Dienogest + Ethinylestradiol (Tablets) Instructions for Use

Marketing Authorization Holder

Mylan Laboratories, Limited (India)

ATC Code

G03AA16 (Dienogest and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Dienogest (Rec.INN registered by WHO)

Dosage Form

Dienogest + Ethinylestradiol

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

Dosage Form, Packaging, and Composition

Film-coated tablets from white to almost white, round, biconvex, with an engraving “D” on one side and smooth on the other side; the tablet core on the cross-section is white or almost white.

* 100 mg of ethinylestradiol in powder form (0.333%) contain: Ethinylestradiol – 0.333 mg, lactose – 69.147 mg, lactose monohydrate – 29 mg, povidone K-25 – 0.5 mg, alpha-tocopherol – 0.02 mg, magnesium stearate – 1 mg.

Excipients: lactose monohydrate – 48.891 mg, corn starch – 20 mg, povidone K-25 – 4.25 mg, magnesium stearate – 0.85 mg.

Film coating composition: opadry white 03F58750 (hypromellose – 82.2%, titanium dioxide – 3.4%, macrogol – 13.7%, talc – 0.7%) – 1.7 mg.

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

Clinical-Pharmacological Group

Monophasic oral contraceptive with antiandrogenic properties

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

Combined low-dose monophasic oral contraceptive.

The contraceptive effect is carried out through complementary mechanisms, the most important of which are suppression of ovulation and an increase in the viscosity of cervical secretion, making it impenetrable to sperm.

With correct use of drugs of this combination, the Pearl index (an indicator reflecting the number of pregnancies in 100 women taking the contraceptive for a year) is less than 1. If a dose is missed or used incorrectly, the Pearl index may increase.

The antiandrogenic effect of the combination of dienogest and ethinylestradiol is based on a decrease in the concentration of androgens in the blood plasma.

Taking the combination of ethinylestradiol with dienogest led to the leveling of symptoms of mild to moderate acne and had a positive result in patients with seborrhea, as confirmed by the results of a number of clinical studies.

Dienogest is a derivative of norethisterone, which has a lower affinity for progesterone receptors in vitro (10-30 times) compared to other synthetic progesterones. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid effects in vivo.

When used alone, Dienogest inhibits ovulation at a dose of 1 mg/day.

In addition, Dienogest improves the blood lipid profile (increases HDL concentration).

In women taking combined oral contraceptives, the cycle becomes more regular, painful menstruation is less common, the intensity and duration of bleeding decreases, thereby reducing the risk of iron deficiency anemia. Furthermore, there is evidence of a reduced risk of endometrial cancer and ovarian cancer when taking combined oral contraceptives.

Pharmacokinetics

Dienogest after oral administration is rapidly and completely absorbed in the intestine. C_max in blood plasma (51 pg/ml) is reached after 2.5 h. Absolute bioavailability when taken simultaneously with ethinylestradiol is 96%. Dienogest binds to plasma albumin and does not bind to SHBG and corticosteroid-binding globulin. The fraction of free dienogest in plasma is 10%, while 90% is non-specifically bound to albumin. The apparent V_d is 37-45 L. The concentration of SHBG in blood plasma does not affect the pharmacokinetics of dienogest. As a result of daily intake, the concentration of dienogest in blood plasma increases by approximately 1.5 times, reaching a steady state after approximately 4 days of intake. Dienogest is mainly metabolized by hydroxylation, with glucuronidation as an alternative pathway. Metabolites are inactive and rapidly eliminated from plasma, so metabolites cannot be detected in significant quantities in blood plasma, but this does not apply to unchanged dienogest. Total clearance after a single dose is 3.6 L/h. T_1/2 of dienogest is about 9 h. An insignificant amount of dienogest is excreted unchanged by the kidneys. Dienogest metabolites are excreted by the kidneys and through the intestine in a ratio of 3:1, T_1/2 – 14.4 h.

