Chloe^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sanofi Russia JSC (Russia)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

ATC Code

G03HB01 (Cyproterone and estrogens)

Active Substances

Cyproterone (Rec.INN registered by WHO)

Ethinylestradiol (Rec.INN registered by WHO)

Dosage Form

Chloe®

Film-coated tablets, 35 mcg + 2 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets, of two types.

Yellow-orange film-coated tablets, round, biconvex (21 pcs. in a blister).

Excipients : lactose monohydrate, povidone, sodium carboxymethyl starch (type A), colloidal anhydrous silicon dioxide, colloidal aluminum oxide, magnesium stearate.

Shell composition dye Opadry Yellow II OY-L-32901 (Opadry II Yellow OY-L-32901) (lactose monohydrate, hypromellose 2910, titanium dioxide, macrogol 4000, yellow iron oxide, black iron oxide, red iron oxide, purified water).

White tablets (placebo), round, biconvex (7 pcs. in a blister).

Excipients : lactose monohydrate, povidone, sodium carboxymethyl starch (type A), colloidal anhydrous silicon dioxide, colloidal aluminum oxide, magnesium stearate.

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

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Contraceptive agent (estrogen + antiandrogen)

Pharmacological Action

A combined low-dose monophasic oral contraceptive drug with antiandrogenic activity. The mechanism of action is due to its constituent antiandrogenic drug of steroid structure – cyproterone acetate and the oral estrogen – ethinylestradiol.

Cyproterone acetate

It has the ability to competitively bind to receptors of natural androgens (including testosterone, dehydroepiandrosterone, androstenedione), which are produced in small amounts in the female body, mainly in the adrenal glands, ovaries, and skin. By blocking androgen receptors in target organs, it reduces the phenomena of androgenization in women (by disrupting processes mediated by hormone-receptor complexes at the level of the main intracellular mechanisms). Thus, it becomes possible to treat diseases caused by increased production of androgens or specific sensitivity to these hormones.

Against the background of taking the drug, the increased activity of the sebaceous glands, which plays an important role in the occurrence of acne and seborrhea, decreases. After 3-4 months of therapy, the existing rash usually disappears. Excessive oiliness of hair and skin disappears even earlier. Hair loss, which often accompanies seborrhea, is also reduced.

Therapy with Chloe^® in women of reproductive age reduces the clinical manifestations of mild forms of hirsutism; however, the effect of treatment should be expected only after several months of use.

Along with antiandrogenic properties, cyproterone acetate has progestogenic activity, mimicking the properties of the corpus luteum hormone. It inhibits the secretion of gonadotropic hormones by the pituitary gland and inhibits ovulation, which causes the contraceptive effect.

Ethinylestradiol

It enhances the central and peripheral effects of cyproterone acetate on ovulation, maintains high viscosity of cervical mucus, making it difficult for sperm to penetrate into the uterine cavity and helping to ensure a reliable contraceptive effect.

Against the background of taking the drug, the cycle becomes more regular, painful menstruation is less often observed, the intensity of bleeding decreases, and the risk of iron deficiency anemia decreases.

Pharmacokinetics

Cyproterone acetate

Absorption

After oral administration of the drug, cyproterone acetate is completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached after 1.6 h and is 15 ng/ml. Bioavailability is 88%.

Distribution

Cyproterone acetate is almost completely bound to plasma albumin, approximately 3.5-4% is in the free state. Since the binding to proteins is nonspecific, changes in the level of sex hormone-binding globulin (SHBG) do not affect the pharmacokinetics of cyproterone acetate.

Metabolism

It is biotransformed by hydroxylation and conjugation, the main metabolite is the 15b-hydroxy derivative.

Excretion

The pharmacokinetics of cyproterone acetate is biphasic: T_1/2 is 0.8 h and 2.3 days for the first and second phases, respectively. Total plasma clearance is 3.6 ml/min/kg. It is excreted mainly in the form of metabolites by the kidneys and through the intestine in a ratio of 1:2, a small part – unchanged through the intestine. Up to 0.2% of the dose of cyproterone acetate is excreted in breast milk. T_1/2 for metabolites of cyproterone acetate is 1.8 days.

Ethinylestradiol

Absorption

After taking the drug, Ethinylestradiol is rapidly and completely absorbed from the gastrointestinal tract. C_max is approximately 80 pg/ml and is reached after 1.7 h. Bioavailability is about 45%, with significant individual variability.

