What Is Drospirenone?

Drospirenone is also known as dispirospirone, with the chemical names 6, 7; 15, 16-dimethylene3-oxo-17-pregnost-4-ene-17, 21 carboxylactone, molecular formula C24H30O3, a white to off-white crystalline powder, density: 1.26 g / cm3, melting point: 196-200ºC, boiling point: 552.2ºC at 760 mmHg, is a new generation of progestogen with high efficiency, low toxicity and good safety.

Chinese name: Drospirenone
Foreign name: drospirenone

CAS number: 67392-87-4
Molecular weight: 366.49300
Density: 1.26 g / cm3

Introduction to Drospirenone Compounds

Drospirenone Basic Information

Chinese name: Drospirenone

Chinese alias: 6b, 7b: 15b, 16b-dimethylene-3-oxo-17a-pregnost-4-ene-21,17-carboxylactone; 15b, 16b-dimethylene-3-oxo Dai-17a-pregn-4-en-21,17-carboxylactone; dihydrospirolidone;

English name: drospirenone

English alias: ZK 3059; 6b, 7b; dihydrospirorenone; arbolactone; Drospirenona;

CAS number: 67392-87-4

Molecular formula: C ₂₄ H ₃₀ O ₃

Structural formula:

Molecular weight: 366.49300

Exact mass: 366.21900

PSA: 43.37000

LogP: 4.30590

Physicochemical Properties of Drospirenone

Appearance and properties: white to off-white crystalline powder

Density: 1.26 g / cm ³

Melting point: 196-200ºC

Boiling point: 552.2ºC at 760 mmHg

Flash point: 241.6ºC

Refractive index: 1.61

Drospirenone Safety Information

Symbol: GHS08

Signal Word: Danger

Hazard statement: H360

Cautionary statement: P201; P308 + P313

Customs code: 2937290090 ^[1]

Drospirenone pharmacology and toxicology

Drospirenone pharmacological action

The contraceptive effects of compound oral contraceptives (COCs) are based on the interaction of multiple factors, the most important of which are inhibition of ovulation and alteration of cervical mucus. In addition to the contraceptive effects, although COCs have the adverse characteristics mentioned in (warnings and adverse reactions), there are many beneficial characteristics: such as a more regular menstrual cycle, less dysmenorrhea, and less bleeding. The latter can reduce the occurrence of iron deficiency.

A large prospective 3-group cohort study showed that the incidence of diagnosis of VTE in women using low-dose estrogen (ethinylestradiol <0.05mg) COCs ranged from 8-10 / 10000 women-years. Recent data show that the incidence of diagnosis of VTE among COC-free and non-pregnant women is approximately 4.4 / 10,000 women-years, and that the range of women during pregnancy or postpartum is 20-30 / 10,000-year women. Regardless of the presence of other risk factors, the incidence of VTE in women using ethinyl estradiol / drospirenone 0.03mg / 3mg (Yuming®) is in the same range as women using COCs and other COCs containing levonorgestrel Inside. A prospective, controlled database study comparing users with ethinyl estradiol 0.03 mg / drospirenone 3 mg showed similar rates of VTE with other COC users.

In addition to contraception, drospirenone has other advantageous properties. Drospirenone has anti-mineral corticosteroid activity, preventing weight gain and other symptoms caused by fluid retention. It combats estrogen-related sodium retention, provides good tolerance, and has a positive effect on premenstrual syndrome (PMS). Compounded with ethinyl estradiol, drospirenone increases high-density lipoprotein (HDL) levels, showing a good lipid mass spectrum. The anti-androgenic activity of drospirenone has a good effect on the skin, reducing acne damage and sebum production. In addition, drospirenone does not counteract the increase in estrogen-associated sex hormone-binding globulin (SHBG), which facilitates binding and inactivation of endogenous androgens.

Drospirenone does not have any androgen, estrogen, glucocorticoid, and antiglucocorticoid activity. This characteristic, combined with its mineralocorticoid and antiandrogenic properties, makes the biochemical and pharmacological properties of drospirenone very similar to that of natural progestins. In addition, there is evidence that the risk of endometrial and ovarian cancer is reduced. Moreover, higher doses of COCs (ethinyl estradiol 0.05 mg) have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease, and ectopic pregnancy. Whether this applies to lower doses of COCs remains to be seen. ^[2]

Drospirenone Toxicology Study

Repeated pre-clinical routine tests of toxicity, genotoxicity, potential carcinogenicity, and reproductive toxicity show no particular danger to humans. However, it must be kept in mind that sex steroid hormones may promote the growth of certain hormone-dependent tissues and tumors. ^[2]

Drospirenone pharmacokinetics

Drospirenone absorption

Oral drospirenone is absorbed quickly and almost completely. The maximum blood concentration can be reached in about 1-2 hours after a single dose, about 37ng / ml. Bioavailability is between 76% -85%. Eating at the same time had no effect on its bioavailability.

