Approval date: xxxxx xx xx
Drospirenone Ethinylestradiol Tablets (II) Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
SMOKING AND SERIOUS CARDIOVASCULAR EVENTS: Smoking increases the risk of serious cardiovascular events associated with compounded oral contraceptives (COC). This risk increases with age (especially in women over 35 years of age) and with the number of cigarettes smoked. Therefore, COCs should not be used in women over 35 years of age who smoke (see [Contraindications]).
Drug Name
Generic Name: Drospirenone Ethinyl Estradiol Tablets (II)
English Name: Drospirenone and Ethinylestradiol Tablets (II)
Hanyu Pinyin: Quluotong Quecichun Pian (Ⅱ)
Ingredients
24 hormone-containing light pink film-coated tablets: each tablet contains 0.02 mg of ethinylestradiol (in the form of b-cyclodextrin inclusions) and 3 mg of drospirenone.
4 hormone-free white film-coated tablets.
[Properties].
The hormone-containing tablets are light pink film-coated tablets, which appear white after removing the coating.
The hormone-free tablets are white film-coated tablets with a square hexagon on one side and the word “DP” engraved in the middle.
Indications
Oral contraception for women.
Moderate acne vulgaris for primiparous females ≥ 14 years of age with no known contraindications to oral contraceptives. This product should only be used to treat acne if the patient wishes to use oral contraceptives as a contraceptive measure.
【Specifications】.
Each tablet contains 3mg of Drospirenone and 0.02mg of Ethinylestradiol (β-cyclodextrin inclusion).
Dosage]
Route of administration
Oral
Dosing regimen
How to take this product
Take one tablet by mouth at the same time every day. If you miss a dose or take it incorrectly, the failure rate will increase.
To achieve maximum contraceptive effectiveness, it is important to take this product correctly as directed. If you miss a dose, you should take an additional dose as soon as you remember.
How to start taking the product
Tell the patient to start taking this product on the 1st day of the menstrual cycle (start of Day 1) or the 1st Sunday after the start of the menstrual cycle (start of Sunday).
Start on Day 1
For the first cycle of this product, inform the patient to take one light pink tablet daily, starting on day 1 of the menstrual cycle (day 1 refers to the first day of menstruation). One light pink tablet should be taken daily for 24 days, followed by one white inactive tablet daily on days 25 to 28. It must be taken in the order indicated on the package, with a small amount of liquid at approximately the same time each day, preferably at dinner or at bedtime. It is not necessary to consider whether or not to eat when taking this product. If the first dose of this product is taken later than day 1 of the menstrual cycle, it should be considered an effective method of contraception only after the first 7 days of continuous dosing. Patients should be advised to use non-hormonal contraception during the first 7 days as a backup method. The possibility of ovulation and conception prior to administration of the drug should be considered.
Sunday Start
For the first cycle of use, advise the patient to take one light pink tablet daily, beginning on the 1st Sunday after the start of the menstrual cycle. One light pink tablet should be taken daily for 24 days, followed by one white inactive tablet daily on days 25 to 28. It must be taken in the order indicated on the package, with a small amount of liquid at approximately the same time each day, preferably after dinner or before bedtime. Administration of this product does not require consideration of food intake. This product should only be considered an effective method of contraception after the first 7 days of continuous administration. Patients should be advised to use non-hormonal contraception during the first 7 days as a backup method. The possibility of ovulation and conception prior to administration of the drug should be considered.
Patients should start the next box of this product and subsequent medications on the same day of the week as the first dose and follow the same regimen. The light pink tablet should be started on the 2nd day after the last white tablet is taken by mouth, regardless of whether the menstrual cycle has started or is still in progress. At any time when a subsequent cycle of treatment with this product begins later than day 2 after the last 1 white tablet is administered, the patient should use other contraception until 7 consecutive days of light pink tablets have been taken.
Switching from a different pill to this product
When switching from another contraceptive pill, start this product on the day that the new box of previous oral contraceptives is expected to start.
Switching from a method other than the pill
If switching from a transdermal patch or vaginal ring, start this product at the time when the transdermal patch or ring is next expected to be used. If switching from an injectable to this product, this product should be started at the time of the next anticipated injection. If switching from an intrauterine device or implant, this product should be started on the day of removal.
Withdrawal bleeding will usually occur within 3 days of taking the last light pink tablet. If spotting or breakthrough bleeding occurs while taking this product, advise the patient to continue taking the product according to the regimen described above. Patients should be advised that such bleeding is usually transient and not significant; however, patients should be advised to consult their physician if the bleeding is prolonged.
Although the likelihood of pregnancy is low when this product is taken according to the instructions, the possibility of pregnancy should be considered if withdrawal bleeding does not occur. If the patient does not comply with the prescribed dosing regimen (misses 1 or more active tablets or starts later than he/she should), consider the possibility of pregnancy and take appropriate diagnostic measures when menstruation does not occur for the first time. If the patient complies with the prescribed regimen but does not experience two consecutive menstrual periods, pregnancy should be ruled out. If pregnancy is confirmed, discontinue administration of this product.
The risk of pregnancy increases as the number of missed doses of active light pink tablets increases. If breakthrough bleeding occurs after a missed dose, it is usually transient and does not have significant consequences. If a patient misses one or more white tablets, she can still prevent pregnancy as long as she starts a new cycle of light pink tablet administration at the appropriate time.
