Manuel (Tablets) Instructions for Use

ATC Code

G03AA09 (Desogestrel and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Desogestrel (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Monophasic oral contraceptive

Pharmacotherapeutic Group

Combined contraceptive agent (estrogen + gestagen)

Pharmacological Action

A combined contraceptive drug containing estrogen and gestagen.

The contraceptive effect of the drug, like other combined oral contraceptives, is primarily based on the ability to suppress ovulation and increase the secretion of cervical mucus.

Desogestrel suppresses the synthesis of gonadotropic hormones, primarily LH, thus preventing follicle maturation (blocks ovulation).

Ethinylestradiol is a synthetic analogue of the follicular hormone estradiol, which, together with the corpus luteum hormone, regulates the menstrual cycle.

In addition to the indicated central and peripheral mechanisms that prevent the maturation of a fertilizable egg, the contraceptive effect is due to an increase in the viscosity of the mucus located in the cervix, which makes it difficult for sperm to penetrate into the uterine cavity.

In addition to contraceptive properties, the drug has a number of effects that can be taken into account when choosing a method of contraception. Menstrual-like reactions become more regular, less painful and are accompanied by less pronounced bleeding. The latter circumstance leads to a decrease in the frequency of concomitant iron deficiency anemia.

Taking contraceptive drugs with a high content of ethinylestradiol (50 mcg) reduces the risk of developing ovarian and endometrial cancer. There are no data confirming this pharmacological effect for contraceptive drugs with a lower content of ethinylestradiol.

Pharmacokinetics

Desogestrel

When taken orally, Desogestrel is rapidly and completely absorbed and converted to etonogestrel. The C_max of etonogestrel in blood plasma is 2 ng/ml and is reached in approximately 1.5 hours. Bioavailability is 62-81%.

Etonogestrel binds to plasma albumin and sex hormone-binding globulin (SHBG). Only 2-4% of the total concentration of etonogestrel in plasma is present as free steroid, and 40-70% is specifically bound to SHBG. The increase in SHBG concentration caused by ethinylestradiol affects the distribution between plasma proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction. The apparent V_d of desogestrel is 1.5 l/kg.

The pharmacokinetics of etonogestrel are influenced by the level of SHBG, the concentration of which increases 3-fold under the influence of ethinylestradiol. With daily use, the concentration of etonogestrel in plasma increases approximately 2-3 times, reaching a constant value in the second half of the drug intake cycle.

Etonogestrel is completely metabolized via known pathways of sex hormone metabolism. The metabolic clearance rate from plasma is about 2 ml/min/kg. No interaction of etonogestrel with simultaneously used ethinylestradiol was found.

The concentration of etonogestrel in plasma decreases in two phases. The distribution in the terminal phase is characterized by a T_1/2 of about 30 hours. Desogestrel and its metabolites are excreted by the kidneys and through the intestines in a ratio of approximately 6:4.

Ethinylestradiol

After oral administration, Ethinylestradiol is rapidly and completely absorbed. C_max in plasma is 80 pg/ml and is reached 1-2 hours after administration. The absolute bioavailability of ethinylestradiol is about 60%.

Ethinylestradiol binds non-specifically to plasma albumin (approximately 98.5%) and causes an increase in SHBG concentration in plasma. The apparent V_d of ethinylestradiol is about 5 l/kg. C_ss is reached after 3-4 days of administration, when the plasma concentration is 30-40% higher than the concentration after a single dose.

Ethinylestradiol undergoes presystemic metabolism, both in the small intestinal mucosa and in the liver. Ethinylestradiol is first metabolized by aromatic hydroxylation to form hydroxylated and methylated metabolites, which are present both in free form and as conjugates with glucuronides and sulfates. The metabolic clearance rate of ethinylestradiol from plasma is about 5 ml/min/kg.

The concentration of ethinylestradiol in plasma decreases in two phases. The final phase is characterized by a T_1/2 of about 24 hours. Ethinylestradiol is not excreted unchanged; ethinylestradiol metabolites are excreted by the kidneys and through the intestines in a ratio of 4:6. The T_1/2 of metabolites is about 24 hours.

Indications

Contraception.

ICD codes

Dosage Regimen

Take one tablet orally once daily at approximately the same time each day.

Follow the blister pack directions strictly. Take tablets in the order indicated by the arrows.

Start the first pack on the first day of your menstrual period. Continue taking one active tablet daily for 21 consecutive days.

After the last active tablet, take no tablets for 7 days. Withdrawal bleeding usually occurs during this tablet-free interval.