Distribution

Binding to plasma proteins (albumin) is high: only 2% is in the plasma in free form.

Ethinylestradiol increases hepatic synthesis of SHBG and corticosteroid-binding globulin (CBG) with continuous use. During treatment with Chloe^®, the concentration of SHBG in serum increases from approximately 100 nmol/l to 300 nmol/l, and the serum concentration of CBG increases from approximately 50 µg/ml to 95 µg/ml.

Metabolism

During absorption and “first pass” through the liver, Ethinylestradiol undergoes intensive metabolism.

Excretion

The pharmacokinetics of ethinylestradiol is biphasic: T_1/2 is 1-2 h and approximately 20 h, respectively. Plasma clearance is about 5 ml/min/kg. Ethinylestradiol is excreted from the body in the form of metabolites: about 40% by the kidneys, 60% through the intestine. Up to 0.02% of the dose of ethinylestradiol is excreted in breast milk.

Indications

• Contraception in women with signs of androgenization.

Androgen-dependent diseases in women

• Acne, especially its severe forms, accompanied by seborrhea, inflammatory phenomena with the formation of nodules (papulopustular acne, nodulocystic acne);
• Androgenic alopecia;
• Mild forms of hirsutism.

ICD codes

Dosage Regimen

The drug should be taken orally, 1 tablet/day. The tablet should be taken without chewing and washed down with a small amount of liquid. It is recommended to take the drug at the same time, preferably after breakfast or dinner.

If no hormonal contraceptive drugs were taken in the previous month

Chloe^® is started on the 1st day of the cycle (i.e., on the first day of menstrual bleeding), using the tablet of the corresponding day of the week from the calendar pack. It is allowed to start taking it on the 2nd-5th day of the menstrual cycle, but in this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking the tablets from the first pack.

Daily intake of the drug is carried out by using the tablets from the calendar pack sequentially in the direction of the arrow printed on the foil until all tablets are taken. After finishing all 21 yellow-orange tablets from the calendar pack, it is necessary to take the remaining white tablets for the next 7 days. During the last 7 days of the treatment cycle (28 days), menstrual-like bleeding should occur (as a result of treatment withdrawal). Menstrual-like bleeding usually begins 2-3 days after the 21st day of the treatment cycle with the drug. The next pack should be started the day after the complete intake of tablets from the previous pack, regardless of whether the bleeding continues or not.

When switching from combined contraceptive drugs (oral contraceptives (COCs), vaginal ring, or contraceptive patch)

Taking the drug Chloe^® should be started the day after taking the last active tablet of the previous drug, but in no case later than the next day after the usual 7-day break in taking (for drugs containing 21 tablets). Then follow the scheme described above.

If the patient took the previous contraceptive daily for 28 days, taking the drug Chloe^® should be started after taking the last inactive tablet. Taking the drug Chloe^® should be started on the day of removal of the vaginal ring or contraceptive patch, but no later than the day when a new ring should be inserted or a new patch should be applied.

When switching from contraceptives containing only progestogens (“mini-pills”, injectable forms, implants, progestogen-releasing intrauterine contraceptive)

When switching from “mini-pills”, the drug Chloe^® can be started without a break.

When using injectable forms of contraceptives, the drug Chloe^® should be taken from the day when the next injection should be made.

When switching from an implant, Chloe^® should be applied on the day of its removal.

In all cases, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the drug.

After abortion in the first trimester of pregnancy, a woman can start using Chloe^® immediately. In this case, there is no need for additional methods of contraception.

After childbirth in the absence of breastfeeding or abortion in the second trimester of pregnancy, taking the drug should be started on the 21st-28th day. If the intake is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of using the drug.

If a woman had sexual intercourse during the period between childbirth or abortion, then before starting to take the drug Chloe^®, pregnancy should first be ruled out or it is necessary to wait for the first menstruation.

Taking missed tablets

A missed tablet should be taken as soon as possible, the next tablet – at the usual time. If the delay is <12 h, the reliability of contraception is not reduced. If the delay in taking the tablet is >12 h, the reliability of contraception may be reduced. The more tablets are missed and the closer the miss is to the 7-day break in taking the tablets, the higher the likelihood of pregnancy. In this case, the following two basic rules can be followed

• Taking the drug should never be interrupted for more than 7 days;
• 7 days of continuous intake of the drug are required to achieve adequate suppression of the hypothalamic-pituitary-ovarian regulation.