For postpartum women who are not breastfeeding or who have miscarried after the third trimester, do not start this product earlier than 4 weeks after delivery, as this increases the risk of thromboembolism. If a patient has started this product after delivery and menstruation has not yet started, assess for possible pregnancy and advise the patient to use alternative contraception until 7 consecutive days of this product have been taken.
Management of missed pills
If 1 light pink tablet is missed.
1. Take the missed pill as soon as possible when you remember. The next tablet should be taken at the regular time. This means that two tablets may be taken during the day.
2. If sex occurs, no additional contraception is needed.
If you miss 2 light pink pills in a row during week 1 or week 2.
1. take 2 pills on the day you think about it and take 2 more pills the next day.
2. then take 1 pill each day until you have taken all the remaining pills in the package. 3.
3. If you have sex within 7 days of restarting the pill, you may become pregnant. Additional contraception (such as condoms and spermicidal pills) must be used as a backup for those 7 days.
If you miss 2 consecutive light pink pills in week 3 or 4.
1. If you are a Day 1 starter.
Throw away the remaining pills from that package and start a new package that day.
If you started on Sunday.
Continue taking 1 pill per day until Sunday. On Sunday, throw away the remaining pills in the package and start the new package of pills on that day. 2.
2. If you have sexual intercourse within 7 days of restarting the pill, you may become pregnant. Additional contraception (such as condoms and spermicidal pills) must be used as a backup for those 7 days.
3. You may not have a period this month, but this is an expected result. However, if you have not had a period for 2 consecutive months, contact your doctor, you may be pregnant.
If in any week you miss 3 or more light pink tablets in a row.
1. If you are a first day starter.
Throw away the remaining tablets from that tablet package and start a new package on the same day.
If you started on Sunday.
Continue to take 1 tablet per day until Sunday. On Sunday, throw away the remaining tablets in the package and start taking the new package of tablets that day. 2.
2. If you have sexual intercourse within 7 days of restarting the pill, you may become pregnant. Additional contraception (such as condoms and spermicidal pills) must be used as a backup for those 7 days.
3. If you do not have your period, contact your doctor, you may be pregnant.
If, during week 4, you miss any of the 4 white tablets.
Throw away the missed tablet.
Continue taking 1 tablet per day until you have taken all the remaining tablets in the package.
No additional birth control is needed.
Finally, if you are still unsure what to do if you miss a dose.
Use additional birth control (such as condoms and spermicidal pills) any time you have sex.
Contact your doctor and continue to take 1 light pink pill daily until your doctor directs other treatment
Advice for people with gastrointestinal disorders
In case of severe gastrointestinal disturbances, absorption may be incomplete and additional contraceptive measures should be taken.
If vomiting occurs within 3-4 hours after taking the active drug, it can be treated as a missed dose. If a woman does not want to change her normal dosing schedule, she will need to take a refill of the medication from another box.
How to change or delay your menstrual cycle
To delay a cycle, a woman should continue to take another box of this product without the hormone-free white film-coated tablets. The cycle may be delayed as long as the user wishes until the second box of light pink film-coated tablets has been taken. During the delay, women may experience breakthrough or spotting bleeding. Resume normal dosing of this product after the hormone-free white tablet phase has been taken.
A woman who wants to move her current menstrual period to another day of the week may be advised to shorten the next dosing period of the hormone-free white tablet if she wishes. The shorter the interval, the higher the risk of breakthrough and spotting bleeding, rather than withdrawal bleeding, when taking the second box of medication (as is the case when delaying a cycle).
Additional information on special populations
Patients with hepatic impairment
This product is contraindicated in patients with hepatic disease [see [Contraindications] and [Precautions]]. In women with moderate hepatic impairment, the mean exposure to drospirenone is approximately three times greater than that in women with normal hepatic function. This product has not been studied in women with severe hepatic impairment.
Patients with renal impairment
This product is contraindicated in patients with renal impairment [see [Contraindications] and [Precautions]].
In subjects with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min), serum drospirenone levels were similar to those in subjects with normal renal function (CLcr, >80 mL/min). In subjects with moderate renal impairment (CLcr, 30-50 mL/min), mean serum drospirenone levels were 37% higher than in the group of subjects with normal renal function. In addition, there is a potential for hyperkalemia in subjects with renal impairment whose serum potassium is at the upper limit of the reference range, and in women with concomitant potassium-preserving diuretics [see [Pharmacokinetics]].
[Adverse Reactions].
The following serious adverse reactions occurring with the use of COCs are discussed at [Precautions] in the instructions.
Cardiovascular events and smoking
Vascular events
Liver disease
Common adverse reactions reported by COC users.
Irregular uterine bleeding
nausea
Breast tenderness
Headache
Foreign studies.
International Clinical Trial Experience
Because clinical trials are conducted under different conditions, the rate of adverse reactions observed in clinical trials of one drug may not be directly comparable to the incidence in clinical trials of other drugs and may not reflect the incidence observed in clinical practice.
Contraceptive and Acne Clinical Trials
The data presented reflect experience with the use of this product derived from well-controlled contraceptive trials (N=1,056) and moderately common acne treatment trials (N=536).