Begin the next pack on the eighth day, even if bleeding has not finished.

If switching from another combined hormonal contraceptive, start the new pack the day after the last active tablet of the previous product. Do not use the placebo tablets from the old pack.

If switching from a progestogen-only method, start the new pack the day after taking the last progestogen-only tablet. Use additional barrier contraception for the first 7 days.

After a first-trimester abortion, start immediately. No additional contraceptive protection is required.

After childbirth or a second-trimester abortion, start no earlier than day 21-28 postpartum. If started later, use a barrier method for the first 7 days.

If a tablet is taken 12 hours late or more, contraceptive protection may be reduced. Take the missed tablet as soon as remembered and the next tablet at the usual time.

Use a barrier method of contraception for the next 7 days if the missed tablet was in the first week of the pack and intercourse occurred in the previous 7 days.

If vomiting or severe diarrhea occurs within 3-4 hours of taking a tablet, handle it as a missed tablet.

Do not discontinue tablets if no withdrawal bleeding occurs, provided the regimen was followed correctly.

Adverse Reactions

Adverse effects associated with taking the drug, which were noted when taking the combination Desogestrel+Ethinylestradiol or other combined contraceptive drugs, are listed below.

The frequency of adverse effects was determined as follows: common (≥1/100), uncommon (≥1/1000 and <1/100), rare (<1/1000).

Allergic reactions uncommon – urticaria; rare – hypersensitivity reactions.

Cardiovascular system rare – venous and arterial thromboembolism.

Psychiatric disorders common – depression, mood changes; uncommon – decreased libido; rare – increased libido.

Nervous system common – headache; uncommon – migraine.

Eye disorders rare – contact lens intolerance.

Gastrointestinal system common – nausea, abdominal pain; uncommon – vomiting, diarrhea.

Skin and subcutaneous tissue disorders uncommon – skin rash; rare – erythema nodosum, erythema multiforme.

Reproductive system and breast disorders common – breast pain, breast tenderness; uncommon – breast enlargement; rare – vaginal discharge, breast discharge.

Other common – weight gain; uncommon – fluid retention; rare – weight loss.

The following are adverse effects that have been observed in women taking combined oral contraceptive drugs.

Cardiovascular system venous or arterial thrombosis or thromboembolism (including myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, thrombosis/thromboembolism of hepatic, mesenteric, renal arteries and veins, retinal artery thrombosis); increased blood pressure.

Benign, malignant and unspecified neoplasms (including cysts and polyps) benign and malignant liver tumors, hormone-dependent breast tumors.

Skin disorders chloasma (especially in case of a history of chloasma during pregnancy).

Gastrointestinal system Crohn’s disease, ulcerative colitis.

Reproductive system acyclic bleeding (more often in the first months of administration).

Other occurrence or exacerbation of jaundice and/or itching associated with cholestasis, cholelithiasis, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea, herpes gestationis, hearing loss due to otosclerosis, allergic reactions.

Contraindications

Venous or arterial thrombosis/thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke); precursors of thrombosis (including transient ischemic attack, angina pectoris); identified predisposition to venous or arterial thrombosis, including resistance to activated protein C, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); migraine with focal neurological symptoms in history; diabetes mellitus with diabetic angiopathy; presence of multiple factors or a high degree of severity of one of the risk factors for the development of venous or arterial thrombosis, thromboembolism; uncontrolled arterial hypertension (BP 160/100 mm Hg and above); pancreatitis (including in history) accompanied by severe hypertriglyceridemia; severe dyslipoproteinemia; hepatic failure, acute or severe liver diseases (until liver function tests normalize), including in history; liver tumors (benign and malignant), including in history; hormone-dependent malignant neoplasms of the genital organs or breast (including suspected); vaginal bleeding of unknown etiology; pregnancy (including suspected); lactation period (breastfeeding); smoking over the age of 35 (more than 15 cigarettes/day); lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome; adolescent girls under 18 years of age (no data on the efficacy and safety of the drug use); hypersensitivity to the components of the drug.

If any of the above diseases (conditions) occur while using the drug (as with other combined oral contraceptives), the drug should be discontinued immediately.

