Diecyclen^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zentiva, k.s. (Czech Republic)

Manufactured By

Laboratorios Leon Farma, S.A. (Spain)

Contact Information

EXELTIS HEALTHCARE S.L. (Spain)

ATC Code

G03AA16 (Dienogest and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Diecyclen®

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

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the cross-section shows a white or almost white core.

Excipients: lactose monohydrate – 54.6 mg, corn starch – 9.89 mg, povidone K30 – 1.73 mg, talc – 1.4 mg, magnesium stearate – 0.33 mg.

Shell composition opadry 2 clear – 0.5 mg (sodium carmellose – 270.8 mcg, maltodextrin – 104 mcg, dextrose monohydrate – 84.7 mcg, soy lecithin – 30.5 mcg, sodium citrate dihydrate – 10 mcg).

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

Clinical-Pharmacological Group

Combined hormonal contraceptive (estrogen + progestogen)

Pharmacotherapeutic Group

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

Pharmacological Action

A low-dose combined monophasic oral hormonal contraceptive drug. The contraceptive effect is based on the interaction of various factors, the most important of which is the suppression of ovulation and the change in the viscosity of cervical secretion, making it impenetrable to sperm.

When used correctly, the Pearl index (an indicator reflecting the number of pregnancies in 100 women using the contraceptive for 1 year) is less than 1. If tablets are missed or used incorrectly, the Pearl index may increase.

In women taking combined oral contraceptives, the cycle becomes more regular, the painfulness, intensity, and duration of withdrawal bleeding decrease, thereby reducing the risk of iron deficiency anemia. There is also evidence of a reduced risk of endometrial and ovarian cancer.

The progestogenic component Dienogest, which is part of the drug, is an active progestogen, a derivative of norethisterone with antiandrogenic activity, and has a positive effect on the lipid profile by increasing HDL concentration.

Pharmacokinetics

Ethinylestradiol

Absorption

When taken orally, it is rapidly and completely absorbed. C_max of ethinylestradiol in blood plasma (about 67 pg/ml) is reached after 1.5-4 hours. After absorption and the first-pass effect through the liver, Ethinylestradiol is metabolized; its absolute bioavailability after oral administration is about 44%.

Distribution

Ethinylestradiol is largely bound to plasma proteins (approximately 98%) and induces the synthesis of sex hormone-binding globulin (SHBG). The V_d of ethinylestradiol is about 2.8-8.6 l/kg.

Steady-state concentration (C_ss) of ethinylestradiol in plasma is achieved in the second half of the treatment cycle with regular intake.

Metabolism

Ethinylestradiol undergoes presystemic conjugation both in the small intestinal mucosa and in the liver. The main metabolic pathway is aromatic hydroxylation with the formation of numerous hydroxylated and methylated derivatives in the form of free metabolites, glucuronide and sulfate metabolites. The plasma clearance rate is approximately 2.3-7 ml/min/kg.

Elimination

The decrease in ethinylestradiol plasma concentration is biphasic: the first phase is characterized by a T_1/2 of about 1 hour, the second – 10-20 hours. It is not excreted unchanged from the body. Ethinylestradiol metabolites are excreted by the kidneys and through the intestines in a ratio of 4:6 with a T_1/2 of about 24 hours.

Dienogest

Absorption

When taken orally, it is rapidly and almost completely absorbed. C_max of dienogest in blood plasma (about 51 pg/ml) is reached after 2.5 hours. The absolute bioavailability of dienogest is 96%.

Distribution

90% of the total dienogest concentration in plasma is bound to serum albumin, but does not bind to SHBG or corticosteroid-binding globulin. 10% of the total plasma dienogest concentration is unbound. The V_d of dienogest is about 37-45 l.

Steady-state concentration (C_ss) in plasma is achieved after 4 days of constant intake.

The induction of globulin synthesis by ethinylestradiol does not affect the pharmacokinetics of dienogest. With daily use of the drug, the serum concentration of dienogest increases by 1.5 times.

Metabolism

It is metabolized mainly by hydroxylation, but also by hydrogenation, conjugation, and aromatization to form inactive metabolites. After a single dose, the total clearance of dienogest is about 3.6 l/h.

