Drospirenone + Ethinylestradiol (Tablets) Instructions for Use

Marketing Authorization Holder

Alkaloid AD (Macedonia)

Manufactured By

Lupin, Ltd. (India)

ATC Code

G03AA12 (Drospirenone and Ethinylestradiol)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Drospirenone (Rec.INN registered by WHO)

Dosage Form

Drospirenone + Ethinylestradiol

Film-coated tablets 3 mg+0.03 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

21 pcs. – blisters – cardboard packs (21 pcs.) – By prescription
21 pcs. – blisters (3 pcs.) – cardboard packs (63 pcs.) – By prescription
21 pcs. – blisters (6 pcs.) – cardboard packs (126 pcs.) – By prescription

Clinical-Pharmacological Group

Contraceptive combined drug (estrogen + progestogen)

Pharmacotherapeutic Group

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

Pharmacological Action

A combined monophasic hormonal contraceptive agent. The contraceptive effect is based on the interaction of various factors, the most important of which are inhibition of ovulation and an increase in the viscosity of cervical secretion, making it impermeable to sperm.

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

At a therapeutic dose, Drospirenone also has antiandrogenic and weak antimineralocorticoid properties. Lacking estrogenic, glucocorticoid, and antiglucocorticoid activity, Drospirenone has a pharmacological profile similar to that of natural progesterone. Possessing antiandrogenic activity, it helps reduce sebum production and improve the clinical course in women with acne (acne vulgaris). This should be taken into account when choosing a contraceptive drug, especially for women with hormone-dependent fluid retention, as well as for women with acne and seborrhea. In combination with ethinylestradiol, it improves the lipid profile and increases HDL concentration.

The use of this combination regulates menstrual-like bleeding, helping to reduce the severity of pain and the volume of menstrual-like bleeding, reducing one of the risk factors for the development of iron deficiency anemia.

Pharmacokinetics

When taken orally, Drospirenone is rapidly and almost completely absorbed. After a single oral dose, C_max in blood plasma is about 35 ng/ml, T_max in blood plasma is 1-2 hours. Bioavailability is 76-85%. Food intake does not affect the bioavailability of drospirenone. It binds to blood plasma albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). The concentration of free drospirenone does not exceed 3-5% of the administered dose. Estradiol-induced increase in SHBG does not affect the binding of drospirenone to plasma proteins. The mean apparent V_d is 3.7±1.2 L/kg. C_ss of drospirenone in blood plasma is reached between days 7 and 14 of treatment and is approximately 60 ng/ml. A further increase in concentration is noted approximately between cycles 1 and 6 of administration, with no subsequent increase in concentration observed. It is metabolized in the liver with practically no involvement of the cytochrome P450 system. Metabolites in blood plasma are mainly represented by the acid forms of drospirenone, formed as a result of lactone ring cleavage, and 4,5-dihydro-Drospirenone-3-sulfate. It is metabolized almost completely. The metabolic clearance rate is 1.5±0.2 ml/min/kg. Metabolites are excreted via the intestine and kidneys in a ratio of 1.2:1.4. T_1/2 of metabolites is about 40 hours.

When taken orally, Ethinylestradiol is rapidly and almost completely absorbed. After a single oral dose, C_max is 88-100 ng/ml, T_max is 1-2 hours. It is metabolized during absorption and during the “first pass” through the liver. The absolute bioavailability after oral administration is 60%. Concomitant food intake reduces bioavailability in approximately 25% of volunteers. Binding to plasma proteins is about 98.5%. Ethinylestradiol induces the synthesis of SHBG in the liver. The apparent V_d of ethinylestradiol is about 5 L/kg. C_ss is achieved during the second half of the administration cycle. Ethinylestradiol penetrates into breast milk in small amounts (0.02% of the administered dose). About 50-60% of ethinylestradiol undergoes presystemic conjugation in the small intestinal mucosa and liver (the “first pass” effect). The main metabolic pathway is aromatic hydroxylation, resulting in hydroxylated and methylated metabolites, both free and as conjugates with glucuronic and/or sulfuric acids. A portion of ethinylestradiol conjugated with glucuronic acid is reabsorbed in the intestine after biliary excretion (enterohepatic recirculation). It is metabolized completely (practically not excreted unchanged). The metabolic clearance rate from blood plasma is 5 ml/min/kg. Ethinylestradiol metabolites are excreted by the kidneys and through the intestine in a ratio of 4:6, T_1/2 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 direction arrows. Start the first tablet on the first day of your menstrual period.

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

For a 28-tablet pack: Take one active tablet daily for 21 consecutive days, followed by one inactive (placebo) tablet daily for 7 days. Continue directly to the next pack without a break.

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 instructions for missed tablets.

