Drospirenone, Ethinyl Estradiol

Pharmacological properties

The contraceptive effect of the drug Darilia is based on the interaction of various factors, the most important of which are inhibition of ovulation and a change in the endometrium.

Daryl, film-coated tablets is a combined oral contraceptive (CPC) containing ethinyl estradiol and the progestogen drospirenone. In a therapeutic dose, drospirenone has antiandrogenic and weak antimineralocorticoid properties. It is devoid of any estrogenic, glucocorticoid and antiglucocorticoid activity. This provides drospirenone with a pharmacological profile that is extremely similar to the natural hormone progesterone. Weak antimineralocorticoid properties of the drug cause a weak antimineralocorticoid effect.

Pharmacokinetics

Drospirenone (3 mg)

Suction. When taken orally, drospirenone is rapidly and almost completely absorbed. C_max the active substance in the blood plasma - 38 ng / ml - is achieved 1-2 hours after a single dose. Bioavailability ranges from 76 to 85%. Eating does not affect the bioavailability of drospirenone.

Distribution. Following oral administration, plasma concentrations of drospirenone decreased with final T_½ 31 hours. Drospirenone binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG), or corticosteroid-binding globulin (CSH). Only 3-5% of the total plasma concentration of the active substance is free hormone. The increase in SHBG induced by ethinyl estradiol does not affect the binding of drospirenone to plasma proteins. The average estimated volume of distribution is 3.7 ± 1.2 L / kg.

Metabolism. Following oral administration, drospirenone is extensively metabolized. Most metabolites in blood plasma are represented by the acid forms of drospirenone, formed during the opening of the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate, which is formed by reduction and further sulfation. Drospirenone also undergoes an oxidative metabolism that is catalyzed by CYP 3A4. In vitro drospirenone may slightly or moderately inhibit cytochrome P450 enzymes: CYP 1A1, CYP 2C9, CYP 2C19 and CYP 3A4.

The metabolic clearance rate of drospirenone in blood plasma is 1.5 ± 0.2 ml / min / kg. Drospirenone is excreted only in trace amounts unchanged. Drospirenone metabolites are excreted in feces and urine in a ratio of about 1.2: 1.4; T_½ metabolites is about 40 hours.

Equilibrium concentration. During one intake cycle, equilibrium C_max drospirenone in blood plasma (about 70 ng / ml) is achieved after 8 days. The plasma concentrations of drospirenone increased approximately 3 times as a result of the ratio (or proportion) of the final T_½ and dosing interval.

Separate categories of patients

Renal failure. The equilibrium plasma level of drospirenone in women with weak renal failure (creatinine clearance of 50–80 ml / min) was comparable to that in women with normal renal function (80 ml / min). Plasma drospirenone was on average 37% higher in women with moderate renal failure (creatinine clearance 30–50 ml / min) compared to women with normal renal function. Drospirenone therapy was well tolerated by patients with renal failure, both mild and moderate, and did not have a clinically significant effect on the concentration of potassium in the blood plasma.

Lack of liver function. It is known that in volunteers with moderate hepatic impairment, the clearance of a single dose after oral administration was reduced by about 50% compared with that in volunteers.The revealed decrease in drospirenone clearance in volunteers with moderate hepatic impairment does not lead to any significant differences in the concentration of potassium in the blood plasma. Even with diabetes mellitus and simultaneous treatment with spironolactone (two factors that can provoke a predisposition to the development of hyperglycemia), there was no increase in the concentration of potassium in the blood plasma above the upper limit of the norm. It can be concluded that drospirenone is well tolerated by patients with mild to moderate hepatic impairment (Child-Pugh class B).

Ethinyl estradiol (0.02 mg)

Suction. Ethinyl estradiol after oral administration is rapidly and completely absorbed. The maximum plasma concentration after a single dose is achieved after 1-2 hours and is about 33 pkg / ml. Absolute bioavailability varies and is about 60%.

Simultaneous food intake reduced the bioavailability of ethinyl estradiol in approximately 25% of the examined patients, and the remaining changes were not observed.

Distribution. The concentration of ethinyl estradiol in blood plasma decreased two-phase, in the phase of the final distribution of T_½ is about 24 hours. Ethinyl estradiol is good, but non-specifically bound to serum albumin (about 98.5%) and induces an increase in plasma concentration of SHBG. Estimated distribution volume is about 5 l / kg.