Ethinylestradiol after oral administration is rapidly and completely absorbed in the small intestine. C_max in plasma (67 pg/ml) is reached after 1.5-4 h. During the first pass through the liver, a significant portion of ethinylestradiol is metabolized. Absolute bioavailability is approximately 44%. Ethinylestradiol is almost completely (about 98%), although non-specifically, bound to albumin. Ethinylestradiol increases the plasma concentration of sex hormone-binding globulin (SHBG). The apparent V_d is 2.8-8.6 L/kg. C_ss is reached during the second half of the cycle, when the concentration of ethinylestradiol in the blood serum increases by approximately 2 times. Ethinylestradiol undergoes presystemic conjugation in the intestinal mucosa and in the liver. The main pathway of ethinylestradiol metabolism is aromatic hydroxylation, but its metabolism also leads to the formation of a large number of hydroxylated and methylated metabolites, which are presented as glucuronides, sulfates and in free form. Clearance is approximately 2.3-7 ml/min/kg. The decrease in the concentration of ethinylestradiol in blood plasma is biphasic: the first phase is characterized by T_1/2 of about 1 h, the second – 10-20 h. It is not excreted unchanged from the body. Ethinylestradiol metabolites are excreted by the kidneys and through the intestine in a ratio of 4:6 with T_1/2 of about 24 h.

Indications

Oral contraception.

ICD codes

Dosage Regimen

Take one tablet orally at the same time every day.

Follow the blister pack order strictly. Start the first tablet on the first day of your menstrual cycle.

For a 21-tablet pack: take one tablet daily for 21 consecutive days, followed by a 7-day tablet-free interval. Menstrual-like bleeding usually occurs during this break.

For a 63-tablet pack: take one tablet daily for 63 consecutive days, followed by a 7-day tablet-free interval.

Begin each new pack on the same day of the week, regardless of bleeding.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet, consider it a missed dose and follow the specific instructions for missed tablets.

If a tablet is missed and remembered within 12 hours, take it immediately and take the next tablet at the usual time. Contraceptive protection is not reduced.

If a tablet is missed for more than 12 hours, contraceptive protection may be reduced. Take the most recent missed tablet immediately, even if it means taking two tablets on the same day. Continue taking the remaining tablets at the usual time.

Use a non-hormonal barrier method of contraception for the next 7 days. If these 7 days run beyond the current pack, start the next pack immediately without a break.

If no menstrual-like bleeding occurs during the tablet-free interval and tablets were missed in the previous pack, rule out pregnancy before starting the next pack.

Adverse Reactions

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

Benign, malignant and unspecified neoplasms (including cysts and polyps) rarely – uterine fibroids, breast lipoma.

From the hematopoietic system rarely – anemia.

From the immune system rarely – allergic reactions.

From the endocrine system rarely – virilism.

From metabolism and nutrition infrequently – increased appetite; rarely – anorexia.

Mental disorders infrequently – depressed mood; rarely – depression, mental disorders, insomnia, sleep disorders, aggression; frequency unknown – mood changes, decreased libido, increased libido.

From the nervous system often – headache; infrequently – dizziness, migraine; rarely – ischemic stroke, cerebrovascular disorders, dystonia.

From the organ of vision rarely – dryness of the eye mucosa, irritation of the eye mucosa, oscillopsia, visual impairment; frequency unknown – contact lens intolerance (discomfort when wearing them).

From the ear and labyrinth disorders rarely – sudden hearing loss, tinnitus, dizziness, hearing impairment.

From the cardiovascular system infrequently – increased BP, decreased BP; rarely – cardiovascular disorders, tachycardia, venous and arterial thromboembolic complications*, thrombophlebitis, diastolic hypertension, orthostatic circulatory dystonia, “hot flashes”, varicose veins, venous pathology, venous pain.

From the respiratory system rarely – bronchial asthma, hyperventilation.

From the gastrointestinal tract infrequently – abdominal pain, including upper and lower abdominal pain, discomfort/bloating, nausea, vomiting, diarrhea; rarely – gastritis, enteritis, dyspepsia.

From the skin and subcutaneous tissues infrequently – acne, alopecia, rash (including macular rash), itching (including generalized itching); rarely – allergic dermatitis, atopic dermatitis/neurodermatitis, eczema, psoriasis, hyperhidrosis, chloasma, pigmentation disorder/hyperpigmentation, seborrhea, dandruff, hirsutism, skin pathology, skin reactions, “orange peel”, telangiectasia; frequency unknown – urticaria, erythema nodosum, erythema multiforme.