With caution

If any of the conditions/risk factors listed below are currently present, the potential risk and expected benefit of using the drug should be carefully weighed in each individual case: age over 35 years; smoking; family history of thromboembolic diseases (venous or arterial thrombosis/thromboembolism in siblings or parents at a relatively young age); obesity (BMI >25 kg/m² and <30 kg/m²); dyslipoproteinemia; arterial hypertension; migraine without focal neurological symptoms; uncomplicated valvular heart disease; varicose veins, superficial thrombophlebitis; postpartum period; diabetes mellitus; SLE; hemolytic-uremic syndrome; chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis); sickle cell anemia; hypertriglyceridemia (including in family history); history of diseases that first appeared or worsened during a previous pregnancy or while taking sex hormones; hereditary angioedema; chloasma; history of mild to moderate liver diseases with normal liver function tests.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated. If pregnancy occurs while using the drug, its use should be discontinued.

The drug may affect lactation, because combined oral contraceptive drugs reduce the amount and change the composition of breast milk. Therefore, the drug is not recommended for use until the nursing mother has completely stopped breastfeeding. A small amount of contraceptive steroids and/or their metabolic products may be excreted in breast milk.

Use in Hepatic Impairment

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

The drug should be prescribed with caution in case of a history of mild to moderate liver diseases with normal liver function tests.

Pediatric Use

The safety and efficacy of the drug in adolescent girls under 18 years of age have not been studied.

Special Precautions

In the presence of any of the diseases/conditions/risk factors listed below, the benefits and possible risks of using the drug should be carefully weighed. This issue should be discussed with the patient before starting to take the drug. If the diseases worsen, the condition deteriorates, or the first symptoms of the above conditions or risk factors appear, the patient should immediately consult a doctor. The decision to discontinue the drug is made by the doctor individually.

Cardiovascular diseases

Epidemiological studies have established that there may be a connection between the use of combined oral contraceptive drugs and an increased risk of arterial and venous thrombosis and thromboembolism, such as myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism. These diseases are observed extremely rarely. The use of any combined contraceptive drug is associated with an increased risk of venous thromboembolism, manifested as deep vein thrombosis and/or pulmonary embolism. The risk is higher in the first year of use than in women taking a combined contraceptive drug for more than 1 year.

When using the combination Desogestrel+Ethinylestradiol, there is an increased (almost 2 times) risk of developing venous thromboembolism compared to drugs containing levonorgestrel, norgestimate or norethisterone as a gestagenic component.

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

At present, there is no consensus on the possible role of varicose veins and superficial thrombophlebitis in the etiology of venous thromboembolism.

If a hereditary predisposition to thromboembolic diseases is suspected, the woman should be referred for consultation with a specialist before deciding to prescribe any hormonal contraceptive drugs.

Risk factors for the development of venous and arterial thrombosis, thromboembolism are: age over 35 years, air travel lasting more than 4 hours (especially in the presence of other risk factors), overweight BMI over 30 kg/m²). The risk of complications increases with increasing BMI, which is especially important to consider in the presence of other risk factors: prolonged immobilization; major surgical interventions; neurosurgical operations; surgical interventions in the pelvic area or on the lower extremities; severe trauma; family history of thromboembolic diseases (venous thrombosis/thromboembolism in siblings or parents at a young age); other conditions/diseases associated with the development of venous thrombosis (cancer, SLE, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis), sickle cell anemia).

In case of prolonged immobilization and the above surgical interventions, it is recommended to stop using the drug; for planned surgical interventions no later than 4 weeks before surgery, and not to resume taking it for 2 weeks after full rehabilitation. To prevent unwanted pregnancy, other methods of contraception should be used. If the drug was not discontinued in advance, antithrombotic therapy is indicated.

The risk of developing venous thromboembolism is increased both with the primary use of a combined oral contraceptive drug and with the resumption of taking the drug after a break of 4 weeks or more. Venous thromboembolism can be fatal in 1-2% of cases.

Symptoms of deep vein thrombosis may include: unilateral swelling of the lower limb, including the foot, or along the affected vein; pain in the lower limb or tenderness when touching the lower limb, which may be felt when standing or walking; a feeling of warmth in the affected limb, redness or discoloration of the skin of the lower limb.

Symptoms of pulmonary embolism: sudden attack of difficulty breathing or rapid breathing of unknown etiology; sudden attack of coughing, which may be accompanied by hemoptysis; sharp chest pain; feeling of severe weakness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., difficulty breathing, cough) are nonspecific, which may complicate diagnosis. Diagnosis of a more common or less dangerous disease (e.g., respiratory tract infection) is possible. Other signs of vessel blockage: sudden pain, swelling and bluish discoloration of the limb. In case of blockage of an eye vessel, symptoms can range from painless blurred vision, which can progress to complete loss of vision. Sometimes complete loss of vision can occur suddenly. Epidemiological studies have revealed a connection between the use of combined oral contraceptive drugs and an increased risk of developing arterial thrombosis (myocardial infarction) or cerebrovascular accidents (e.g., transient ischemic attack, stroke). Arterial thromboembolism can be fatal.