Metabolism. Ethinyl estradiol undergoes a significant presystemic metabolism in the small intestine and liver. Ethinyl estradiol is initially metabolized by aromatic hydroxylation, with the formation of a wide range of hydroxylated and methylated metabolites present in the form of free metabolites and conjugates with glucuronides and sulfates. The clearance rate of ethinyl estradiol metabolites is about 5 ml / min / kg.

In vitro studies have shown that ethinyl estradiol is a reverse inhibitor of CYP 2C19, CYP 1A1 and CYP 1A2, and also, based on its mechanism of action, an inhibitor of CYP 3A4 / 5, CYP 2C8 and CYP 2J2.

Ethinyl estradiol is practically not excreted unchanged. Ethinyl estradiol metabolites are excreted in the urine and bile in a ratio of 4: 6. T_½ for metabolites is about 1 day.

Equilibrium concentration. The state of equilibrium concentration is achieved during the second half of the cycle, and the serum level of ethinyl estradiol accumulates with a ratio of about 2–2.3.

Ethnic groups. It is known that there are no clinically significant differences in the pharmacokinetics of drospirenone and ethinyl estradiol in women of the Caucasoid and Mongoloid races.

Preclinical safety data. In laboratory animals, the effects of drospirenone and ethinyl estradiol were limited to those associated with a known pharmacological effect. In particular, studies on the identification of reproductive toxicity in animals showed the presence of species-specific embryotoxic and fetotoxic effects. When the exposure to drospirenone and ethinyl estradiol is higher than therapeutic, the effect on sexual differentiation in rat embryos, but not in monkeys, was noted.

Indications

Oral contraception.

Before prescribing Darilia, you should assess the presence of individual risk factors in a woman, especially the risk of venous thromboembolism (VTE), and also compare the risk of VTE when taking Darilia with the risk when taking other CPC (see CONTRAINDICATIONS, SPECIAL INDICATIONS).

Application

One blister pack contains 28 tablets (24 + 4): 24 tablets of white or almost white color (active tablets) and 4 tablets of green color (placebo tablets are inactive).

How to take the drug Darilia (24 + 4). Tablets must be taken every day at about the same time, if necessary, washed down with a small amount of liquid, in the sequence indicated on the blister pack.It is necessary to take 1 tablet per day for 28 consecutive days. Reception of tablets from each following packaging should begin after reception of the last tablet from the previous packaging. Menstrual bleeding usually occurs on the 2nd – 3rd day after taking placebo tablets (green tablets in the last row) and does not necessarily end before taking tablets from a new package.

How to start taking Darilia (24 + 4)

If hormonal contraceptives in the previous period (last month) were not used. Pills should be started on the first day of the menstrual cycle (that is, on the first day of menstrual bleeding).

Transition from another PDA (tablets, vaginal ring or transdermal patch). A woman should start taking Darilia the next day after a normal break or after taking the last inactive tablet of the previous PDA. When switching from a vaginal ring or transdermal patch, it is advisable to start taking Darilia tablets on the day the previous agent is removed, but no later than the day when the planned use of the vaginal ring or transdermal patch should take place.

The transition from a method based on the use of only a progestogen ("mini-drank", injections, implants), or an intrauterine system with a progestogen. A woman can start taking Darilia on any day after stopping the "mini-pill" (in the case of an implant or intrauterine system - on the day of their removal, in case of an injection - instead of the next injection). However, in all cases, it is recommended to additionally use the barrier method of contraception during the first 7 days of taking the drug.

After an abortion in the first trimester of pregnancy. The use of the drug should be started immediately on the same day after the operation. In this case, there is no need to use additional contraceptives.

After childbirth or abortion in the second trimester of pregnancy. If a woman is breastfeeding - see SPECIAL INSTRUCTIONS.

Women should be advised to start taking Darilia from the 21st to 28th day after childbirth or abortion in the second trimester of pregnancy. If a woman later starts taking the pills, it should be recommended to additionally use the barrier method of contraception during the first 7 days of taking the pills. However, if sexual intercourse has already taken place, then before starting the use of CPC, it is necessary to exclude pregnancy or wait for the first menstruation.

Skip taking the pill. You can ignore the passage of a green placebo pill from the 4th row. However, it must be discarded in order to avoid accidental lengthening of the placebo phase. The instructions below only apply to the omission of active white tablets.

If the delay in taking the pill does not exceed 12 hours, the contraceptive effect of the drug does not decrease. The missed pill should be taken as soon as they remember about it. The next tablet from this package should be taken at the usual time. If the delay in taking a forgotten pill exceeds 12 hours, contraceptive protection may be reduced. In this case, you can be guided by two basic rules:

1. A break in taking pills can never be more than 4 days.

2. Adequate inhibition of the hypothalamus-pituitary-ovary system is achieved with continuous administration of tablets for 7 days. In accordance with this in everyday life should be guided by such recommendations.