From the musculoskeletal system rarely – back pain, musculoskeletal discomfort, myalgia, limb pain.

From the genital organs and breast often – breast pain, discomfort sensation, breast engorgement; infrequently – changes in volume, duration and interval of menstrual-like bleeding (including heavy menstrual-like spotting/bleeding, scanty or infrequent menstrual-like bleeding, absence of menstrual-like bleeding, acyclic spotting/bleeding), breast enlargement, breast swelling and distension, breast edema, painful menstrual-like spotting/bleeding, genital tract discharge/vaginal discharge, ovarian cysts, pelvic pain; rarely – cervical dysplasia, uterine adnexal cysts, uterine adnexal pain, breast cysts, fibrocystic mastopathy, dyspareunia, galactorrhea, menstrual cycle disorder; frequency unknown – breast discharge.

General disorders and administration site conditions infrequently – fatigue, asthenia, malaise; rarely – chest pain, peripheral edema, flu-like symptoms, inflammation, fever, irritability; frequency unknown – fluid retention.

Effect on laboratory and instrumental test results infrequently – change in body weight (increase, decrease and fluctuations in body weight); rarely – increased blood triglycerides, hypercholesterolemia.

Congenital, hereditary and genetic disorders rarely – detection of accessory breast/polymastia.

Contraindications

Thromboses (arterial and venous) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke), cerebrovascular disorders; conditions preceding thrombosis (including transient ischemic attacks, angina pectoris), currently or in history; identified acquired or hereditary predisposition to venous or arterial thrombosis, including resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); presence of a high risk of venous or arterial thrombosis.

Migraine with focal neurological symptoms currently or in history.

Planned surgery (at least 4 weeks before it) and the period of immobilization, for example, after trauma (including after application of plaster casts) and for at least 2 weeks after restoration of full motor activity.

Diabetes mellitus with vascular complications.

Uncontrolled or severe arterial hypertension.

Severe dyslipoproteinemia.

Pancreatitis with severe hypertriglyceridemia currently or in history.

Hepatic insufficiency and severe liver diseases (until liver tests normalize); liver tumors (benign or malignant) currently or in history.

Identified hormone-dependent malignant diseases (including of the genital organs or breast) or suspicion of them; vaginal bleeding of unknown origin.

Pregnancy or suspicion of it; breastfeeding period.

With caution

Presence of risk factors for thrombosis and thromboembolism (smoking; obesity; dyslipoproteinemia; controlled arterial hypertension; migraine without focal neurological symptoms; heart valve diseases; hereditary predisposition to thrombosis (thromboses, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives); other diseases in which peripheral circulation disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn’s disease and ulcerative colitis, sickle cell anemia, superficial phlebitis); hereditary angioedema; hypertriglyceridemia; liver diseases not classified as contraindications; diseases that first appeared or worsened during pregnancy or during previous use of sex hormones (for example, jaundice and/or itching associated with cholestasis, gallbladder diseases, otosclerosis with hearing impairment, porphyria, herpes during pregnancy, Sydenham’s chorea); postpartum period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated for use in hepatic insufficiency and severe liver diseases (until liver tests normalize); liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

The drug is approved for use in renal impairment

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Geriatric Use

The drug is contraindicated for use in elderly patients

Special Precautions

If any of the conditions, diseases or risk factors listed below are currently present, the potential risk and expected benefit of using this contraceptive should be carefully weighed.

There is epidemiological data on an increased incidence of venous and arterial thromboses and thromboembolisms (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) when taking combined oral contraceptives.

The risk of developing venous thromboembolism (VTE) is highest in the first year of taking such drugs. An increased risk is present after initial use of combined oral contraceptives (COCs) or resumption of use of the same or another combined oral contraceptive (after a break in taking the drug of 4 weeks or more). Data from a large prospective study involving 3 patient groups show that the increased risk is present mainly during the first 3 months. The overall risk of VTE in women taking low-dose COCs (<0.05 mg ethinylestradiol) is 2-3 times higher than in non-pregnant patients who do not take combined oral contraceptives, nevertheless, this risk remains lower compared to the risk of VTE during pregnancy and childbirth. VTE can be life-threatening or fatal (in 1-2% of cases). VTE, manifested as deep vein thrombosis or pulmonary embolism, can occur with the use of any combined oral contraceptives. Very rarely, when using COCs, thrombosis of other blood vessels occurs, for example, hepatic, mesenteric, renal, cerebral veins and arteries or retinal vessels.