Elimination

After a dose of 0.1 mg/kg, the ratio of dienogest excretion as metabolites by the kidneys and through the intestines is 3:1. Only a small amount of unchanged dienogest is excreted by the kidneys. The T_1/2 of dienogest is approximately 8.5-10.8 hours. After oral administration, 86% of the administered dienogest dose is excreted within 6 days; a significant part is excreted in the first 24 hours after administration, mainly by the kidneys.

Indications

• Oral contraception;
• Treatment of mild to moderate acne in women requiring contraception, when topical treatment has been ineffective.

ICD codes

Dosage Regimen

Orally, daily, preferably at the same time, in the order indicated on the packaging, or in any other non-random order, with a small amount of water.

Take 1 tablet/day continuously for 21 days. Taking tablets from each new pack starts after a 7-day break, during which withdrawal bleeding (menstrual-like bleeding) occurs. It usually starts on the 2nd-3rd day after taking the last tablet and may continue until the start of taking tablets from the new pack.

Starting Diecyclen^®

If no hormonal contraceptives were taken in the previous month, Diecyclen^® should be started on the first day of the menstrual cycle (the first day of menstrual bleeding). Starting on days 2-5 of the menstrual cycle is allowed, but in this case, it is recommended to additionally use a barrier method of contraception during the first 7 days of taking tablets from the first pack.

Switching from other combined contraceptive drugs (COCs, vaginal ring, or contraceptive patch)

When switching from other combined contraceptive drugs, it is preferable to start taking the drug the day after taking the last active tablet from the previous pack, but no later than the day after the usual 7-day break in taking (for drugs containing 21 tablets) or after taking the last inactive tablet (for drugs containing 28 tablets per pack).

When switching from a vaginal ring or transdermal patch, it is preferable to start taking the drug on the day of ring or patch removal, but no later than the day when a new ring should be inserted or a new patch applied.

Switching from progestogen-only contraceptives (“mini-pills”, injectable forms, implant), or a progestogen-releasing intrauterine contraceptive

When switching from “mini-pills”, the drug can be taken on any day (without a break), from an implant – on the day of its removal, from an injectable form – on the day the next injection is due. In all cases, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets.

After a first-trimester abortion

The drug can be started immediately. If this condition is met, there is no need for additional contraceptive protection.

After childbirth or a second-trimester abortion

It is recommended to start taking the drug on day 21-28 after childbirth (in the absence of breastfeeding) or abortion. If intake is started later, it is necessary to additionally use a barrier method of contraception during the first 7 days of taking the tablets. However, if the woman has already had sexual intercourse before starting the drug, pregnancy must be ruled out or the first menstruation must be awaited.

Recommendations in case of irregular intake

In case of a missed dose, if the delay in taking the tablet is less than 12 hours, contraceptive protection is not reduced. The woman should take the tablet as soon as possible, and the next tablet should be taken at the usual time.

If the delay in taking the tablet is more than 12 hours, contraceptive protection may be reduced. In this case, the following two basic rules can be followed:

• The break in taking tablets should never exceed 7 days;
• 7 days of continuous tablet intake are necessary to achieve adequate suppression of the hypothalamic-pituitary-ovarian regulation.

Recommendations if the delay in taking tablets is more than 12-36 hours

Missed tablets during the first week of taking the drug. The last missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. The next tablet is taken at the usual time. Additionally, a barrier method of contraception (e.g., a condom) should be used for the next 7 days. If sexual intercourse occurred within the 7 days before the missed tablet, the possibility of pregnancy should be considered.

Missed tablets during the second week of taking the drug. The last missed tablet should be taken as soon as possible, even if this means taking two tablets at the same time. The next tablet is taken at the usual time. Provided that the tablets were taken correctly during the 7 days preceding the first missed tablet, there is no need to use additional contraceptive measures. Otherwise, and also if two or more tablets are missed, it is necessary to additionally use barrier methods of contraception (e.g., a condom) for 7 days.