For the contraceptive indication, a Phase 3, multicenter, multinational, open trial has been conducted to evaluate safety and efficacy for up to 1 year in 1,027 women aged 17-36 years who had taken the product at least once. The second Phase 3 trial was a single-center, open, active-controlled trial evaluating the effects of this product on carbohydrate metabolism, lipids, and coagulation over seven 28-day cycles in 29 women aged 18-35 years. For the acne indication, 2 multicenter, double-blind, randomized, placebo-controlled trials were conducted to evaluate the safety and efficacy of this product over up to 6 cycles in 536 women aged 14-45 years with moderate acne vulgaris who received at least one dose of this product in the trial.
There was overlap in adverse reactions between the 2 indications, and incidence rates were reported based on the pooled data set. The most common adverse reactions (≥ 2% of users) included.
Headache/migraine (6.7%), irregular menstruation (including vaginal bleeding [mainly spotting] and irregular uterine bleeding (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (mood swings, depression, depressive mood and emotional instability) (2.2%).
Adverse reactions leading to trial discontinuation (≥1%)
Contraceptive clinical trials
Of the 1,056 women, 6.6% discontinued the trial due to adverse reactions; the most common adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1%).
Acne Clinical Trials
Of 536 women, 5.4% discontinued the trial due to adverse reactions; the most common adverse reaction leading to discontinuation was irregular menstruation (including excessive menstruation, irregular uterine bleeding and vaginal bleeding) (2.2%).
Serious adverse reactions.
Contraceptive clinical trials: migraine and atypical cervical hyperplasia
Acne clinical trial: no serious adverse reactions reported in clinical trials
2. International post-marketing experience
The following adverse reactions have been identified in the post-approval use of this product. Because these adverse reactions are spontaneous reports from an unspecified number of people, it is often not possible to credibly estimate the incidence of adverse reactions or to determine a causal relationship with drug use.
Adverse reactions were grouped according to systemic organ classes and ranked by incidence.
Vascular conditions: venous and arterial thromboembolic events (including pulmonary embolism, deep vein thrombosis, cerebral thrombosis, retinal vascular thrombosis, myocardial infarction, and stroke), hypertension (including hypertensive crisis)
Hepatobiliary conditions: gallbladder disease, liver dysfunction, liver tumors
Immune system disorders: hypersensitivity reactions (including allergic reactions)
Metabolic and nutritional conditions: hyperkalemia, hypertriglyceridemia, altered glucose tolerance or affecting peripheral insulin resistance (including diabetes mellitus)
Skin and subcutaneous tissue conditions: chloasma, angioedema, erythema nodosum, erythema multiforme
Gastrointestinal conditions: inflammatory bowel disease
Musculoskeletal and connective tissue conditions: systemic lupus erythematosus
National studies.
Contraceptive clinical trials
The most common adverse events associated with this product were nausea (3.4%), elevated blood triglycerides (1.3%), breast tenderness, dizziness, and vaginal bleeding (1.2% each). There were no deaths in the study, and none of the serious adverse events were related to the study drug.
Acne Clinical Trials
The most common adverse events associated with this product were menorrhagia (8.0%), irregular uterine bleeding (8.0%), abdominal pain (2.3%), and breast pain (1.1%). No deaths or serious adverse events were observed.
[Contraindication].
This product should not be used in women with known
– Renal impairment
– Hyperaldosteronism
– Those at increased risk of arterial or venous thromboembolic disease. This includes women who are known to
– Smoke and are older than 35 years of age
– Current or past deep vein thrombosis or pulmonary embolism
– Cerebrovascular disease
– Coronary heart disease
– Thrombotic heart valve disease or thrombotic heart rhythm disease (e.g., subacute bacterial endocarditis with valvular disease or atrial fibrillation)
– Inherited or acquired hypercoagulable disease
– Uncontrolled hypertension
– Diabetes mellitus with vascular disease
– Headache with focal neurological symptoms; or migraine with or without aura, and over 35 years of age
– Undiagnosed abnormal uterine bleeding
– Current or previous breast cancer or other estrogen- or progestin-sensitive cancer
– Benign or malignant tumors of the liver or liver disease
Pregnancy, as there is no reason to use COCs in pregnancy Compounding
Hypersensitivity to the active ingredient of the product or any of its excipients
[Precautions].
1. Thromboembolic disease and other vascular problems
Stop taking this product if an arterial or venous thrombosis (VTE) event has occurred.
The use of COCs may increase the risk of venous thromboembolism. However, the risk of venous thromboembolism due to pregnancy is the same or higher than the risk due to the use of COCs. The risk of venous thromboembolism in women using COCs is estimated to be 3 to 9 cases/10,000 women-years. the risk of VTE is highest in the first year of use. Based on interim data from a large, prospective safety cohort trial of different COCs, the elevated risk was greatest in the first 6 months of COC use compared with non-COC users. Interim data from this safety trial suggest that the risk of VTE is greatest after initial initiation of a COC or restart (≥4-week untreated interval) of the same or a different COC.
Use of COCs also elevates the risk of arterial thrombosis, such as stroke and myocardial infarction, particularly in women with other risk factors for these events.
The risk of thromboembolic disease due to oral contraceptives fades after discontinuation of COC use.
If feasible, discontinue this product at least 4 weeks before and 2 weeks after major surgery or other procedures known to have an elevated risk of thromboembolism.
In women who are not breastfeeding, do not take this product earlier than 4 weeks after delivery. The risk of postpartum thromboembolic disease decreases after the 3rd week postpartum and the risk of ovulation increases after the 3rd week postpartum.