Arterial thromboembolism can lead to stroke, vascular occlusion or myocardial infarction. Arterial thromboembolism 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, drugs containing this combination are contraindicated.

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

An increase in the frequency and severity of migraine during the use of this contraceptive (which may precede cerebrovascular disorders) is grounds for its immediate discontinuation.

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

The most significant risk factor for cervical cancer is persistent papillomavirus infection. There are reports of a slight increase in the risk of cervical cancer with long-term use of COCs. However, the connection with the use of COCs remains controversial. Controversy persists regarding the extent to which these data are related to screening for cervical pathology or to sexual behavior characteristics (less frequent use of barrier contraceptive methods).

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

If persistent clinically significant increase in BP develops during COC use, COCs should be discontinued and treatment for arterial hypertension should be initiated. COC use may be continued if normal BP values are achieved with antihypertensive therapy.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Acute or chronic liver function disorders may require discontinuation of COCs until liver function tests return to normal. Recurrence of cholestatic jaundice that first developed during a previous pregnancy or previous use of sex hormones requires discontinuation of COCs.

In diabetes mellitus, women taking combined oral contraceptives (COCs) should be carefully monitored.

Women with a tendency to chloasma during the use of this contraceptive should avoid prolonged exposure to the sun and UV radiation.

The use of this contraceptive may affect the results of some laboratory tests, including indicators of liver, kidney, thyroid, and adrenal function, the concentration of transport proteins in blood plasma, parameters of carbohydrate metabolism, and parameters of blood coagulation and fibrinolysis. Changes usually do not exceed the limits of normal values.

Conditions requiring medical consultation: any changes in health status, especially the occurrence of conditions listed in the “Contraindications” and “Precautions” sections; a localized lump in the breast; concurrent use of other medications; if prolonged immobilization is expected (e.g., a cast on a lower limb), hospitalization or surgery is planned (at least 4 weeks before the planned surgery); unusually heavy vaginal bleeding; a missed pill in the first week of taking the pack and a sexual intercourse occurred 7 days or less before that; absence of the expected menstrual-like bleeding twice in a row or suspicion of pregnancy (do not start taking the drug from the next pack until consulting a doctor).

You should stop taking the drug and consult a doctor immediately if there are possible signs of thrombosis, myocardial infarction, or stroke: unusual cough; unusually severe pain behind the breastbone, radiating to the left arm; sudden onset of shortness of breath; unusual, severe, and prolonged headache or migraine attack; partial or complete loss of vision or double vision; slurred speech; sudden changes in hearing, smell, or taste; dizziness or fainting; weakness or loss of sensation in any part of the body; severe abdominal pain; severe pain in a lower limb or sudden swelling of any of the lower limbs.

It should be remembered that sex hormones may promote the growth of some hormone-dependent tissues and tumors.

Drug Interactions

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

Agents that increase the clearance of the active substances of this combination (reducing effectiveness by enzyme induction): phenytoin, barbiturates, bosentan, primidone, carbamazepine, rifampicin, and agents for the treatment of HIV infection (ritonavir, nevirapine, and efavirenz) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

When used concomitantly with this combination, 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 progestins. In some cases, this effect may be clinically significant.

Dienogest is a substrate of the CYP3A4 isoenzyme.

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 progestin, or both.

It has been shown that etoricoxib at doses of 60 and 120 mg/day, when taken concomitantly with combined oral contraceptives containing 0.035 mg of ethinyl estradiol, increases the plasma concentrations of ethinyl estradiol by 1.4 and 1.6 times, respectively.

In vitro, Ethinyl Estradiol 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 administration of a hormonal contraceptive containing Ethinyl Estradiol did not lead to any increase or led only to a weak increase in the plasma concentrations of CYP3A4 substrates (e.g., midazolam), while the plasma concentrations of CYP1A2 substrates may increase weakly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.