Missed tablets during the third week of taking the drug. The risk of reduced contraceptive effectiveness is inevitable due to the upcoming 7-day break in taking the tablets. However, if one of the following two options is followed, there will be no need to use any other method of contraception, provided that the dosing regimen was strictly followed during the 7 days preceding the day of the missed tablet. Otherwise, the woman should follow the first of these two proposed options and simultaneously use an additional method of contraception for the next 7 days.

1. The last missed tablet should be taken as soon as the woman remembers, even if this means taking two tablets at the same time. The following tablets should be taken at the usual time. Taking tablets from each subsequent pack should start immediately after the previous one is finished, without any break. Bleeding after stopping the drug before using the second pack is unlikely, but “spotting” or “breakthrough” bleeding may occur during tablet intake.

2. The woman can also interrupt taking the tablets from the current pack for up to 7 days, including the days when the tablets were missed, after which it is necessary to start taking tablets from a new pack.

If tablets were missed and subsequently there was no withdrawal bleeding during the first break in taking the tablets, pregnancy should be ruled out.

Recommendations in case of gastrointestinal disorders

If a woman had vomiting or diarrhea within 3-4 hours after taking the drug, absorption may be incomplete. In this case, it is necessary to refer to the recommendations regarding missed doses. If the woman does not want to change the normal drug regimen, she should take an additional tablet from another pack if necessary.

Changing the day of onset of withdrawal bleeding

To delay the onset of withdrawal bleeding, it is necessary to continue taking tablets from a new pack immediately after all tablets from the previous pack have been taken, without a break in intake. Tablets from the new pack can be taken until the pack is finished. While taking the drug from the second pack, the woman may experience “spotting” or “breakthrough” uterine bleeding. Resumption of taking the drug from a new pack should occur after the usual 7-day break.

To shift the day of onset of withdrawal bleeding to another day of the week, it is necessary to shorten the nearest break in taking tablets by the number of days by which it is necessary to shift the day of onset of withdrawal bleeding. The shorter the interval, the higher the risk of absence of withdrawal bleeding and the subsequent appearance of spotting and breakthrough bleeding while taking tablets from the second pack (as in the case of delaying the onset of withdrawal bleeding).

Use in specific patient groups

Adolescents. Diecyclen^® can be used in adolescents only after the establishment of regular menstrual cycles following menarche.

Elderly patients. Diecyclen^® is not indicated after menopause.

Patients with impaired liver function. Diecyclen^® is contraindicated in hepatic insufficiency, acute and severe liver diseases until liver function tests return to normal (see section “Contraindications”).

Patients with impaired renal function. Diecyclen^® has not been specifically studied in patients with impaired renal function. Available data do not suggest a change in the regimen of use in such patients.

Adverse Reactions

When using Diecyclen^®, irregular bleeding (“spotting” or “breakthrough” uterine bleeding) may occur, especially during the first months of use. While taking Diecyclen^®, women may experience other adverse reactions listed below.

The following classification is used to determine the frequency of adverse reactions: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), frequency unknown.

Nervous system disorders common – headache; uncommon – migraine, dizziness; rare – ischemic stroke, cerebrovascular disorders, dystonia.

Psychiatric disorders uncommon – depressed mood; rare – depression, mental disorders, insomnia, sleep disorders, aggression; frequency unknown – mood changes, decreased libido, increased libido.

Eye disorders rare – dry eye syndrome, eye irritation, oscillopsia, visual impairment; frequency unknown – contact lens intolerance.

Ear and labyrinth disorders rare – sudden hearing loss, tinnitus, vertigo, hearing impairment.

Cardiac and vascular disorders uncommon – increased or decreased blood pressure; rare – cardiac dysfunction, tachycardia, thrombophlebitis, venous or arterial thrombosis/thromboembolism, incl. pulmonary embolism, increased diastolic pressure, orthostatic dystonia, “hot flashes”, varicose veins, venous diseases, pain along the veins.

Blood and lymphatic system disorders rare – anemia.

Respiratory, thoracic and mediastinal disorders rare – bronchial asthma, pulmonary hyperventilation.

Gastrointestinal disorders uncommon – abdominal pain, discomfort, bloating, nausea, vomiting, diarrhea; rare – gastritis, enteritis, indigestion.