Accordingly, the following recommendations can be given if the delay in taking the tablets is more than 12 h (the interval from the moment of taking the last tablet is more than 36 h).

First week of taking the drug

The woman should take the last missed tablet as soon as possible, as soon as she remembers (even if this means taking two tablets at the same time). The next tablet should be taken at the usual time. Additionally, a barrier method of contraception should be used for the next 7 days. If sexual intercourse took place during the week before missing the tablet, the possibility of pregnancy should be considered.

Second week of taking the drug

The woman should take the last missed tablet as soon as possible, as soon as she remembers (even if this means taking two tablets at the same time). The next tablet should be taken at the usual time.

Provided that the woman took the tablets correctly for 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, as well as if two or more tablets are missed, it is necessary to additionally use barrier methods of contraception (for example, a condom) for 7 days.

Third week of taking the drug

The risk of pregnancy increases due to the upcoming break in taking the tablets; however, if during the 7 days preceding the first missed tablet, all tablets were taken correctly, there is no need to use additional contraceptive methods.

1. The woman should take the last missed tablet as soon as possible, as soon as she remembers (even if this means taking two tablets at the same time). The following tablets are taken at the usual time until the tablets from the current pack run out. The next pack should be started immediately. Withdrawal bleeding is unlikely until the tablets from the second pack run out, but spotting and breakthrough bleeding may be noted while taking the tablets.

2. The woman can also interrupt taking the tablets from the current pack. Then she should take a break for 7 days, including the day of missing the tablet, and then start taking tablets from a new pack. If a woman missed taking a tablet, and then during the break in taking she does not have withdrawal bleeding, pregnancy must be ruled out.

Recommendations for gastrointestinal disorders

If a woman had vomiting within 3 to 4 hours after taking the drug, the absorption of active substances may be incomplete. In this case, it is necessary to focus on the recommendations for a missed tablet.

Changing the day of menstrual-like bleeding

In order to delay the onset of menstrual-like bleeding, the woman should continue taking tablets from a new pack of the drug immediately after all tablets from the previous pack have been taken, without a break in taking. Tablets from this new pack can be taken for as long as the woman wishes (until the pack runs out). While taking the drug from the second pack, the woman may experience spotting or breakthrough uterine bleeding. Resumption of taking Chloe^® from a new pack should be after the usual 7-day break.

In order to move the day of the onset of menstrual-like bleeding to another day of the week, the woman should shorten the nearest break in taking the tablets by as many days as she wants. The shorter the interval, the higher the risk that she will not have withdrawal bleeding and will subsequently have spotting and breakthrough bleeding while taking the second pack (just as in the case when she would like to delay the onset of menstrual-like bleeding).

For the treatment of hyperandrogenic conditions

The duration of administration is determined by the severity of the disease. After the symptoms disappear, it is recommended to take the drug for at least another 3-4 months. If a relapse occurs several weeks or months after the completion of the course, repeated therapy with the drug Chloe^® can be carried out. In case of resumption of taking the drug (after a break of 4 weeks or more), the increased risk of VTE should be taken into account.

Children and adolescents

The drug Chloe^® is indicated only after menarche.

Postmenopausal women

The drug Chloe^® is not indicated after menopause.

Liver function disorders

The drug Chloe^® is contraindicated in women with severe liver diseases until liver function tests return to normal.

Renal function disorders

The drug Chloe^® has not been specifically studied in patients with renal disorders. Available data do not suggest dose adjustment in such cases.

Adverse Reactions

Definition of the frequency of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency unknown (frequency cannot be estimated from the available data).

Nervous system disorders: common – headache; uncommon – migraine; frequency unknown – worsening of epilepsy.

Eye disorders: rare – contact lens intolerance.

Gastrointestinal disorders: common — nausea, abdominal pain; uncommon – vomiting, diarrhea.

Skin and subcutaneous tissue disorders: uncommon – rash, urticaria; frequency unknown – erythema nodosum, erythema multiforme.

Metabolism and nutrition disorders: common – weight gain; uncommon – fluid retention; rare – weight loss.

Immune system disorders: rare – hypersensitivity reactions.

Reproductive system and breast disorders: common – breast pain/tenderness, breast engorgement; uncommon – breast enlargement; rare – vaginal discharge, breast discharge*; frequency unknown – acyclic spotting/bleeding (metrorrhagia).