COCs have been found to elevate the relative and absolute risk of cerebrovascular events (thrombotic and hemorrhagic stroke), although, overall, the risk is highest in hypertensive women who are older (> 35 years) and who smoke. COCs can also increase the risk of stroke in women with other underlying risk factors.
Oral contraceptives must be used with caution in women with risk factors for cardiovascular disease.
Discontinue this product if there is unexplained vision loss, ocular proptosis, diplopia, optic nerve papillary edema, or retinal vasculopathy. And evaluate immediately for retinal vein thrombosis. [See [Adverse Reactions]].
Epidemiologic studies on drospirenone-containing COCs
The relative risk of thromboembolism in women using a drospirenone-containing COC (Eusemin® with 0.03 mg ethinyl estradiol and 3 mg drospirenone) was studied in several trials and compared to women using other progestin-containing COCs. At the time of approval of Eusemide®, 2 prospective cohort trials were initiated to assess the risk of venous and arterial thromboembolism and death.1,2 The first study (EURAS) demonstrated that the risk of thromboembolism (particularly venous thromboembolism) and death among those on Eusemide® was similar to that of other oral contraceptives, including those containing levonorgestrel (also known as 2nd generation COCs). A second prospective cohort study (Ingenix) also showed that the risk of thromboembolism among users of Eusemide® was similar to that of users of other COCs, including those containing levonorgestrel. in the second study, the COC control group was selected based on characteristics similar to those of women taking Eusemide®.
Two other epidemiological studies, a case-control study (van Hylckama Vlieg et al.3) and a prospective cohort study (Lidegaard et al.4), showed that the risk of venous thromboembolism was higher among users of Eusemin® than among users of levonorgestrel-containing COCs, but lower than among users of deoxyprogesterone-/pregnandienone-containing COCs (so-called 3rd generation COCs) users. However, in case-control studies, the small sample size (1.2% of the total) in the Eusemide® group made the outgoing risk assessment unreliable. In retrospective cohort studies, the relative risk was higher for users of Eusemide® than for users of other COC products in women who had used contraceptives for less than 1 year. However, these 1-year estimates may not be reliable because women with different levels of risk were included in this analysis. Among women who used contraceptives for 1 to 4 years, the relative risk for Eusebio® users was similar to that of other COC users.
2. Hyperkalemia
This product contains 3 mg of the progestin drospirenone, which has anti-salt corticosteroid activity and may have the potential to cause hyperkalemia in high-risk patients, an effect similar to that of 25 mg of spironolactone. It should not be used in patients with conditions that promote hyperkalemia (i.e., renal impairment, hepatic dysfunction, and hyperalgesia). In women receiving daily long-term therapy with potassium-raising drugs for chronic disease, serum potassium levels should be monitored during the first treatment cycle. Drugs that may elevate potassium include ACE inhibitors, angiotensin II receptor antagonists, potassium-protective diuretics, potassium supplements, heparin, aldosterone antagonists, and NSAIDS.
3. Breast and genital cancers
This product should not be used in women who currently have or have had breast cancer because breast cancer is a hormone-sensitive tumor.
There is substantial evidence that COCs do not elevate the incidence of breast cancer. Although some past studies have suggested that COCs may increase the incidence of breast cancer, several recent studies have not confirmed these findings.
Some trials have shown that COCs are associated with an increased risk of cervical cancer or intraepithelial neoplasia. However, the extent to which these findings are associated with differences in sexual behavior and other factors remains controversial.
4. Liver disease
The product should be discontinued if jaundice occurs. Steroid hormones are metabolized very slowly in patients with hepatic impairment. If there is acute or chronic hepatic dysfunction, COC may need to be discontinued until after liver function markers have returned to normal and an association with COC has been ruled out.
COC use can be associated with hepatic adenomas. The estimate of attributable risk is 3.3 cases/100,000 COC users. Rupture of a hepatic adenoma can lead to death due to intra-abdominal hemorrhage.
Studies have shown an increased risk of hepatocellular carcinoma in long-term (>8 years) COC users. However, among COC users, the attributable risk of hepatocellular carcinoma is less than 1 case per 1 million users.
Oral contraceptive-associated cholestasis may occur in women with a history of pregnancy-associated cholestasis. Recurrence of cholestasis may occur in women with a history of COC-associated cholestasis with subsequent use of COC.
5. Hypertension
In women with adequately controlled hypertension, monitor blood pressure and discontinue the product if it is significantly elevated. COCs should not be used in women with inadequately controlled blood pressure or hypertension with vascular disease.
Elevated blood pressure has been reported in women taking COCs, and elevated blood pressure is more likely to occur in women who are older and on long-term use, with the incidence of hypertension increasing with progesterone concentrations.
6. Gallbladder disease
Studies have shown that there is a small increase in the relative risk of gallbladder disease in COC users.
7. Carbohydrate and lipid metabolism effects
COCs may dose-dependently reduce glucose tolerance.
In women with uncontrolled dyslipidemia, other contraceptive measures should be considered. Adverse changes in blood lipids occur in a small number of women on COCs.
In women with hypertriglyceridemia or a family history of it, the risk of pancreatitis may be elevated with COCs.
8. Headache
If recurrent, persistent or severe headaches occur in women taking this product, the cause should be evaluated and discontinued if needed.
In COC use, COCs may be discontinued immediately because of increased frequency or severity of migraine (which may be a precursor to cardiovascular events).