Drospirenone distribution

Drospirenone binds to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG). Only 3% -5% of the total serum dose is in free form, and 95% -97% is non-specifically combined with albumin. The increase of SHBG concentration induced by ethinylestradiol does not affect the binding of drospirenone to serum proteins. The apparent distribution volume of drospirenone is about 3.7-4.2L / kg.

Drospirenone metabolism

After oral administration, drospirenone is completely metabolized. The main metabolites in plasma are the acid form of drospirenone produced by opening the lactone ring and 4,5-dihydro-drospirenone-3-sulfate formed by reduction and subsequent vulcanization reactions. Drospirenone is also oxidatively metabolized by CYP3A4.
Plasma clearance is approximately 1.2-1.5 ml / min / kg.

Drospirenone clearance

Drospirenone showed a biphasic decrease in serum levels. The terminal half-life is approximately 31 hours. Drospirenone is not excreted as a prototype. The ratio of metabolites of drospirenone excreted by the bile and urine is about 1.2 to 1.4. The half-life of fecal and urine excreted metabolites is approximately 1.7 days.

Drospirenone homeostasis

The pharmacokinetics of drospirenone are not affected by SHBG levels. After taking the medicine daily, the blood concentration rises 2-3 times and reaches a steady state in the second half of a treatment cycle.

Drospirenone special population

Impact of renal impairment: in women with mild renal impairment (muscle-liver clearance CLcr, 50-80ml / min), women with normal serum drospirenone levels and normal renal function (CLcr,> 80ml / min) quite. Compared with women with normal renal function, the average serum level of drospirenone in women with moderate renal impairment (CLcr, 30-50ml / min) increased by 37%. Drospirenone treatment was well tolerated in all experimental groups. Drospirenone treatment did not have any clinically significant effects on serum potassium concentrations.

Effects of liver dysfunction: For women with moderate liver dysfunction, (Child-Pugh B) the curve of mean serum drospirenone concentration and time at the absorption / distribution phase is comparable to that of women with normal liver function, with similar Cmax values. Volunteers with moderate liver damage had an average terminal half-life of 1.8 times that of those with normal liver function, and their apparent oral clearance (CL / f) decreased by about 50%. Compared with volunteers with normal liver function, the decrease in drospirenone clearance observed in volunteers with moderate liver impairment does not imply any significant difference in serum potassium concentrations between the two groups of volunteers. Even in the presence of diabetes and concomitant treatment with spironolactone (both factors may lead to the patient's tendency to develop hyperkalemia), serum potassium concentrations exceeding the upper limit of normal values were not observed. Therefore, it can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).

Racial factors: The effects of racial factors on the pharmacokinetics of drospirenone and ethinyl estradiol after single or multiple oral administrations in healthy young Caucasian and Japanese women have been studied. The results showed that racial differences between Japanese and Caucasian women did not show clinically relevant effects on the pharmacokinetics of drospirenone and ethinyl estradiol. ^[2]

Drospirenone indication

Female contraception ^[2]

Drospirenone dosage

Route of administration: oral

If taken correctly, the annual contraceptive failure rate of compound oral contraceptives is about 1%. If you miss a medication or take it incorrectly, your contraceptive failure rate will increase.

They must be delivered with a small amount of liquid at the same time each day in the order indicated on the packaging. 1 tablet daily for 21 days. After taking the medicine for 7 days, the next box of pills is taken, during which withdrawal bleeding usually occurs. Bleeding usually starts 2-3 days after the last tablet of the cycle is taken, and the bleeding may not be over when the next box of pills is started.

How to start taking this product

· Women who have not used hormonal contraceptives before starting medication (past month)
Medication should be taken on the first day of a woman's natural menstrual cycle (ie, on the first day of menstrual bleeding). It can also start on days 2-5, in which case it is recommended to use barrier contraception during the first 7 days of the first dosing cycle.