Skin and subcutaneous tissue disorders uncommon – acne, alopecia, rash, including maculopapular, pruritus (incl. generalized); rare – allergic dermatitis, atopic dermatitis, neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorder/hyperpigmentation, seborrhea, dandruff, hirsutism, skin diseases, skin reaction – cellulitis, spider veins; frequency unknown – urticaria, erythema nodosum, erythema multiforme.

Musculoskeletal and connective tissue disorders rare – back pain, muscle and bone discomfort, myalgia, limb pain.

Reproductive system and breast disorders common – breast discomfort or pain; uncommon – changes in the duration and volume of withdrawal bleeding, including menorrhagia, hypomenorrhea, oligomenorrhea and amenorrhea; acyclic bleeding, incl. vaginal bleeding and metrorrhagia; breast enlargement, breast engorgement and feeling of fullness, breast swelling, dysmenorrhea, vaginal discharge, pelvic pain; rare – cervical epithelial dysplasia, dyspareunia, galactorrhea, menstrual cycle disorders; frequency unknown – breast discharge.

Endocrine disorders rare – virilism.

Immune system disorders rare – allergic reactions.

Metabolism and nutrition disorders uncommon – increased appetite; rare – anorexia.

Benign, malignant and unspecified neoplasms (including cysts and polyps) uncommon – ovarian cysts; rare – uterine adnexa cysts, breast cysts, uterine fibroids, breast lipoma, fibrocystic mastopathy.

Infectious and parasitic diseases infrequently – vaginitis/vulvovaginitis, vaginal candidiasis or other fungal vulvovaginal infections; rarely – salpingo-oophoritis, urinary tract infections, cystitis, mastitis, cervicitis, fungal infections, candidiasis, oral herpes, influenza, bronchitis, sinusitis, upper respiratory tract infections, viral infection.

General disorders and administration site conditions infrequently – increased fatigue, asthenia, malaise, change in body weight (increase, decrease, and fluctuations in body weight); rarely – chest pain, peripheral edema, influenza-like illness, increased body temperature; frequency unknown – fluid retention.

Laboratory and instrumental data rarely – increased blood triglycerides, hypercholesterolemia.

The following serious adverse events have been reported in women using COCs

• Venous thromboembolic disorders;
• Arterial thromboembolic disorders;
• Cerebrovascular disorders;
• Increased blood pressure;
• Hypertriglyceridemia;
• Impaired glucose tolerance or insulin resistance;
• Liver tumors (benign and malignant);
• Impaired liver function;
• Chloasma;
• Induction or worsening of angioedema symptoms;
• Onset or worsening of diseases for which the association with COC use is not conclusive: jaundice and/or pruritus associated with cholestasis; cholelithiasis; porphyria; SLE; 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 breast cancer diagnosis in women using COCs is very slightly increased. Breast cancer is rarely observed in women under 40 years of age; the excess frequency is slight in relation 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 (for additional information, see the sections “Contraindications” and “Special Precautions”).

Contraindications

• Hypersensitivity to dienogest and/or ethinylestradiol or to any of the excipients of the drug;
• Current or history of thrombosis (venous and arterial) and thromboembolism (including deep vein thrombosis, pulmonary embolism, myocardial infarction);
• Current or history of conditions preceding thrombosis (including angina pectoris);
• Cerebrovascular disease: current or history of stroke, transient ischemic attacks;
• Multiple or pronounced risk factors for venous or arterial thrombosis, including complicated valvular heart disease, atrial fibrillation, cerebrovascular or coronary artery disease, severe dyslipoproteinemia, uncontrolled arterial hypertension, major surgical intervention with prolonged immobilization, smoking over the age of 35, obesity with BMI >30 kg/m²;
• Diabetes mellitus with diabetic angiopathy;
• Identified predisposition to venous or arterial thrombosis, including resistance to activated protein C (including Factor V Leiden), antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin, lupus anticoagulant);
• Hepatic insufficiency, acute and severe liver diseases (until liver function tests normalize);
• Benign or malignant liver tumors, including history;
• Identified or suspected hormone-dependent malignant diseases of the genital organs or mammary glands, including history;
• Vaginal bleeding of unknown origin;
• Current or history of migraine with focal neurological symptoms;
• Current or history of pancreatitis accompanied by severe hypertriglyceridemia;
• Breastfeeding period;
• Hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

With caution

Risk factors for thrombosis and thromboembolism: overweight (BMI <30 kg/m²), smoking, dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve defects, hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any first-degree relative).