High-risk factors for arterial thrombosis are: age over 35 years; smoking; arterial hypertension; overweight (BMI over 30 kg/m²); family history of thromboembolic diseases (arterial thrombosis/thromboembolism in siblings or parents at a young age); migraine; other conditions/diseases associated with the development of vascular adverse events (diabetes mellitus, hyperhomocysteinemia, heart valve disease and atrial fibrillation, dyslipoproteinemia and SLE).

Women taking combined contraceptive drugs are advised to refrain from smoking. Women over 35 who smoke should not take combined oral contraceptive drugs.

The risk of complications increases with increasing BMI, which is especially important to consider in the presence of other risk factors.

An increase in the frequency and intensity of migraine when taking combined contraceptive drugs (which may be a sign of cerebrovascular disorders) is grounds for discontinuing the drug.

Symptoms of cerebrovascular accidents: sudden numbness or weakness of the facial muscles, arms or legs, affecting one side or part of the body; sudden gait disturbance, dizziness, loss of balance or coordination; sudden confusion, speech impairment or understanding; sudden visual impairment in one or both eyes; sudden severe or prolonged headache of unknown etiology; loss of consciousness or severe weakness with or without convulsions. Temporary symptoms may indicate the development of a transient ischemic attack.

Symptoms of myocardial infarction: pain, discomfort, feeling of pressure, heaviness or fullness in the chest; pain in the arm or below the breastbone; unpleasant sensation (discomfort) radiating to the back, jaw, throat, arm, stomach area; feeling of stomach fullness, indigestion or feeling of suffocation; sweating, nausea, vomiting or dizziness; severe fatigue, anxiety or difficulty breathing; rapid or irregular heart rhythm.

The risk of developing thromboembolic complications increases with the combination of several risk factors for these complications.

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

Tumors

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV infection). Some epidemiological studies note an increased risk of cervical cancer in women who have been taking combined oral contraceptives for a long time, but to date there are controversies regarding the extent of the influence of various confounding factors on these data, such as cervical screening and sexual behavior, including less frequent use of barrier contraceptive methods, or their interrelation.

There is evidence of a small increase in the relative risk (1.24) of breast cancer in women using combined oral contraceptives. The increased risk gradually decreases within 10 years after discontinuation of the combined contraceptive. Since breast cancer in women under 40 is quite rare, the increase in the risk of breast cancer in women currently taking combined oral contraceptives or who have recently stopped using them is small relative to the baseline probability of developing cancer. These studies do not provide data on the etiology of cancer. The increased risk of breast cancer may be a consequence of medical supervision and earlier diagnosis of cancer in women taking combined oral contraceptives (they are diagnosed with earlier stages of cancer than women who have never taken combined oral contraceptives), the biological effect of combined oral contraceptives, or a combination of these two factors.

Very rarely, cases of benign, and even more rarely, malignant liver tumors have been observed with the use of the Desogestrel+Ethinylestradiol combination. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. The physician should consider the possibility of a liver tumor in the differential diagnosis of a woman taking the Desogestrel+Ethinylestradiol combination if symptoms include acute pain in the upper abdomen, liver enlargement, or signs of intra-abdominal bleeding.

Other diseases

If a woman or her family members have been diagnosed with hypertriglyceridemia, the risk of pancreatitis may increase when taking the drug.

If clinically significant persistent arterial hypertension develops in a woman taking the drug, the physician should discontinue this drug and prescribe treatment for arterial hypertension. In cases where normal blood pressure values are achieved with antihypertensive therapy, the physician may consider it possible for the patient to resume taking the drug.

There are reports that jaundice and/or itching caused by cholestasis, gallstone formation, porphyria, SLE, hemolytic-uremic syndrome, Sydenham’s chorea (chorea minor), herpes gestationis, hearing loss due to otosclerosis, (hereditary) angioedema develop or worsen both during pregnancy and when taking combined oral contraceptives, however, evidence regarding the use of the Desogestrel+Ethinylestradiol combination is inconclusive.

Acute or chronic liver dysfunction may be grounds for discontinuing the drug until liver function tests return to normal. Recurrence of cholestatic jaundice, previously observed during pregnancy or with the use of sex hormone drugs, requires discontinuation of the drug.

Although the use of the drug may affect peripheral insulin resistance and glucose tolerance, as a rule, adjustment of the dosage regimen of hypoglycemic drugs in patients with diabetes mellitus is not required. Nevertheless, careful monitoring of blood glucose concentration is necessary, especially during the first months of taking the combined oral contraceptive.