Women who switch to another combination of hormonal contraceptives (compound oral contraceptives / COC), vaginal rings or transdermal patches

It is best to start taking the product on the second day after taking the last COC-containing hormonal drug. The product should be taken at the latest at the end of the previous COC withdrawal period or at the end of the hormone-free tablets. For women who have used vaginal rings or transdermal patches, it is best to start taking this product on the day of removal, but it should be taken at the latest when the next medication is taken.

· Women who have switched from a progestin-only method (pellets, injections, implants) or from an intrauterine system (IUS) that releases progestogens can switch from pellets (implants or from IUS) The product should be changed from the injection on the day of removal, and the product should be changed on the next injection day), but in all these cases, it should be recommended to use barrier contraception within the first 7 days of taking the drug.

· Women who have an abortion in early pregnancy can start taking the medicine immediately. In this case, no other contraceptive method is needed.

After childbirth or after mid-term pregnancy miscarriage

For the method of taking lactating women, please refer to [Medication for pregnant women and lactating women]

Women should be advised to start taking it after childbirth or on days 21-28 after abortion in the second trimester. If started late, women should be advised to use barrier contraception during the first 7 days of taking the medicine. However, if you have sex, you should eliminate the possibility of pregnancy before taking this product, or wait until the first menstrual period.

Management of missed medication

If the user forgets to take the medicine within 12 hours, the protective effect of contraception will not be reduced. Once a woman remembers it, she must take it immediately, and the next tablet should be taken in the regular elbow.

If you forget to take the medicine for more than 12 hours, the protective effect of contraception may be reduced. The management of missed medication can follow two basic principles:

1. Do not stop taking the medicine under any circumstances for more than 7 days

2. Need to be taken continuously for 7 days to maintain adequate inhibition of the hypothalamic-pituitary-ovarian axis. Therefore, the following suggestions can be given in daily medication:

· Week 1

Users should take the missed tablet as soon as they remember, even if it means taking two pills at the same time. Then continue taking the medication at regular times. In addition, barrier contraceptive methods such as condoms should be added in the next 7 days. If you have had sex within the previous 7 days, you should consider the possibility of pregnancy. The more pills you miss and the closer you are to the regular withdrawal period, the higher the risk of pregnancy.

· Week 2

Users should take the missed tablet as soon as they remember, even if it means taking two pills at the same time. Then continue taking the medication at regular times. If the user takes the medicine correctly within 7 days before the first tablet is missed, no additional contraceptive measures are needed. However, if this is not the case, or if she missed more than 1 tablet, she should be advised to use additional contraceptives for 7 days.

· Week 3

As the withdrawal period is approaching, the risk of reduced reliability of contraception increases. However, by adjusting the medication plan, the reduction in the protective effect of contraception can still be prevented. If women take their medications correctly within the first 7 days of missing the first pill, follow either of the two recommendations below, and users do not need to take extra contraceptives. If this is not the case, women are advised to follow the first of these two recommendations and add extra contraceptives within the next 7 days.

1. Users should take the missed tablet as soon as they remember, even if it means taking two pills at the same time. Then continue taking the medication at regular times. Immediately after taking this box of pills, the next box of pills will be taken, that is, there is no stopping period between the two boxes of pills. The user is unlikely to have withdrawal bleeding before taking the second box of pills, but may experience drips or breakthrough bleeding during the dose.

2. Women can also be advised not to continue taking this cycle of medication. The woman should go through a 7-day withdrawal period, which includes the number of days of missed medication, before continuing to take the next cycle of medication. The possibility of pregnancy should be considered if the woman missed the medication and did not experience withdrawal bleeding during the first subsequent interval between normal withdrawals.

Advice for those with gastrointestinal disorders

If severe gastrointestinal disorders occur, absorption may be incomplete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after taking the drug, you can use the recommendations given in "Treatment of Missing Drugs". If a woman does not want to change her normal medication schedule, she must remove the medication from another box.
How to change or delay your menstrual period

To postpone menstruation, a woman can take one box of pills and then continue to take the next box of pills without an interval between withdrawals. Menstruation can be postponed to any time before the second box of medication is taken, if desired. Breakthrough bleeding or spotting may occur during extended medication. After the usual 7-day withdrawal period, you can resume taking this product regularly.