9. Irregular bleeding
Unanticipated (breakthrough or intermenstrual) bleeding and spotting may occur in patients taking COCs, especially in the first 3 months of use. If bleeding persists or occurs after a previous regular cycle, look for a cause such as pregnancy or malignancy. If disease and pregnancy are ruled out, irregular bleeding may subside with prolonged periods or after switching to a different COC.
In 2 foreign clinical trials on this product for contraception, unintended bleeding occurred in 8% to 25% of women per 28-day cycle, based on patient diaries. Of 1,056 subjects, a total of 12 subjects (1.1%) discontinued the trial due to menstrual disturbances, including intermenstrual bleeding, excessive menstruation, and uterine bleeding.
Women using this product may not experience withdrawal bleeding, even if they are not pregnant. According to the diaries of subjects in contraceptive trials of up to 13 cycles, 6% to 10% of women experience menstrual cycles without withdrawal bleeding. Some women may experience amenorrhea or light menstrual flow after taking the pill, especially if these conditions were previously present.
If withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient does not follow the dosing regimen (misses ≥1 active tablet or starts dosing 1 day later than planned), consider the possibility of pregnancy when the first menstrual period does not occur and use appropriate diagnostic measures. If the patient follows the dosing regimen and does not have 2 consecutive menstrual cycles, pregnancy should be ruled out.
10. Use of COC before pregnancy or in early pregnancy
Numerous epidemiological studies have shown no elevated risk of birth defects among women who used oral contraceptives before pregnancy. Studies have found no teratogenic effects in cases of accidental COC use in early pregnancy, particularly the cardiac anomalies and short limb defects of concern.
Oral contraceptives should not be used for withdrawal bleeding as a pregnancy test [see [Medications for Pregnant and Lactating Women]].
11. Depression
Women with a history of depression should be closely monitored and the product should be discontinued if depression recurs and reaches a severe level.
12. Effects on laboratory findings
The use of COCs may alter the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women receiving thyroxine replacement therapy may need to increase the dose of thyroxine because of increased serum concentrations of thyroid-binding globulin during the use of COCs. Drospirenone may elevate plasma renin activity and plasma aldosterone activity due to its mild anti-salt corticosteroid activity.
13. Monitoring
Women taking COCs should have their blood pressure checked annually at a health service and any other applicable tests.
14. Other conditions
In women with hereditary angioedema, exogenous estrogen may induce or exacerbate angioedema symptoms. Occasional melasma may occur, especially in women with a history of melasma in pregnancy. Women with a propensity for melasma should avoid exposure to sunlight or ultraviolet radiation while taking COCs.
For Pregnant and Lactating Women]
Pregnancy
There is little or no elevated risk of birth defects in women who have accidentally taken COCs in early pregnancy. Epidemiologic studies and meta-analyses have found no elevated risk of genital or non-genital birth defects (including cardiac anomalies and short limb defects) following exposure to low doses of COCs prior to conception or early in pregnancy.
Withdrawal bleeding induced by COCs administration should not be used as a pregnancy test. COCs should not be used in pregnancy for the treatment of preterm or habitual abortions.
COCs should be administered to postpartum women who are not breastfeeding no earlier than 4 weeks postpartum.
Breastfeeding
If possible, it is recommended that breastfeeding women use other contraception before weaning. COCs containing estrogen may reduce lactation in breastfeeding women. This is less likely to occur once a pattern of breastfeeding has been established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.
Following oral administration of 3 mg drospirenone/0.03 mg ethinyl estradiol (Eusemide®) tablets, approximately 0.02% of the drospirenone dose is secreted into the milk of postpartum women over a 24-hour period. The maximum daily intake for infants is approximately 0.003 mg drospirenone.
Pediatric Dosage]
The safety and efficacy of this product have been established in females of childbearing age. In adolescent girls under 18 years of age, the expected safety and efficacy are the same as in females ≥18 years of age. This product should not be used before menarche.
[Geriatric Use].
This product has not been studied in postmenopausal women and is not indicated for use in this population.
Drug Interactions]
Effects of other drugs on compounded hormonal contraceptives
Substances that reduce the effectiveness of COCs: Drugs or herbs that induce specific enzymes (including CYP3A4) can reduce the effectiveness of COCs or aggravate breakthrough bleeding. Drugs or herbs that can reduce the effectiveness of hormonal contraceptives include: phenytoin, barbiturates, carbamazepine, bosentan, felbamate, ashwagandha, oxcarbazepine, rifampin, topiramate, and medicines containing St. John’s wort (onychomycetes). Interactions between oral contraceptives and other drugs may result in breakthrough bleeding and/or contraceptive failure. When combining enzyme-inducing agents with COCs, women are advised to use other contraceptive measures or back-up methods and to continue using a 28-day back-up method after discontinuing enzyme-inducing agents to ensure contraceptive reliability.
Substances that can elevate plasma levels of COCs: Combining atorvastatin with specific COCs containing ethinylestradiol can increase the AUC of ethinylestradiol by approximately 20%. CYP3A4 inhibitors such as itraconazole or ketoconazole can increase plasma levels of the hormone.
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes in plasma levels of estrogen and progesterone (elevated and decreased) have been observed in some cases where HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors have been combined.
Antibiotics: Pregnancies have been reported with concomitant use of hormonal contraceptives and antibiotics, however, clinical pharmacokinetic trials have not found consistent effects of antibiotics on plasma concentrations of anabolic steroids.