There is evidence of an association between the use of combined oral contraceptives and Crohn’s disease and ulcerative colitis.

Sometimes, skin pigmentation of the face (chloasma) may be observed when taking the drug, especially if it was previously noted during pregnancy. Women predisposed to chloasma should avoid direct sunlight and UV radiation from other sources when using the Desogestrel+Ethinylestradiol combination.

Medical examinations/consultations

Before starting or resuming the drug, it is necessary to collect a detailed medical history (including family history) from the patient and conduct a thorough examination, taking into account contraindications and precautions. It is important to repeat periodic medical examinations, because diseases that are contraindications to taking the drug (for example, transient ischemic attack) or risk factors (for example, a family history of venous or arterial thrombosis) may first appear during drug use. The frequency and list of examinations should be based on accepted practice and tailored individually for each woman (but not less than once every 6 months). In any case, special attention should be paid to measuring blood pressure, examining the breasts, abdominal and pelvic organs, including cytological examination of the cervix.

The woman should be informed that combined oral contraceptives do not protect against HIV (AIDS) and other sexually transmitted infections.

Reduced effectiveness

The effectiveness of the drug may decrease in case of missed doses, gastrointestinal disorders, or concomitant use of certain medications.

Irregular bleeding

When taking the drug, especially in the first months of use, irregular spotting or heavy bleeding may occur. Therefore, the assessment of irregular bleeding should be carried out only after the end of the adaptation period, lasting 3 months.

If irregular bleeding persists or appears after previous regular cycles, possible non-hormonal causes of cycle disorders should be considered and appropriate investigations should be carried out to rule out malignant neoplasms or pregnancy. These measures may include diagnostic curettage.

Some women may not have menstrual-like bleeding during the break in taking the drug. If the drug was used in accordance with the above recommendations, the likelihood of pregnancy is low. Otherwise, or if bleeding is absent 2 times in a row, the possibility of pregnancy should be excluded and a doctor should be consulted.

Laboratory tests

Combined oral contraceptives may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, the content of transport proteins in blood plasma, for example, corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, parameters of coagulation and fibrinolysis. Usually these changes are within the normal range of laboratory values.

Effect on ability to drive vehicles and mechanisms

No effect of the drug on the ability to drive vehicles and work with mechanisms has been noted.

Drug Interactions

Interactions between combined oral contraceptives and other drugs can lead to acyclic bleeding and/or reduced contraceptive effectiveness.

Concomitant use with inducers of liver microsomal enzymes (e.g., hydantoins, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, bosentan, modafinil, rifabutin and preparations containing St. John’s wort) may lead to an increase in the clearance of sex hormones. Maximum induction of microsomal enzymes is not observed in the first 2-3 weeks of taking the Desogestrel+Ethinylestradiol combination, but may persist for at least 4 weeks after discontinuation of the drug. When using inducers of microsomal enzymes concomitantly, an additional barrier method of contraception (e.g., a condom) should be used throughout the course of treatment and for 28 days after stopping treatment. If long-term use of inducer drugs is necessary, it is advisable to consider other effective non-hormonal methods of contraception. In case of finishing the cycle of using the Desogestrel+Ethinylestradiol combination earlier than the inducer drug, it is recommended to start taking tablets from a new package of the drug without the usual break.

Cases of reduced contraceptive effectiveness have been described with the concomitant use of the Desogestrel+Ethinylestradiol combination with antibiotics such as ampicillin and tetracycline. During the use of antibiotics (except for rifampicin and griseofulvin, which are inducers of microsomal enzymes), it is necessary to use a barrier method of contraception throughout the course of treatment and for 7 days after the end of therapy.

Concomitant administration of atorvastatin and some combined oral contraceptives containing Ethinylestradiol increases the AUC of ethinylestradiol by approximately 20%.

Ascorbic acid may increase the plasma concentration of ethinylestradiol, possibly due to inhibition of conjugation.

The drug reduces the effectiveness of indirect anticoagulants, anxiolytics (diazepam), tricyclic antidepressants, theophylline, caffeine, hypoglycemic drugs, clofibrate and corticosteroids.

Combined oral contraceptives may affect the metabolism of other drugs and accordingly change their concentration in plasma and tissues: increase (e.g., cyclosporine) or decrease (lamotrigine, salicylic acid, morphine).

When using other drugs concomitantly, the instructions for medical use of the simultaneously taken drugs should be consulted to determine possible interactions.

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.