If she wants to change her current menstrual period and move to another day of the week, she can suggest that she shorten the interval between withdrawals to the time she wants. The shorter the discontinuation interval, the greater the risk of no withdrawal bleeding and breakthrough and spotting bleeding (as described in delayed menstruation) during the next box of medication.

Medication for special populations

Patients with impaired liver function

This product is contraindicated in women with severe liver disease: see [Contraindications] and [Pharmacokinetics].

Patients with impaired renal function

This product is contraindicated in women with severe renal insufficiency or acute renal failure. ^[2]

Drospirenone adverse reactions

Specific adverse reaction description

The list of adverse reactions with extremely low incidence or delayed symptoms considered to be related to the compound oral contraceptive group is as follows (see [Contraindications], [Cautions]):
Tumor

A slight increase in breast cancer diagnosis among OC users. Because breast cancer rarely occurs in women under the age of 40, the increase is small relative to the overall risk of breast cancer. The relationship with COC is unclear.

Liver tumors (benign and malignant)

Other situations

· Nodular erythema

· Women with hypertriglyceridemia (using COC increases the risk of pancreatitis)

· Hypertension

· The relationship between the occurrence or deterioration of the following conditions and the use of COC is uncertain:
Jaundice and / or pruritus associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremia; petit chorea; herpes pregnancy; hearing loss associated with otosclerosis.

· In women with hereditary angioedema, exogenous estrogen can induce or aggravate the symptoms of angioedema.

Liver dysfunction

Change glucose tolerance or affect peripheral insulin resistance

Crohn's disease and ulcerative colitis

Melasma

· Hypersensitivity (including symptoms such as rash, rubella) ^[2]

Drospirenone contraindications

Compound oral contraceptives (COCs) should not be used in any of the following situations. If any of the following conditions occur for the first time during the use of COC, the drug must be discontinued immediately.
· Presence of venous or arterial thrombosis / thromboembolism (eg, deep vein thrombosis, pulmonary embolism, myocardial infarction) or cerebrovascular accident, or a history of the foregoing Blood attack, angina)
· High risk of venous or arterial thrombosis (see [Precautions])
· History of migraine with focal neurological symptoms · Diabetes involving blood vessels · Pancreatitis or history of severe hypertriglyceridemia · Severe liver disease as long as liver function indicators do not return to normal · Severe renal insufficiency Or acute renal failure · Adrenal insufficiency · Presence or history of liver tumors (benign or malignant) · Known or suspected malignancies affected by sex steroid hormones (eg reproductive organs or breast)
· Unexplained vaginal bleeding · Known or suspected pregnancy · Allergic to the active ingredient of this product or any of its excipients ^[2]

Drospirenone considerations

caveat

If any of the following conditions / risk factors are present, each woman should weigh the benefits of COC application with the possible risks and discuss it with her before she decides to start taking the medication. If any of the following conditions or risk factors worsen, worsen, or appear for the first time, you should contact your doctor. The doctor should decide whether COC should be stopped.

Diseases of the circulatory system

Epidemiological studies have shown that the use of COCs is associated with an increased risk of arterial and venous thrombosis and thromboembolic diseases such as myocardial infarction, deep vein thrombosis, pulmonary embolism, and cerebrovascular events. These events are rare.

The risk of venous thromboembolism (VTE) is highest during the first year of use. The risk increases when COC is started or when the same or a different COC is used again (withdrawal interval lasting 4 weeks or more). Data from a large prospective 3-group cohort study showed that the increase in risk occurred mainly in the first 3 months.

In summary, women who use COCs with low-dose estrogen (<50 µg ethinylestradiol) have a risk of venous thromboembolism that is two to three times higher than those who do not use COCs and are not pregnant, but the risks are lower than during pregnancy and delivery.
VTE can be life threatening or cause death (1% -2%).

Epidemiological studies have shown that VTE risk with drospirenone-containing OCs is higher than that with levonorgestrel-containing OCs (that is, second-generation oral contraceptives) Oral contraceptives) are equally risky.

Venous thromboembolism (VTE) is manifested as deep vein thrombosis and / or pulmonary embolism, which can occur during all COCs use.

It is extremely rare to report thrombosis of other blood vessels in COC users, such as the liver, mesentery, kidney, brain or retinal veins and arteries. Whether these incidents are related to the use of COCs has not been agreed.

Symptoms of deep vein thrombosis (DVT) include swelling of the unilateral leg or swelling along the veins of the leg; pain or tenderness in the leg when standing or walking; increased warmth in the leg; redness or discoloration of the leg skin.