Other diseases in which peripheral circulatory disorders may be noted: diabetes mellitus without diabetic angiopathy, superficial phlebitis, SLE, hemolytic-uremic syndrome, Crohn’s disease, ulcerative colitis, sickle cell anemia, oncological diseases.

Diseases that first occurred or worsened during pregnancy or during previous use of sex hormones, for example, jaundice and/or pruritus due to cholestasis, gallbladder disease, porphyria, Sydenham’s chorea, history of herpes during pregnancy, hearing loss (associated with otosclerosis).

Endogenous depression, epilepsy.

Hereditary angioedema.

Hypertriglyceridemia.

Liver diseases with normal liver function test results.

Postpartum period (in the absence of breastfeeding).

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy. If pregnancy is detected, oral contraceptive use should be discontinued immediately.

Combined oral contraceptives may affect the quantity and composition of breast milk, and also pass into breast milk in small amounts, therefore the use of the drug during breastfeeding is contraindicated.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency, acute and severe liver diseases (until liver function tests normalize); benign or malignant liver tumors, including history.

With caution: in liver diseases with normal liver function test results.

Use in Renal Impairment

The drug Diecyclen^® has not been specifically studied in patients with renal impairment. Available data do not suggest a change in the dosage regimen in such patients.

Pediatric Use

The drug Diecyclen^® can be used in adolescents only after the establishment of regular menstrual cycles following menarche.

Geriatric Use

The drug Diecyclen^® is not indicated after menopause.

Special Precautions

In the presence of any of the conditions/diseases or risk factors listed below, the potential risk and expected benefit of using the drug should be carefully assessed and discussed with the woman before she decides to start taking the drug. If symptoms of an existing disease worsen, the disease exacerbates, or the first signs of these conditions/diseases or risk factors appear during the use of this drug, it is necessary to consult a doctor who may decide to discontinue the drug.

Thrombosis

Thrombosis is the formation of a blood clot (thrombus) that can block a blood vessel. If a thrombus breaks loose, thromboembolism develops. Sometimes thrombosis develops in the deep veins of the limbs (deep vein thrombosis), heart vessels (myocardial infarction), brain vessels (stroke) and very rarely – in the vessels of other organs. The risk of deep vein thrombosis in women taking COCs is higher than in those who do not take them, but not as high as during pregnancy.

Results of epidemiological studies indicate an association between the use of COCs and an increased risk of thrombosis and thromboembolic diseases, such as myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism when taking COCs. These complications are rare.

The risk of developing venous thromboembolism (VTE) is highest in the first year of taking such drugs, mainly during the first 3 months. An increased risk is present after initial use of COCs or upon resumption of use of the same or different COCs (after a break in drug use of 4 weeks or more).

The overall risk of VTE in patients taking low-dose COCs (<50 mcg ethinylestradiol) is 2-3 times higher than in non-pregnant patients who do not take COCs, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth.

In very rare cases, venous or arterial thromboembolism can be fatal.

VTE, manifested as deep vein thrombosis and/or pulmonary embolism, can occur with the use of any COC.

Very rarely, when using COCs, thrombosis occurs in other blood vessels, for example, veins and arteries of the liver, mesentery, kidneys, brain or retina.

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

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

If the above symptoms occur in women taking COCs, it is necessary to consult a doctor immediately.

The risk of developing VTE increases

• With 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 the drug Diecyclen^®);
• 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, before deciding on any hormonal contraception, a woman should consult a specialist;
• With prolonged immobilization, major surgery, any surgery on the lower limbs or extensive trauma; in these situations, it is necessary to discontinue the use of COCs (in the case of planned surgery at least 4 weeks in advance) and not resume it until 2 weeks after full restoration of mobility; if the use of the drug Diecyclen^® was not discontinued in advance, antithrombotic therapy should be considered;
• Air travel lasting more than 4 hours;
• With obesity (BMI >30 kg/m²).