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

If a tablet is missed and it is more than 12 hours late, contraceptive protection may be reduced. Take the most recent missed tablet immediately, even if it means taking two tablets on the same day. Discard any other earlier missed tablets.

Continue taking the remaining tablets at the usual time. For the next 7 days, use a barrier method of contraception.

If the missed tablets were in the last week of active tablets (days 15-21), omit the tablet-free interval. Finish the active tablets in the current pack and start the next pack of active tablets the next day.

If unsure how to manage missed doses, use a barrier method of contraception and continue taking tablets until medical advice is obtained.

To delay a period, finish all active tablets in the current pack and start the next pack of active tablets the next day, omitting the tablet-free interval.

When switching from another combined hormonal contraceptive, start on the day after the last active tablet of the previous product or at the latest on the day following the usual tablet-free or placebo tablet interval.

After a first-trimester abortion, start immediately. After childbirth or a second-trimester abortion, start at 21-28 days postpartum. If started later than day 28, use a barrier method for the first 7 days.

Adverse Reactions

From the immune system rarely – bronchial asthma, hypersensitivity reactions.

From the nervous system often – headache.

Mental disorders often – depressive state; infrequently – change in libido.

From the hearing organ rarely – hearing loss.

From the cardiovascular system often – migraine; infrequently – increased blood pressure, decreased blood pressure; rarely – thromboembolism.

From the digestive system often – nausea; infrequently – vomiting, diarrhea.

From the skin and subcutaneous tissues infrequently – acne, eczema, itching; rarely – erythema nodosum, erythema multiforme.

From the reproductive system and breast often – menstrual cycle disorders, acyclic bleeding, breast tenderness, breast hypersensitivity, leucorrhea, candidal vulvovaginitis; infrequently – breast enlargement, vaginitis; rarely – breast discharge.

Other infrequently – fluid retention, change in body weight.

Contraindications

Thrombosis (venous and arterial) currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders); conditions preceding thrombosis (including transient ischemic attacks, atrial fibrillation, angina) currently or in history; presence of multiple or pronounced risk factors for venous or arterial thrombosis, including complicated lesions of the heart valves, atrial fibrillation, cerebrovascular or coronary artery diseases; uncontrolled arterial hypertension, prolonged immobilization, major surgery, surgical operations on the lower limbs, extensive trauma, smoking over the age of 35, obesity with BMI over 30 kg/m²; hereditary or acquired predisposition to venous or arterial thromboses, such as 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); migraine with focal neurological symptoms currently or in history; diabetes mellitus with diabetic angiopathy; hepatic insufficiency and severe liver diseases (until normalization of liver function tests and for 3 months after these indicators return to normal); liver tumors (benign or malignant) currently or in history; severe or acute renal failure; identified hormone-dependent malignant diseases (including of the genital organs or breasts) or suspicion of them; vaginal bleeding of unknown origin; pregnancy or suspicion of it; lactation period (breastfeeding); pancreatitis with severe hypertriglyceridemia currently or in history; hypersensitivity to the components of the combination.

If any of the above diseases or conditions develop for the first time while using a drug containing this combination, it should be discontinued immediately.

With caution

Risk factors for the development of thrombosis and thromboembolism: smoking, obesity with BMI less than 30 kg/m², dyslipoproteinemia, controlled arterial hypertension, migraine without focal neurological symptoms, uncomplicated heart valve defects, family history of thrombosis and thromboembolism (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives); age over 35 years in non-smoking women.

Diseases in which peripheral circulation disorders may be noted: diabetes mellitus without vascular complications, SLE, hemolytic-uremic syndrome, Crohn’s disease, ulcerative colitis, sickle cell anemia, superficial phlebitis.

Hereditary angioedema.

Hypertriglyceridemia;

Mild to moderate liver diseases.

Diseases that first appeared or worsened during pregnancy or during previous use of sex hormones (including jaundice and/or itching associated with cholestasis, cholelithiasis, otosclerosis with hearing impairment, porphyria, herpes during pregnancy in history, Sydenham’s chorea, chloasma, postpartum period).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in women with severe liver diseases until liver function test indicators normalize; liver tumors (benign or malignant) currently or in history.

Use in Renal Impairment

Contraindicated in severe or acute renal failure.

Pediatric Use

The drug is indicated only after menarche.

Geriatric Use

The drug is not indicated after menopause.

Special Precautions

Before starting the use of drugs containing this combination, pregnancy should be excluded and a thorough general medical and gynecological examination is recommended, including breast examination and cytological examination of the cervix. In addition, disorders of the blood coagulation system should be excluded. In case of long-term use, preventive check-up examinations should be performed at least once every 6 months.