Symptoms of pulmonary embolism (PE) may include sudden, unexplained shortness of breath or shortness of breath; sudden cough may be accompanied by bleeding; sharp chest pain may be accompanied by increased deep breathing; anxiety; severe dizziness or dizziness; rapid or irregular heartbeat. Some of these symptoms (eg, shortness of breath, coughing) are not endemic and may be thought to originate from other common or non-serious events (eg, respiratory infections).

Arterial thromboembolic events may include cerebrovascular accidents, vascular occlusion, or myocardial infarction (MI). Cerebrovascular accident symptoms may include: sudden numbness or weakness in the face, arms, or legs, especially unilateral body; sudden blurred consciousness, speech or understanding impairment; sudden unilateral or bilateral vision impairment; sudden Walking disorders, dizziness, loss of balance or coordination; sudden, severe, or unexplained long-term headaches; loss of consciousness or syncope with or without seizures. Other signs of vascular occlusion may include sudden pain, swelling of the extremities and pale blue discoloration; acute abdominal pain.

Symptoms of myocardial infarction (MI) include: chest, arm or substernal pain, discomfort, pressure, heaviness, squeezing or fullness; discomfort radiates to the back, jaw, throat, arms, stomach Sensation of swelling, nausea, vomiting, or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeat.
Arterial thromboembolic events can be life threatening or cause death.

In women with multiple risk factors or more severe individual risk factors, the possibility of increased synergistic risk of thrombosis must be considered. This increased risk may be greater than the cumulative risk of factors alone. If the risk-benefit assessment is negative, a COC prescription must not be prescribed (see [Contraindications]).

The risk of venous or arterial thrombosis / thromboembolic events or cerebrovascular accidents can increase with:

-Increase in age;

-Obesity (body mass index exceeding 30 kg / m2);

-Positive family history (ie siblings or parents had venous or arterial thromboembolism at an earlier age). If genetic susceptibility is suspected, you should consult a specialist before deciding to use any COC;

-Prolonged braking, major surgery, any leg surgery, or major trauma. In these cases, it is recommended to stop taking COC (at least 4 weeks before elective surgery), and then to take the medicine after two weeks of full recovery.

-Smoking (the greater the risk of smoking and increasing age, the higher the risk, especially for women over 35);

-Dyslipoproteinemia;

-Hypertension;

- Migraine;

-Heart valve disease;

-Atrial fibrillation;

There is no consensus on the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.
The increased risk of thromboembolism during puerperium should be considered (see [Medication for pregnant and lactating women]).

Other clinical conditions associated with adverse events in the circulatory system include diabetes, systemic lupus erythematosus, hemolytic uremic syndrome, chronic inflammatory bowel disease (Clone's disease or ulcerative colitis), and sickle cell disease.

During the use of COC, the frequency or severity of migraine attacks may increase (possibly a precursor to cerebrovascular accidents), and the occurrence of this condition may require immediate withdrawal of COC.

Suggests biochemical factors that may be susceptible to hereditary or acquired venous or arterial thrombosis, including active protein C (APC) resistance, homocysteineemia, lack of antithrombin III, protein C deficiency, and protein S Deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulants).

When weighing the pros and cons, physicians should consider that adequate treatment of a condition may reduce the risk of associated thrombosis, and that the risk of thrombosis associated with pregnancy is higher than the use of low-dose COC (ethinylestradiol <0.05mg) Related dangers.

Tumor

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have shown that long-term use of COCs can further increase this risk. But the extent to which this result should be attributed to confusion, such as cervical screening and sexual behavior, including the use of barrier contraception, has been controversial.

A meta-analysis of 54 epidemiological studies showed a slightly increased relative risk of breast cancer diagnosis in women who are currently using COCs (RR = 1.24). Within 10 years after stopping COC use, the increased risk gradually disappeared. Because breast cancer rarely occurs in women under 40 years of age, there is a small increase in the number of diagnoses of breast cancer among those currently using and recently using COC relative to the overall risk of breast cancer. These studies did not provide causal evidence. The increased risk observed may be due to earlier diagnosis of breast cancer in COC users, the biological effects of COCs, or both. Compared to those who have never used COC, breast cancer in those who have used COC is often clinically staged earlier.
COCs users have reported rare benign liver tumors and even more rare malignant liver tumors. In individual cases, these tumors have caused life-threatening intra-abdominal bleeding. When women taking COCs experience severe epigastric pain, hepatomegaly, or signs of intra-abdominal bleeding, the differential diagnosis should consider liver tumors.

