylestradiol, such as combined hormonal contraceptives, and receiving glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir (see section “Contraindications”).

Therefore, women taking chlormadinone and ethinylestradiol should switch to another method of contraception (e.g., drugs containing only progestogen, or non-hormonal methods) before starting therapy with these drug combinations. The use of chlormadinone and ethinylestradiol can be resumed 2 weeks after completion of treatment with the specified drug combinations.

Pharmacokinetic interaction

Effect of other drugs on the chlormadinone + ethinylestradiol combination

Interaction with drugs that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, which, in turn, will lead to breakthrough bleeding and/or loss of the contraceptive effect of the chlormadinone + ethinylestradiol combination.

Risk reduction measures

Induction of hepatic microsomal enzymes can be observed within a few days of drug use. Maximum induction of hepatic microsomal enzymes is usually observed within a few weeks. After drug discontinuation, enzyme induction may persist for up to 4 weeks.

Short-term therapy

Women receiving inducers of hepatic microsomal enzymes concomitantly with COCs are advised to temporarily use a barrier or other non-hormonal method of contraception. The barrier method of contraception should be used throughout the period of concomitant therapy and for another 28 days after discontinuation of the inducer drug. If the use of the inducer continues after taking the last COC tablet from the current package, tablet intake from a new package should be started, omitting the break in use.

Long-term therapy

Women receiving long-term therapy with inducers of hepatic microsomal enzymes are recommended to use another reliable non-hormonal method of contraception.

Known interaction

Substances leading to increased clearance of COCs (reduced effectiveness of COCs due to induction of hepatic microsomal enzymes), for example

Barbiturates, bosentan, carbamazepine, barbexaclone, phenytoin, primidone, modafinil, rifampicin, rifabutin and drugs for HIV treatment: ritonavir, nevirapine, efavirenz and possibly felbamate, griseofulvin, oxcarbazepine, topiramate and preparations containing St. John’s wort (Hypericum perforatum).

Drugs/active substances that may reduce the concentration of ethinylestradiol in blood serum

All drugs that increase gastrointestinal motility (e.g., metoclopramide) or impair absorption (e.g., activated charcoal).

Substances with varying effects on COC clearance

When used concomitantly with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with hepatitis C virus protease inhibitors, may increase or decrease the plasma concentrations of estrogens or progestogens. The overall effect of such changes may in some cases be clinically significant.

To identify possible drug interactions and related recommendations, information presented in the medical instructions for use of concomitant drugs intended for the treatment of HIV infection/hepatitis C should be analyzed. In case of any doubts, women receiving protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use an additional barrier method of contraception.

The following drugs/active substances may increase the concentration of ethinylestradiol in blood serum

• Substances that inhibit the sulfation of ethinylestradiol in the intestinal wall, for example, ascorbic acid or paracetamol;
• Atorvastatin (increases the AUC of ethinylestradiol by 20%);
• Substances that inhibit the activity of hepatic microsomal enzymes, such as antifungal agents derived from imidazole (e.g., fluconazole), indinavir, or troleandomycin.

Effect of the chlormadinone + ethinylestradiol combination on other drugs

• By inhibiting the activity of hepatic microsomal enzymes and, accordingly, increasing the serum concentration of substances such as diazepam (and other benzodiazepines metabolized by hydroxylation), cyclosporine, theophylline, and prednisolone;
• By inducing glucuronidation in the liver and, accordingly, reducing the serum concentration of substances such as lamotrigine, clofibrate, paracetamol, morphine, and lorazepam.

The chlormadinone + ethinylestradiol combination affects glucose tolerance, so the need for insulin and oral hypoglycemic agents may change. The described interaction features may also apply to drugs that have been used recently.

The instructions for use of each prescribed drug should be studied to identify possible interactions with the chlormadinone + ethinylestradiol combination.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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