Psychiatric disorders: common – depressed mood, mood swings; uncommon – decreased libido; rare – increased libido; frequency unknown – worsening of endogenous depression.

Cardiac and vascular disorders: rare – thromboembolism.

*During post-marketing studies, painful menstrual-like bleeding and absence of menstrual-like bleeding were reported, the frequency of which could not be estimated.

Serious adverse events reported in women using COCs (which include the drug Chloe^®)

Cardiac and vascular disorders venous thromboembolic disorders, arterial thromboembolic disorders, stroke, increased blood pressure.

Metabolic side effectshypertriglyceridemia, impaired glucose tolerance or effect on peripheral insulin resistance.

Digestive system side effects:liver tumors (benign and malignant), impaired liver function tests, pancreatitis, cholecystitis.

Skin and subcutaneous tissue side effectschloasma.

Allergic reactions in women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Nervous system and sensory organs side effectsvisual impairment, dizziness.

Occurrence or worsening of conditions for which the association with the use of COCs (which include the drug Chloe^®) is not indisputablejaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea; herpes during a previous pregnancy; hearing loss associated with otosclerosis; Crohn’s disease; ulcerative colitis; cervical cancer.

The frequency of diagnosis of breast cancer is very slightly increased in women using COCs (which include the drug Chloe^®). Breast cancer is rarely observed in women under 40 years of age, and the increase in frequency is slight relative to the overall risk of breast cancer. A causal relationship between the occurrence of breast cancer and the use of COCs has not been established.

Contraindications

• Concomitant use with other hormonal contraceptives;
• Thrombosis and thromboembolism, including in the anamnesis (deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders, e.g., stroke);
• Conditions preceding thrombosis (including transient ischemic attacks, angina pectoris);
• Multiple or pronounced risk factors for venous or arterial thrombosis (including complicated heart valve defects, atrial fibrillation, cerebrovascular or coronary artery diseases; uncontrolled arterial hypertension, severe dyslipoproteinemia, subacute bacterial endocarditis, prolonged immobilization, surgical interventions on the lower extremities, neurosurgical operations, extensive trauma, smoking at the age over 35 years, obesity with BMI over 30 kg/m²);
• Identified hereditary or acquired predisposition to venous or arterial thrombosis, e.g., resistance to activated protein C (APC), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• Diabetes mellitus with diabetic angiopathy;
• Severe liver diseases currently or in the anamnesis or significant liver function impairments not earlier than 6 months after normalization of liver function tests;
• Liver tumors (benign and malignant);
• Hormone-dependent malignant tumors or suspicion thereof, including tumors of the breast or genital organs (including in the anamnesis);
• Vaginal bleeding of unknown etiology;
• Pancreatitis with severe hypertriglyceridemia (including in the anamnesis);
• History of migraine accompanied by focal neurological symptoms;
• Pregnancy or suspected pregnancy;
• Period of breastfeeding;
• Congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson and Rotor syndromes);
• Age over 40 years;
• Hyperprolactinemia;
• Lactose intolerance, lactase deficiency, glucose/galactose malabsorption syndrome;
• Hypersensitivity to the drug components.

If any of these conditions develop for the first time while taking Chloe^®, the drug should be discontinued immediately.

The drug Chloe^® is not intended for use in men.

Caution should be exercised when using Chloe^® in epilepsy, depression, ulcerative colitis, liver and gallbladder diseases, uterine fibroids, mastopathy, chorea, tetany, porphyria, multiple sclerosis, varicose veins, tuberculosis, kidney diseases, in adolescence (without regular ovulatory cycles), dyslipoproteinemia, sickle cell anemia, idiopathic jaundice or pruritus during a previous pregnancy, otosclerosis with hearing impairment during a previous pregnancy.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy, suspected pregnancy, and during breastfeeding.

Use in Hepatic Impairment

The use of the drug is contraindicated in liver diseases or significant liver function impairments, liver tumors (including in the anamnesis), congenital hyperbilirubinemias (Gilbert’s, Dubin-Johnson, Rotor syndromes), idiopathic jaundice or pruritus during the last pregnancy.

The drug should be used with caution in liver and gallbladder diseases.

Use in Renal Impairment

The drug should be used with caution in kidney disease.

Geriatric Use

Contraindicated in age over 40 years.