Malignant tumors can be life threatening or cause death.

· Other conditions In patients with renal insufficiency, potassium excretion is limited. In a clinical study, taking drospirenone in patients with mild or moderate renal impairment showed no effect on serum potassium concentrations. Only in patients with impaired renal function whose serum potassium is within the upper limit of the normal range before treatment and who are using potassium-sparing diuretics can theoretically be at risk for hyperkalemia.

In women with hypertriglyceridemia or a family history, taking COCs may increase the risk of pancreatitis.
Although mild increases in blood pressure have been reported in many women taking COCs, clinically significant increases are rare. Elevated ethinyl estradiol-induced blood pressure increases in women with normal blood pressure may be counteracted by the anti-mineral corticosteroid effect of drospirenone. However, if persistent clinically significant hypertension occurs during the use of a COC, physicians should carefully consider discontinuing COC and treating hypertension. If blood pressure returns to normal after antihypertensive treatment, the doctor can resume taking COC when appropriate.

The following conditions have been reported to occur or worsen during pregnancy and when taking COC, but the evidence related to the use of COC is uncertain: jaundice and / or itching associated with cholestasis; gallstone formation; porphyria; systemic lupus erythematosus Hemolytic uremic syndrome; minor chorea; herpes of pregnancy; hearing loss associated with otosclerosis.

In women with hereditary angioedema, exogenous estrogen can induce or exacerbate the symptoms of angioedema.
Acute or chronic liver dysfunction requires COC to be stopped until liver function indicators return to normal. COCs should be discontinued when cholestatic jaundice first occurs during pregnancy or during previous steroid hormone use.

Although COCs may affect peripheral insulin resistance and glucose tolerance, there is no evidence that diabetic patients taking low doses of COCs (ethinylestradiol <0.05mg) need to change their treatment regimen. However, you should carefully observe the situation of women with diabetes taking COCs.
Crohn's disease and ulcerative colitis are related to the use of COC.

Chloasma occurs occasionally, especially in women with a history of chloasma during pregnancy. Women with chloasma tend to avoid exposure to sunlight or ultraviolet radiation while taking COCs.

Each tablet contains 46 mg of lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption who are unable to consume lactose should be considered.
Medical examination / consultation

Before taking COC for the first time or taking it again, you should collect a complete medical history and conduct a comprehensive physical examination in accordance with the requirements of contraindications (see [Contraindications]) and warnings (see [Precautions]), and regularly review them. Regular medical evaluation is also important because contraindications (eg, transient ischemic attacks, etc.) or risk factors (eg, family history of venous or arterial thrombosis) may appear for the first time during COC administration. The frequency and nature of these medical assessments should be based on established clinical norms and adjusted for individual women, but generally should focus on blood pressure, breast, abdominal and pelvic organs, including cervical cytology.

Women should be told that oral contraceptives do not prevent HIV infection (AIDS) and other sexually transmitted diseases.
Reduced efficacy

If missed doses (see [Dosage and Administration]), gastrointestinal disorders (see [Dosage and Administration]), or other drugs are taken at the same time, the efficacy of COC may be reduced (see [Drug interactions]).
Impact cycle control

Irregular bleeding (drip or breakthrough bleeding) may occur in all COCs users, especially during the first few months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation period of about 3 cycles.
If irregular bleeding persists or occurs after a regular cycle, non-hormonal causes should be considered and appropriate diagnostic measures should be taken to exclude malignancy or pregnancy. These measures may include curettage.

Some women may not experience withdrawal bleeding during the withdrawal period. If you take COC as described in [Usage and Dosage], women are less likely to get pregnant. However, if the medication is not taken in accordance with these methods before the first time no relapsed bleeding occurs, or if no relapsed bleeding occurs twice, pregnancy must be ruled out before continuing to take COC.
· Laboratory inspection