The risk of arterial thromboembolic complications or cerebrovascular accident increases

• With 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 the drug Diecyclen^®);
• 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, before deciding on any hormonal contraception, a woman should consult a specialist.

Peripheral circulatory disorders may also be noted in diabetes mellitus, SLE, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (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 and severity of migraine attacks during the use of COCs (which may be a precursor to cerebrovascular accident) is a reason for immediate discontinuation of these drugs.

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

Tumors

The most significant risk factor for cervical cancer is persistent human papillomavirus infection. Some epidemiological studies indicate that long-term use of COCs may contribute to an increase in this risk. However, there is still debate about how much this result depends on other factors, such as cervical screening, more liberal sexual behavior, and refusal of barrier contraceptive methods.

A meta-analysis of the results of 54 epidemiological studies indicates a slightly increased relative risk of detecting breast cancer in women using COCs (relative risk 1.24). The increased risk gradually decreases over 10 years after stopping COC use. Given the fact that breast cancer is rare in women under 40 years of age, the increase in the number of diagnosed breast cancers in women taking or having taken COCs is small compared to the overall risk of this disease. These studies do not confirm a causal relationship. The reason for the observed increase in the number of detected breast cancers in women taking COCs may be earlier diagnosis, the biological effect of the drugs, or a combination of these factors. In women taking or having taken COCs, earlier stages of breast cancer are detected than in women who have never taken them.

Isolated cases of benign liver tumors and, much less frequently, malignant liver tumors have been diagnosed in women taking COCs. In rare cases, such tumors have caused life-threatening intra-abdominal bleeding. If severe pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding occur in women taking COCs, it is necessary to consult a doctor immediately.

Other conditions

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

Although many women taking COCs have experienced a slight increase in blood pressure, clinically significant increases are rare. However, if a clinically significant increase in blood pressure (above 140/90 mm Hg) develops during COC use, the use of the drug Diecyclen^® should be discontinued and treatment for arterial hypertension should be initiated. Use of the drug may be continued if normal blood pressure values are achieved with antihypertensive therapy.

Use of the drug should be discontinued in cases of acute and chronic liver dysfunction until all liver function indicators return to normal. Recurrence of cholestatic jaundice that first occurred during pregnancy or previous use of COCs also requires discontinuation of the drug.

The use of COCs may cause the appearance or worsening of conditions for which the association with the use of these drugs is not indisputable: jaundice and/or pruritus associated with cholestasis; gallstone formation; porphyria; SLE; hemolytic-uremic syndrome; Sydenham’s chorea; herpes during pregnancy; hearing loss associated with otosclerosis.

Although COCs may affect peripheral insulin resistance and glucose tolerance, women with diabetes mellitus taking low-dose COCs generally do not require adjustment of the dose or dosage regimen of hypoglycemic drugs. Nevertheless, such women should be under close observation.

Crohn’s disease and ulcerative colitis may be associated with COC use.

Chloasma (hyperpigmentation of the facial skin) may sometimes appear, especially if it was observed during pregnancy. Women predisposed to chloasma during the use of COCs should avoid direct sunlight and exposure to other ultraviolet radiation.

Disappearance of acne symptoms is usually noted after 3-4 months of therapy.

Women should be warned that the drug Diecyclen^® does not protect them from HIV infection and other sexually transmitted diseases.

Reduced efficacy

The contraceptive efficacy of COCs may decrease, for example, in case of missed tablets, gastrointestinal disorders (vomiting, diarrhea) or simultaneous use of other medicinal products.

Cycle irregularity

During the use of any COCs, irregular bleeding (“spotting” or “breakthrough” bleeding) may occur, especially during the first months of taking the tablets. Bleeding usually stops as the body adapts to the drug Diecyclen^® (usually after three cycles of taking the tablets). If bleeding continues and its severity increases, a specialist should be consulted.

Absence of scheduled withdrawal bleeding

In some women, withdrawal bleeding does not occur during the tablet-free interval. If the drug was taken in accordance with the instructions, pregnancy is unlikely. However, if the tablets were taken irregularly or withdrawal bleeding did not occur 2 times in a row, then pregnancy must be ruled out before continuing the use of the drug.