Special Precautions

Before starting the use of Chloe^®, a general medical examination (including breast examination and cytological examination of cervical mucus) should be performed, pregnancy should be excluded, and disorders of the blood coagulation system should be ruled out. With long-term use of the drug, preventive control examinations should be performed every 6 months.

In the presence of risk factors, the potential risk and expected benefit of therapy should be carefully assessed and discussed with the woman before starting the drug.

If the severity increases, intensifies, or if any of the conditions or risk factors listed below first appear, discontinuation of the drug may be required.

The use of the drug Chloe^® leads to an increased risk of developing venous thromboembolism (VTE) compared to the risk in women not taking the drug. The additional risk of VTE is highest during the first year of using Chloe^® or when resuming use after a break of 4 weeks or more. VTE can be fatal in 1-2% of cases. The approximate frequency of VTE when taking low-dose estrogen oral contraceptives (less than 50 mcg ethinyl estradiol) is up to 4 per 10,000 women per year compared to 0.5-1 per 10,000 women not taking COCs. At the same time, the frequency of VTE when taking COCs is less than the frequency of VTE associated with pregnancy (6 per 10,000 pregnant women per year).

Epidemiological studies have shown that the frequency of VTE is 1.5 to 2 times higher in women taking Chloe^® compared to COCs containing levonorgestrel, and is similar for COCs containing desogestrel/gestodene/drospirenone. In patients with polycystic ovary syndrome, there is an increased risk of developing cardiovascular diseases. Epidemiological studies have also shown an association between the use of hormonal contraceptives and an increased risk of arterial thromboembolism (myocardial infarction, transient ischemic attacks).

Very rarely, thrombosis of other blood vessels, namely, hepatic, mesenteric, renal, cerebral or retinal veins and arteries, has been reported in persons taking hormonal contraceptives.

The patient should be warned that if symptoms of venous or arterial thrombosis develop, she should immediately consult a doctor. These symptoms include unilateral pain in the lower limb and/or swelling; sudden severe chest pain with or without radiation to the left arm; sudden shortness of breath; sudden attack of coughing; any unusual, severe, prolonged headache; increased frequency and severity of migraine; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; dizziness; collapse with/or without partial seizure; weakness or significant loss of sensation, suddenly appearing on one side or in one part of the body; motor disturbances; “acute abdomen” symptom complex.

The risk of VTE increases

• With increasing age;
• With smoking (with heavy smoking and with increasing age, the risk additionally increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to quit smoking if they wish to take Chloe^®);
• With a burdened family history (i.e., if there is a history of venous thromboembolism at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, a woman should consult a specialist before deciding on any hormonal contraception;
• With prolonged immobilization, surgical interventions on the lower extremities, neurosurgical operations or extensive trauma. In these situations, it is necessary to discontinue use (in case of planned surgery at least 4 weeks before), and not resume it until 2 weeks after full restoration of motor activity. If the use of Chloe^® was not discontinued in advance, the issue of antithrombotic therapy should be considered;
• With obesity (BMI over 30 kg/m²).

The risk of arterial thromboembolic complications or cerebrovascular disorders increases

• With increasing age;
• With smoking (with heavy smoking and with increasing age, the risk additionally increases, especially in women over 35 years of age. Women over 35 years of age should be strongly advised to quit smoking if they wish to take Chloe^®);
• With dyslipoproteinemia;
• With arterial hypertension;
• With migraine;
• With heart valve diseases;
• With atrial fibrillation;
• With a burdened family history (i.e., if there is a history of arterial thrombosis at a relatively young age in parents or close relatives). If a hereditary predisposition is suspected, a woman should consult a specialist before deciding on any hormonal contraception.

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

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

An increase in the frequency or severity of migraine attacks during the use of Chloe^® (which may be a precursor to cerebrovascular disorders) is grounds for immediate discontinuation of the drug.

There is no consensus regarding the potential role of varicose veins and superficial thrombophlebitis in the development of venous thromboembolism.

Biochemical factors that may indicate a hereditary or acquired predisposition to venous or arterial thrombosis include resistance to activated protein C (APC), hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

When assessing the risk/benefit ratio, the physician should consider that appropriate treatment of the underlying pathology may reduce the risk of thrombosis. Women taking Chloe^® should be explained the need to promptly inform their doctor about the occurrence of possible symptoms of thrombosis. In case of thrombosis or suspicion of its occurrence, treatment with Chloe^® should be discontinued. Given the teratogenicity of coagulants (coumarins), adequate contraceptive methods should be initiated.