The use of steroidal contraceptives may affect the results of certain laboratory tests, including biochemical indicators of liver, thyroid, adrenal, and renal function, plasma (carrier) protein levels, such as corticosteroid-binding globulin and lipid / lipoprotein ratio, and carbohydrate Indicators of compound metabolism, as well as indicators of coagulation and fibrinolysis. Changes usually remain within the scope of normal laboratory inspections. Drospirenone causes an increase in plasma renin activity, and its mild antimineral cortex activity induces an increase in plasma aldosterone levels.
No studies have been conducted on the effects on driving and machine operation capabilities. The effects of using COCs on driving and machine operating capabilities were not observed.
Store all medicines in a safe place and keep out of reach of children. ^[2]

Drospirenone for pregnant and lactating women

Drospirenone pregnant women

This product is contraindicated during pregnancy. If pregnancy occurs while taking this product, you must stop taking the medicine. However, a large number of epidemiological studies have shown that the incidence of birth defects in babies born to women who took COCs before pregnancy did not increase, and that the teratogenic effects of women who did not take COCs during early pregnancy did not increase. One case was born with esophageal atresia. The causal relationship between this event and this product is unclear.
The information on taking this product during pregnancy is very limited, and it cannot be concluded that it has adverse effects on the health of pregnancy, fetus, or newborn. There is no relevant epidemiological data so far.

Drospirenone lactation

Breastfeeding may be affected by COCs because they reduce milk secretion and alter the composition of milk. Therefore, it is generally not recommended to use COCs until the woman is weaned completely. A small amount of contraceptive steroid hormones and / or their metabolites may be secreted from milk. ^[2]

Drospirenone for children

This product can only be used after menarche. No data indicate that dose adjustments are needed. ^[2]

Drospirenone drug interactions

The effects of drospirenone and other drugs on this product

Microsomal enzyme inducers can increase clearance of sex steroid hormones, leading to breakthrough bleeding and / or contraceptive failure. In addition to taking COC, women using these drugs should temporarily add barrier contraception or choose other contraceptives. Barrier contraceptives should be added during the combined use of microenzyme-inducing drugs and within 28 days after discontinuation.

If the combined use period of the barrier contraceptive method exceeds the last tablet in the COC package, the next box of drugs should be started directly without the usual withdrawal period.

Substances that increase COC clearance (enzyme inducers that reduce the effectiveness of COC), such as: phenytoin, barbiturates, ecdysone, carbamazepine, rifampicin, possible drugs are oxcarbazepine, topiramate, non Urethane, griseofulvin and products containing St. John's wort).
Substances that have an effect on COC clearance, such as:

When co-administered with COC, many HIV / HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors may increase or decrease the plasma concentration of estrogen or progesterone. In some cases, these changes may be clinically relevant.

Substances that reduce COC clearance (enzyme inhibitors)

Strong and intermediate CYP3A4 inhibitors, such as azole antifungals (eg, itraconazole, voriconazole, fluconazole), verapamil, macrolides (eg, clarithromycin, erythromycin ), Diltiazem and grapefruit juice may increase the concentration of estrogen or progesterone in the plasma, or increase the concentration of both components at the same time.

Etocoroxib at a dose of 60 to 120 mg / day, when administered concurrently with a compound hormone contraceptive containing 0.035 mg of ethinyl estradiol, increased the plasma concentration of ethinyl estradiol by 1.4 to 1.6 times, respectively.
Effects of COCs on other drugs

COCs may affect the metabolism of certain other drugs, so their plasma and tissue concentrations may increase (eg, cyclosporine) or decrease (eg, lamotrigine).

Based on in vivo interactions of female volunteers using omeprazole, simvastatin, or midazolam as marker substrates, it can be concluded that at a dose of 3 mg, drospirenone is unlikely to interact with other cytochromes P450-mediated drug metabolism produces clinically relevant interactions.
In clinical studies, the administration of ethinylestradiol-containing hormonal contraceptives did not cause any or only a slight increase in the plasma concentration of the CYP3A4 substrate (eg, midazolam), while the plasma concentration of the CYP1A2 substrate may occur Slight (such as theophylline) or moderate (such as melatonin and tizanidine) elevations.

Drospirenone other interactions

When used with other drugs that can increase serum potassium concentration, the blood potassium level of women taking this product may theoretically increase. This class of drugs includes angiotensin II receptor antagonists, potassium-sparing diuretics, and aldosterone antagonists. However, in studies evaluating the interaction of drospirenone (combined with ethinylestradiol) with ACE antagonists or indomethacin, no clinically significant or statistically significant changes in serum potassium concentrations were observed.
Note: You should know the prescription information that accompanies the medication to discover possible interactions. ^[2]