Days 1–7. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take pills at the usual time. In addition, over the next 7 days it is necessary to use a barrier method of contraception, such as a condom.If sexual intercourse took place in the previous 7 days, the possibility of pregnancy should be considered. The more tablets missed and the closer this gap to the placebo tablet phase, the higher the risk of pregnancy.

Days 8-14. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take pills at the usual time. If a woman took the pill correctly for 7 days before skipping, there is no need to use additional contraceptives. Otherwise, or when skipping more than one tablet, it is recommended to additionally use the barrier method of contraception for 7 days.

Days 15-24. The likelihood of a decrease in the contraceptive effect is significant due to the approaching phase of the placebo tablets. However, if you follow the pill regimen, you can avoid a decrease in contraceptive protection. If you adhere to one of the following options, then there will be no need to use additional contraceptives if you take the tablets correctly within 7 days before skipping. Otherwise, it is recommended to adhere to the first of the following options and use additional methods of contraception for the next 7 days.

1. A woman should take the last missed pill as soon as possible, even if she has to take two tablets at the same time. After that, she continues to take the pills at the usual time until the active pills run out, but 4 placebo pills should not be taken, you should immediately start taking the pills from the next blister pack. It is unlikely that a woman will begin to have menstrual bleeding before taking the pills from the second package, although when taking the pills, bloody discharge or breakthrough bleeding may be noted.

2. A woman may also be advised to stop taking active tablets from the current package. Instead of active pills, you should take a placebo pill from the last row for 4 days, including days of skipping pills, and then start taking pills from the next blister pack.

If a woman has missed taking the pills and she does not have menstrual bleeding during the first usual break in taking the drug, the probability of pregnancy should be considered.

Recommendations in case of gastrointestinal disorders. In severe disorders of the gastrointestinal tract (vomiting, diarrhea), incomplete absorption of the drug is possible. In this case, additional contraceptives should be used. If vomiting is noted within 3-4 hours after taking the pill, you must take a new pill (from another package) as soon as possible, which will replace the previous one. A new tablet should be taken within 12 hours after the usual time of administration. If more than 12 hours have passed, you must follow the rules for taking the drug indicated in the "Skipping pill" section. If a woman does not want to change her usual regimen of taking the drug, she needs to take additional tablet (s) from another package.

How to shift the time of occurrence of bleeding "cancellation". To delay the day the menstruation begins, you should skip the placebo pill and start taking the active Darilia pills from a new package. If desired, the period of admission can be continued until the end of the second package. In this case, breakthrough bleeding or spotting may be noted. The usual intake of Darilia is restored after taking the placebo pill phase.

To shift the onset of menstruation to another day of the week, it is recommended to shorten the placebo phase by the desired number of days. It should be noted that the shorter the break, the higher the likelihood of absence of menstrual bleeding and the higher the risk of breakthrough bleeding or spotting during the period of taking tablets from the next package (as in the case of delayed menstruation).

Preparing to use the weekly sticker calendar strip. In order to help the patient to monitor the intake of pills, a weekly sticker calendar is inserted in the package, on which 7 days of the week are indicated.

A woman should choose a self-adhesive strip of the calendar, the designations on which begin from the day of the week when she begins to take pills. For example, if she starts taking pills on Wednesday, she selects a strip sticker that starts with the designation “Environment.”

Attach the “→” symbol on the strip to the same symbol in the blister pack and stick the strip on the blister to the place circled by the line. Each day of the week will be indicated parallel to the line of tablets in blister packs. Thus, you can see what day of the week a woman takes the pill. It is necessary to take the tablets in the sequence indicated on the blister pack until all 28 tablets have been taken.

Within 4 days, when a woman takes a green placebo pill, menstrual bleeding should begin. It usually begins on the 2nd or 3rd day after taking the last white active pill Darilia.

After the woman has taken the last green pill, it is necessary to start taking the pills from the new blister pack and apply the next strip of the 7-day calendar-sticker, regardless of whether the withdrawal bleeding has ended or not.

This means that a woman will start using each strip of the weekly calendar on the same day of the week and withdrawal bleeding will occur on the same days of each month.