Other conditions

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

The relationship between COC use and arterial hypertension has not been established. If persistent arterial hypertension occurs, Chloe^® should be discontinued and appropriate antihypertensive therapy prescribed. Contraceptive use can be continued when blood pressure normalizes.

If liver function disorders occur, temporary discontinuation of Chloe^® may be required until laboratory parameters normalize. Recurrent cholestatic jaundice, which develops for the first time during pregnancy or previous use of sex hormones, requires discontinuation of COCs.

Although COCs affect insulin resistance and glucose tolerance, there is usually no need to adjust the dose of hypoglycemic drugs in patients with diabetes mellitus. Nevertheless, this category of patients should be under careful medical supervision.

Women prone to chloasma while taking COCs should avoid prolonged exposure to the sun and ultraviolet radiation.

If symptoms of hirsutism in women have developed recently or significantly worsened, other causes, such as an androgen-producing tumor, congenital adrenal cortex dysfunction, should be considered in the differential diagnosis.

While taking Chloe^®, irregular bleeding (spotting or breakthrough bleeding) may sometimes occur, especially during the first months of therapy. Therefore, the assessment of any irregular bleeding should be carried out only after an adaptation period of approximately 3 cycles.

If irregular bleeding recurs or develops after previous regular cycles, non-hormonal causes should be considered and adequate diagnostic measures should be carried out to exclude malignant neoplasms (including diagnostic curettage of the uterine cavity) or pregnancy. In some cases, withdrawal bleeding may not occur during the break in taking the pills. If pills are taken irregularly or if two consecutive menstrual-like bleedings are absent, pregnancy should be excluded before continuing to take the drug.

Changes in the results of skin allergy tests, a decrease in the concentration of LH and FSH are possible. Since the contraceptive effect is fully manifested by the 7th day from the start of taking the drug, additional non-hormonal methods of contraception are recommended during the first week.

It is recommended to prescribe the drug after childbirth in the absence of breastfeeding only after the completion of the first normal menstrual cycle.

Treatment should be discontinued 3 months before the planned pregnancy.

In case of diarrhea and vomiting, the contraceptive effect is reduced (without discontinuing the drug, it is necessary to use additional non-hormonal methods of contraception).

Tumors

There are reports of a certain increase in the risk of developing cervical cancer with long-term use of COCs. The connection with COC use has not been proven. It remains controversial to what extent these findings are related to cervical pathology or to sexual behavior characteristics (less frequent use of barrier contraceptive methods). The most significant risk factor for the development of cervical cancer is persistent papillomavirus infection. A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk of developing breast cancer diagnosed in women currently taking COCs (relative risk 1.24). The increased risk gradually disappears within 10 years after stopping these drugs. Since breast cancer is rare in women under 40 years of age, the increase in the number of breast cancer diagnoses in women currently taking or recently taking COCs is insignificant relative to the overall risk of this disease. Its connection with COC use has not been proven. The observed increase in risk may also be a consequence of earlier diagnosis of breast cancer in women using COCs. In women who have ever used COCs, earlier stages of breast cancer are detected than in women who have never used them.

In rare cases, the development of liver tumors has been observed while taking COCs, which in some cases led to life-threatening intra-abdominal bleeding. This should be taken into account when conducting a differential diagnosis in case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding.

Laboratory tests

The use of COCs may affect the results of laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, the concentration of plasma proteins, e.g., corticosteroid-binding globulin, as well as the lipid/lipoprotein composition of the blood, carbohydrate metabolism parameters and blood coagulation system parameters. However, deviations usually remain within the range of normal laboratory values.

Overdose

Symptoms: nausea, vomiting, slight vaginal bleeding.

Treatment: symptomatic therapy is carried out. There is no specific antidote.

Drug Interactions

With the simultaneous use of Chloe^® with inducers of liver microsomal enzymes (hydantoins, barbiturates, primidone, carbamazepine and rifampicin; and also, possibly, with oxcarbazepine, topiramate, felbamate and griseofulvin), the clearance of ethinyl estradiol and cyproterone increases, which can lead to “breakthrough” uterine bleeding or reduced contraceptive reliability.

With simultaneous use with ampicillin, rifampicin and tetracyclines, the contraceptive reliability of Chloe^® is reduced.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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