Laboratory tests

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

Medical examinations

Before the first prescription or resumption of use of the drug Diecyclen^®, a detailed history must be taken and a medical examination performed, taking into account contraindications, special precautions and warnings. The examination must be repeated regularly. Regular medical examination is also necessary due to the presence of contraindications (e.g., transient ischemic conditions, etc.) or risk factors (e.g., family history of venous or arterial thrombosis) that may occur for the first time only during COC use. The frequency and nature of such examinations should be based on approved practical methods, adapted to the specific patient, but in general they should include: exclusion of pregnancy; checking blood pressure; condition of the mammary glands, abdominal and pelvic organs, including cytological examination of the cervical epithelium; exclusion of disorders of the blood coagulation system.

In case of long-term use of the drug, examination should be performed at least once every 6 months.

A woman should consult a doctor as soon as possible

• In case of any changes in health, especially any conditions listed in this instruction for use (see sections “Contraindications”, “With caution”);
• In case of a local lump in the breast;
• If she intends to use other medicinal products (see section “Drug Interactions”);
• If prolonged immobilization is expected (e.g., a cast on a leg), hospitalization or surgery is planned (it is necessary to consult a doctor 4-6 weeks before it);
• If unusually severe uterine bleeding occurs;
• If a woman forgot to take a tablet in the first week of taking the package (blister) and had sexual intercourse within the week before that;
• If a woman did not have a scheduled withdrawal bleeding twice in a row or she suspects she is pregnant (she should not start taking tablets from the next package (blister) until she consults a doctor).

Effect on ability to drive vehicles and mechanisms

No effect of the drug Diecyclen^® on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions has been identified.

Overdose

Symptoms nausea, vomiting, irregular spotting, absence of menstrual-like bleeding are possible.

Treatment symptomatic therapy is carried out if necessary.

Drug Interactions

Effect of other medicinal products on the drug Diecyclen^®

Interaction with medicinal products that induce hepatic microsomal enzymes is possible, which may increase the clearance of sex hormones, which in turn may lead to breakthrough uterine bleeding and/or a decrease in the contraceptive effect of the drug.

Women who take such drugs concomitantly with Diecyclen^® are advised to use a barrier method of contraception or choose another non-hormonal method of contraception. The barrier method of contraception should be used throughout the entire period of taking the concomitant drugs, as well as for 28 days after their discontinuation. If the period of using the barrier method of contraception ends later than the tablets in the Diecyclen^® package, the patient should start taking tablets from a new Diecyclen^® package without a break in tablet intake.

Medicinal products that increase the clearance of Diecyclen^® (reducing effectiveness by inducing hepatic microsomal enzymes) phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as medicinal products containing St. John’s wort (Hypericum perforatum).

Medicinal products with varying effects on the clearance of Diecyclen^®. When used concomitantly with Diecyclen^®, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentrations of estrogens or progestogens. In some cases, this effect may be clinically significant.

Medicinal products that reduce the clearance of Diecyclen^® (inhibitors of hepatic microsomal enzymes). Dienogest is a substrate of cytochrome P450 CYP3A4. Strong and moderate CYP3A4 inhibitors, such as azole antifungals (e.g., itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem and grapefruit juice may increase the plasma concentrations of estrogen or progestogen, or both.

It has been shown that etoricoxib at doses of 60 and 120 mg/day when taken concomitantly with COCs containing 0.035 mg ethinylestradiol increases plasma concentrations of ethinylestradiol by 1.4 and 1.6 times, respectively.

Effect of the drug Diecyclen^® on other medicinal products

COCs may affect the metabolism of other drugs, leading to an increase (e.g., cyclosporine) or decrease (e.g., lamotrigine) in their plasma and tissue concentrations.

In vitro, Ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, as well as an irreversible inhibitor of CYP3A4/5, CYP2C8 and CYP2J2. In clinical studies, the use of a hormonal contraceptive containing Ethinylestradiol did not lead to any increase or led to only a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam), while plasma concentrations of CYP1A2 substrates may increase slightly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

Storage Conditions

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

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

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.