Effects of Drospirenone: The major metabolite production of drospirenone in human plasma is independent of the cytochrome P450 system. Therefore, inhibitors of this enzyme system are unlikely to affect the metabolism of drospirenone.
Effect of compounded oral contraceptives on other drugs
COCs containing ethinylestradiol may inhibit the metabolism of other compounds. COCs have been found to significantly reduce plasma concentrations of lamotrigine, possibly due to the induction of glucuronide binding of lamotrigine. This could reduce the seizure control effect of lamotrigine; therefore, dose adjustment of lamotrigine may be required. For additional information on interactions with COCs or potential enzyme changes, refer to the instructions for the currently used drug.
In vitro and clinical trials have not found inhibition of human CYP450 enzymes by drospirenone at clinically meaningful doses [see [Pharmacokinetics]].
Interactions with Potentially Elevated Blood Potassium
Concurrent administration of Drospirenone and other drugs that can elevate blood potassium may increase blood potassium concentrations in women [see [Precautions] and [Pharmacokinetics]].
Overdose]
Serious adverse reactions due to overdose have not been reported, including ingestion by children. Overdose may result in withdrawal bleeding and nausea in women.
Drospirenone is an analogue of spironolactone, which has anti-salicylic hormone properties. In case of overdose
, serum potassium and sodium concentrations should be monitored, as well as for signs of metabolic acidosis.
Clinical trials]
Contraceptive
International clinical trial: In the primary contraceptive effectiveness trial of this product (3 mg drospirenone/0.02 mg ethinyl estradiol) lasting up to 1 year, 1,027 subjects were enrolled and completed 11,480 28-day cycles. The age range was 17 to 36 years. Ethnic demographics: 87.8% Caucasian; 4.6% Hispanic; 4.3% Black; 1.2% Asian; 2.1% other. Women with a BMI over 35 were excluded from the trial. The Biel index was 1.41 (95% CI [0.73, 2.47])/100 female-years based on 12 pregnancies that occurred in women aged 35 years or older who were not receiving other contraception between the start of treatment and 14 days after the last dose of this product.
Domestic clinical trial: Study A52976 enrolled 670 healthy Chinese female subjects between 18 and 45 years of age who required contraceptive protection to assess bleeding patterns, cycle control, contraceptive reliability and overall safety. The reliability of contraception was derived from the PI. Four pregnancies were observed in the study that occurred during the treatment period, i.e., the estimated date of conception was during the administration of study drug or within 4 days of the last dose of study drug. The uncorrected Pearl index based on 603.8 woman-years of exposure and 4 pregnancies during treatment was 0.7, making this product a reliable contraceptive (adjusted PI based on 502.5 woman-years of exposure and 3 pregnancies due to method failure during treatment was 0.6). Meier estimate was 0.0066, which means that the probability of successful contraceptive protection was 0.9934 (i.e., 99.34%).
Acne vulgaris
International Clinical Trials: In two multicenter, double-blind, randomized, placebo-controlled trials, 889 subjects aged 14 to 45 years with moderate acne received six 28 -day cycles of this product or placebo. The primary effectiveness endpoints were: percentage change in inflammatory lesions, non-inflammatory lesions, and total lesions, and percentage of subjects rated as “clean” or “almost clean” on the Investigator’s Static Global Assessment (ISGA) scale on day 15 of cycle 6. The results of the key validity variables are shown in the following table.
Table I: Effectiveness Results of Acne Trials*
Trial 1 Trial 2 This product N=228 Placebo N=230 This product N=218 Placebo N=213 ISGA success rate 35 (15%)10 (4%)46 (21%)19 (9%)Inflammatory lesions Mean baseline count 33333232 Mean absolute (%)reduction 15 (48%)11 (32%)16 (51%)11 (34%)Non-inflammatory lesions Mean Baseline Count 47474444 Mean Absolute (%) Reduction 18 (39%)10 (18%)17 (42%)11 (26%)Total Lesions Mean Baseline Count 80807676 Mean Absolute (%) Reduction 33 (42%)21 (25%)33 (46%)22 (31%)* Assessed on Day 15 of Cycle 6 in the intention-to-treat population using the end observation advancement method.
Domestic Clinical Trial: Trial A51123 was a multicenter, double-blind, randomized, placebo-controlled study to evaluate and compare the efficacy and safety of this product and placebo over 6 treatment cycles in Chinese women with moderate acne vulgaris. 173 (96.6%) subjects were suitable for enrollment in the full analysis set, 87 subjects in the product treatment group and 86 subjects in the placebo treatment group. The primary effectiveness measure was the mean percentage change in the total number of acne lesions (open and closed acne, papules, pustules, and nodules) from baseline to cycle 6 in the full analysis set and the eligible protocol set. In the 2 analysis sets, the product produced a clinically significant anti-acne effect compared with placebo based on key effectiveness indicators. At Cycle 6, the total number of lesions decreased in the 2 treatment groups (improvement expressed as a greater percentage change). In the conforming regimen set, effectiveness was better than (mean reduction of 72.6% and 55.6% in the product-treated and placebo-treated groups) the full analysis set (mean reduction of 66.8% and 37.7% in the product-treated and placebo-treated groups).
Pharmacology and Toxicology
Pharmacological effects
Drospirenone Ethinylestradiol Tablets (II) is a combination oral contraceptive consisting of drospirenone and ethinylestradiol.