Contraindications

PDA should not be used in the presence of one of the following conditions or diseases. in the event that any of these conditions or diseases occurs for the first time during the use of the PDA, the drug should be stopped immediately:

• hypersensitivity to active substances or any of the excipients of the drug;
• hypersensitivity to peanuts or soy;
• the presence or risk of VTE:
• existing VTE (use of anticoagulants) or a history of (for example, deep vein thrombosis or pulmonary embolism);
• hereditary or acquired predisposition to the development of VTE, for example resistance to activated protein C (including Leiden factor V), antithrombin III deficiency, protein C deficiency, protein S deficiency;
• extensive surgery with prolonged immobilization (see SPECIAL INSTRUCTIONS);
• high risk of developing VTE due to the presence of numerous risk factors (see SPECIAL INSTRUCTIONS);
• the presence or risk of arterial thromboembolism:
• existing arterial thromboembolism, including a medical history (e.g. myocardial infarction), or a prodromal condition (e.g. angina pectoris);
• cerebrovascular disease, including a history of stroke, or a prodromal condition (transient ischemic attack);
• hereditary or acquired predisposition to the development of arterial thromboembolism, for example, hyperhomocysteinemia and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
• migraine with local neurological symptoms in history;

high risk of arterial thromboembolism due to the presence of numerous risk factors (see SPECIAL INSTRUCTIONS) or the presence of one of these serious risk factors:

• diabetes mellitus with vascular complications;
• severe hypertension;
• severe dyslipoproteinemia;
• severe liver disease, including a history if liver function indicators have not returned to normal;
• severe renal failure or acute renal failure;
• liver tumors (benign or malignant), including a history of;
• known or suspected malignant tumors (for example, genitals or mammary glands) that are dependent on sex hormones;
• vaginal bleeding of unknown etiology.

Side effects

The most serious side effects associated with the use of PDA are described in the special instructions section.

With the simultaneous use of drospirenone and ethinyl estradiol, the following adverse reactions were reported:

* Irregular menstruation usually disappears with continued use of the drug.

Description of individual adverse reactions. A high risk of developing arterial and venous thrombotic and thromboembolic complications, including myocardial infarction, stroke, transient ischemic attack, venous thrombosis and pulmonary embolism, was noted in women taking CPC. For more information, see SPECIAL INSTRUCTIONS.

The following serious adverse reactions have been reported in women taking birth control (described in the SPECIAL INSTRUCTIONS section):

• venous and arterial thromboembolic disorders;
• Hypertension;
• tumors of the liver;
• the onset or worsening of conditions whose association with oral contraceptive use has not been proven: Crohn’s disease, ulcerative colitis, epilepsy, migraine, endometriosis, uterine fibroids, porphyria, systemic lupus erythematosus, pregnant herpes, Sydenham chorea, hemolytic-uremic syndrome, cholestatic jaundice;
• chloasma;
• acute or chronic liver dysfunction may require the abolition of oral contraceptives before normalization of laboratory markers of liver function;
• in women with hereditary angioedema, exogenous estrogens can cause or exacerbate symptoms of angioedema.

The frequency of diagnosis of breast cancer among women using oral contraceptives is slightly increased. Since breast cancer in women under 40 years of age is rare, the increase is small compared to the overall risk of developing breast cancer. A causal relationship with oral contraceptives has not been proven. See CONTRAINDICATIONS and SPECIAL INSTRUCTIONS for more information.

Interactions. Breakthrough bleeding and / or a decrease in the severity of contraceptive action may occur as a result of the interaction of other drugs (enzyme inducers) with oral contraceptives (see INTERACTIONS).

Reporting suspected adverse reactions. Reporting suspected adverse reactions during post-marketing surveillance is very important. This makes it possible to monitor the benefit / risk ratio for medicines. Healthcare providers should report suspected adverse reactions.

special instructions

If you have any of the following conditions / risk factors, you should carefully weigh the potential risk and expected benefits of using PDA in each individual case and discuss it with a woman before she decides to start using darilia. in case of exacerbation, amplification, or first occurrence of any of the following conditions or risk factors, a woman is recommended to consult a doctor who can decide whether to stop using the drug.

In case of suspected or confirmed VTE or arterial thromboembolism, the use of CPC should be discontinued. If anticoagulant therapy is started, alternative adequate contraception should be provided due to the teratogenic effect of anticoagulants (coumarins).

Violations of the circulatory system. The risk of VTE. The use of any CPC increases the risk of developing VTE in women compared to those that do not use them. The use of drugs containing levonorgestrel, norgestimate or norethisterone are associated with a lower risk of VTE. The use of other drugs, such as D