A number of epidemiological studies have revealed an increased incidence of venous and arterial thrombosis and thromboembolism when taking COCs. The greatest risk of developing these complications exists in the first year of taking the drug (especially in the first 3 months) or resuming intake after a 4-week break. The use of any COC can be complicated by the development of venous thromboembolism (VTE), manifested as deep vein thrombosis and pulmonary embolism. The approximate frequency of VTE in women taking oral contraceptives with a low dose of estrogens (less than 50 mcg of ethinylestradiol) is up to 4 per 10,000 women per year compared to 0.5-3 per 10,000 women not using oral contraceptives.

The risk of thrombosis (venous and/or arterial) and thromboembolism increases: with age, in smokers (with an increase in the number of cigarettes smoked or increasing age, the risk further increases, especially in women over 35 years of age), in the presence of a family history (i.e., venous or arterial thromboembolism ever in close relatives or parents at a relatively young age), obesity (BMI over 30 kg/m²); dyslipoproteinemia, arterial hypertension, heart valve diseases, atrial fibrillation; prolonged immobilization; temporary immobilization, including air travel for more than 4 hours; major surgical intervention; any surgery on the lower limbs or extensive trauma – in these situations, it is necessary to stop taking the drug; in case of planned surgery – 4 weeks before it and not to resume intake for 2 weeks after the end of immobilization.

Peripheral circulation disorders can also be noted in diabetes mellitus, SLE, hemolytic-uremic syndrome, chronic inflammatory bowel diseases (Crohn’s disease or ulcerative colitis) and sickle cell anemia.

An increase in the frequency and severity of migraine during the use of COCs (which may precede cerebrovascular disorders) may be grounds for immediate discontinuation of these drugs.

In rare cases, the development of liver tumors has been observed during the use of COCs. In case of severe abdominal pain, liver enlargement or signs of intra-abdominal bleeding, this should be taken into account when conducting a differential diagnosis.

Recurrent cholestatic jaundice, which developed for the first time during pregnancy or during previous use of sex hormones, requires discontinuation of COCs.

In women with hypertriglyceridemia or a family history, the risk of developing pancreatitis increases during the use of COCs.

Although a slight increase in blood pressure has been described in many women taking COCs, clinically significant increases have been rare. The relationship between COC use and clinically significant increases in blood pressure has not been established. However, if a persistent, clinically significant increase in blood pressure develops during COC use, it is necessary to discontinue the drug and treat arterial hypertension. COC use may be continued after consultation with a doctor if blood pressure has normalized with antihypertensive therapy.

Although COCs can affect insulin resistance and glucose tolerance, there is no need to change the therapeutic regimen in patients with diabetes using COCs. Nevertheless, women with diabetes should be carefully monitored during COC use.

Women prone to chloasma during COC use should avoid prolonged sun exposure and UV radiation.

Due to the antimineralocorticoid activity of Drospirenone, it increases the concentration of renin and aldosterone in blood plasma.

During COC use, the course of endogenous depression and epilepsy may worsen.

During COC use, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the assessment of any irregular bleeding is significant only after 3-4 months of contraception.

If irregular bleeding recurs or develops after previous regular cycles, a thorough examination should be carried out to exclude malignant neoplasms or pregnancy.

In some women, withdrawal bleeding may not occur during the break in taking the pills. If the COC was taken according to the instructions, pregnancy is unlikely. However, if the COC was taken irregularly before, or if two consecutive withdrawal bleedings are absent, then pregnancy must be excluded before continuing the drug.

Drug Interactions

Long-term treatment with drugs that are inducers of liver microsomal enzymes, which increases the clearance of sex hormones, can lead to a decrease in contraceptive effectiveness. Such drugs include: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, rifampicin, rifabutin, topiramate, felbamate, griseofulvin and preparations containing St. John’s wort.

HIV protease inhibitors (ritonavir), non-nucleoside reverse transcriptase inhibitors (nevirapine) and their combinations may also potentially affect hepatic metabolism. Maximum enzyme induction is usually achieved approximately 10 days after starting these medications, but may persist for at least 4 weeks after their discontinuation. When taking drugs that affect the induction of liver microsomal enzymes concomitantly and for 28 days after their discontinuation, it is necessary to temporarily use a barrier method of contraception.

Contraceptive protection is reduced while taking antibiotics of the penicillin and tetracycline series due to their reduction of intrahepatic estrogen circulation, and consequently, a decrease in the concentration of ethinylestradiol. During the intake of these antibiotics and for 7 days after their discontinuation, it is necessary to additionally use a barrier method of contraception.

Since the main metabolites of drospirenone in human plasma are formed without the involvement of the cytochrome P450 system, inhibitors of this enzyme system do not affect the metabolism of drospirenone.

Oral combined estrogen-progestogen contraceptives can affect the metabolism of other drugs, leading to an increase (cyclosporine) or decrease (lamotrigine) of their concentration in plasma and tissues.

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.