Drospirenone has anti-salicorticoid activity, counteracts estrogen-related sodium retention, and has anti-androgenic activity. Drospirenone does not counteract the increase in sex hormone binding globulin (SHBG) associated with ethinylestradiol, which facilitates binding and inactivation of endogenous androgens.
Ethinylestradiol is a steroidal hormone oral contraceptive that acts mainly by inhibiting ovulation and altering cervical mucus properties.
Toxicological studies
Drospirenone
Drospirenone was negative in the Ames test, mammalian cell mutation test, human hepatocyte DNA test, and mouse micronucleus test; positive in the human peripheral lymphocyte chromosome aberration test and rat hepatocyte DNA test.
Drospirenone and/or its metabolites were administered orally to pregnant rats and rabbits, and drospirenone and/or its metabolites could cross the placenta and enter the fetus. No evidence of teratogenicity of drospirenone was seen in rats or rabbits.
No increase in tumor incidence was observed in mice and rats given drospirenone for 2 years. Drospirenone exposure (based on AUC) was 3 times (mice) and 8 times (rats) the exposure at the recommended clinical dose in humans.
Ethinylestradiol
Among other drugs containing ethinylestradiol, it has been previously observed that ethinylestradiol can induce tumors in rodents, which is thought to be due to species-specific effects of estrogen on prolactin secretion in rodents.
Compounding studies
The combined administration of drospirenone and ethinylestradiol to female rats during the second third of gestation induced a dose-dependent feminization of male fetuses and androgenization of female fetuses. Male fetal feminization was associated with the antiandrogenic effects of drospirenone at a systemic exposure approximately 8-13 times the expected clinical exposure (based on AUC). Systemic exposure to drospirenone in the presence of female fetal androgyny was approximately 2-5 times the expected clinical exposure (based on AUC). A dose-dependent increase in abortion rates was observed in pregnant monkeys following daily administration of drospirenone and ethinyl estradiol during organogenesis and sexual organ differentiation, but no teratogenic effects were observed. Administration of drospirenone and ethinylestradiol to pregnant rabbits resulted in a dose-dependent increase in embryonic mortality and increased loss before and after implantation.
In a 2-year oral carcinogenicity test in rats and mice given drospirenone 10 mg/kg/d or drospirenone:ethinyl estradiol in combination: 1:0.01, 3:0.03, 10:0.1 mg/kg/day, exposure to drospirenone in mice (AUC) was 0.1 to 2 times greater than exposure in humans given a single contraceptive, and in the group given drospirenone alone, the Hastings gland In rats, exposure was 0.8 to 10 times higher than human exposure when given as a single contraceptive, and the incidence of benign and malignant adrenal pheochromocytomas was increased in the high-dose drospirenone test group.
The combined administration of drospirenone and ethinyl estradiol resulted in an increased incidence of tumors in the following sites: mammary gland and uterus in mice and rats and pituitary gland in mice. Tumor incidence was similar when ethinyl estradiol was given alone, but the incidence was further increased, suggesting that ethinyl estradiol is associated with an increased incidence of tumors. Co-administration of drospirenone with ethinyl estradiol reduced the potential carcinogenicity of ethinyl estradiol in the pituitary gland of mice and the uterus and mammary gland of rats.
It is important to note that sex steroid hormones can promote certain hormone-dependent tissue growth and tumor growth.
Pharmacokinetics]
Absorption
With a single tablet, the absolute bioavailability of drospirenone is about 76%. The absolute bioavailability of ethinyl estradiol is approximately 40% due to pre-binding and first-pass metabolism in the blood. This product is a combination tablet of drospirenone and ethinyl estradiol, and ethinyl estradiol is stabilized in the form of a b-cyclodextrin inclusion (inclusion), which prevents the absolute bioavailability of this product. When administered in the b-cyclodextrin inclusion form, the bioavailability of ethinylestradiol is similar to that when administered as a free steroid. Serum concentrations of drospirenone and ethinylestradiol peak within 1-2 hours after administration of this product.
The pharmacokinetics of drospirenone are proportional to the dose after a single dose of 1-10 mg. Steady-state concentrations of drospirenone were observed after 8 days following once-daily administration of this product. The serum Cmax and AUC (0-24h) accumulation ratio of drospirenone was approximately 2 to 3 times higher after multiple dosing of this product (see Table I).
Steady-state concentrations of ethinyl estradiol occur in the second half of the treatment cycle. After once-daily dosing, serum ethinylestradiol Cmax and AUC (0-24h) accumulation ratios are approximately 1.5 to 2 (see Table I).
Table II: Pharmacokinetic parameters of this product (drospirenone 3 mg and ethinylestradiol 0.02 mg)
Drospirenone cycles/day Number of subjects Cmaxa
(ng/mL)Tmaxb
(h)AUC (0-24h)a
(ng-h/mL)t1/2 a
(h)1/12338.4 (25)1.5 (1-2)268 (19)NAc1/212370.3 (15)1.5 (1-2)763 (17)30.8 (22)Ethinylestradiol cycles/day Number of subjects Cmaxa
(pg/mL)Tmaxb
(h)AUC(0-24h)a
(pg-h/mL)t1/2 a
(h)1/12332.8 (45)1.5 (1-2)108 (52)NAc1/212345.1 (35)1.5 (1-2)220 (57)NAc geometric mean (geometric mean coefficient of variation)
Median (range)
NA = Not applicable
Food Effects
Following a single dose of a formulation similar to this one, absorption of drospirenone and ethinyl estradiol was slowed after feeding (high-fat meal), and serum Cmax for both components decreased by approximately 40%. However, there was no change in the absorption of drospirenone. The absorption of ethinylestradiol decreased by approximately 20% after feeding.
Distribution
Serum concentrations of drospirenone and ethinylestradiol decreased biphasically. The apparent volume of distribution is approximately 4 L/kg for drospirenone and 4-5 L/kg for ethinylestradiol.
Drospirenone did not bind to SHBG or corticosteroid-binding globulin (CBG), however, the binding rate to other serum proteins was approximately 97%. There was no change in free classification (as measured by trough concentrations) after multiple dosing over 3 cycles. Ethinylestradiol has a high (approximately 98.5%) but non-specific binding to serum albumin and induces elevated serum SHBG and CBG concentrations. The effects of ethinylestradiol on SHBG and CBG are not affected by changes in drospirenone dose in the dose range of 2 to 3 mg.
Metabolism
The 2 major metabolites in human plasma are the acid form of drospirenone, which is produced by opening the lactone ring, and 4,5-dihydro-drospirenone-3-sulfate. These metabolites have no pharmacological activity. In human liver microsomal in vitro assays, drospirenone was metabolized only in small amounts, primarily via cytochrome P450 3A4 (CYP3A4).
Ethinylestradiol is bound in the mucosa of the small intestine and in the liver before entering the bloodstream. Ethinylestradiol is metabolized primarily by aromatic hydroxylation, but a variety of hydroxylated and methylated metabolites are produced, which are present in free form and may also form glucuronide conjugates and sulfate esters. CYP3A4 in the liver is associated with 2-hydroxylation, which is the primary oxidation reaction. The 2-hydroxylated metabolites are further converted by methylation and glucuronide binding prior to excretion through urine and feces.
Excretion
After single and multiple doses, drospirenone serum concentrations are in the terminal disposition phase with a half-life of approximately 30 h. After 10 days, drospirenone is almost completely excreted, with excretion in the feces being slightly greater than that in the urine. Drospirenone undergoes extensive metabolism, with only trace amounts of drospirenone excreted in its original form in the urine and feces. At least 20 different metabolites were observed in the urine and feces. Approximately 38-47% of the metabolites in the urine were glucuronide and sulfate bound. In feces, approximately 17-20% of the metabolites were excreted as glucuronide and sulfate bound.
The terminal disposal phase half-life of ethinylestradiol is approximately 24 hours. Ethinylestradiol is not excreted in its native form. Ethinylestradiol in the urine and feces is glucuronide and sulfate bound and occurs in the enterohepatic circulation.
Special Populations
Ethnicity: No clinically meaningful differences in the pharmacokinetics of drospirenone or ethinyl estradiol were observed between Japanese women and Caucasian women (25-35 years of age) when administered 3 mg drospirenone/0.02 mg ethinyl estradiol daily for 21 days. Studies have not been conducted specifically in other ethnic groups.
Renal Impairment.
This product is contraindicated in patients with renal impairment.
The effect of renal impairment on the pharmacokinetics of drospirenone (3 mg/day x 14 days) and the effect of drospirenone on blood potassium were studied in female subjects (n=28, 30-65 years) with normal renal impairment and mild and moderate renal impairment. All subjects received a low-potassium diet. In this trial, 7 subjects continued to use potassium-preserving drugs to treat their underlying disease. At day 14 of drospirenone treatment (steady state), serum drospirenone levels in the mild renal impairment group (creatinine clearance CLcr, 50-80 mL/min) were similar to those in the normal renal function group (CLcr, >80 mL/min). Mean serum levels of drospirenone were 37% higher in women with moderate renal impairment (CLcr, 30 – 50 mL/min) compared to women with normal renal function. Drospirenone treatment did not produce clinically meaningful effects on serum potassium concentrations. In this trial, although no hyperkalemia was observed, five of the seven subjects who continued potassium-preserving medications had mean serum potassium concentrations elevated to 0.33 mEq/L during the trial. [see “Use in Special Populations” in [Contraindications], [Precautions] and [Dosage and Administration]]
Hepatic Impairment.
This product is contraindicated in patients with hepatic disease.
In women with moderate hepatic impairment, the average exposure to drospirenone is approximately 3 times higher than that of women with normal hepatic function. This product has not been studied in women with severe hepatic impairment [see “Use in Special Populations” in [Contraindications], [Precautions] and [Dosage]].
Drug Interactions
Effects of Other Drugs on Combination Hormonal Contraceptives
Substances that reduce the effectiveness of COCs: Drugs or herbs that induce specific enzymes (including CYP3A4) may reduce the effectiveness of COCs or exacerbate breakthrough bleeding. [See [Drug Interactions]]
Substances that can elevate plasma levels of COCs: Combining atorvastatin with specific COCs containing ethinyl estradiol can increase the AUC of ethinyl estradiol by approximately 20%. Plasma levels of ethinylestradiol can be elevated by ascorbic acid and acetaminophen, possibly through inhibition of binding. plasma levels of the hormone can be elevated by CYP3A4 inhibitors such as itraconazole or ketoconazole. [See [Drug Interactions]]
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes in plasma levels of estrogen and progesterone (elevated and decreased) have been observed in some cases where HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors were combined. [See [Drug Interactions]]
Antibiotics: Pregnancies have been reported with concomitant use of hormonal contraceptives and antibiotics; however, clinical pharmacokinetic trials have shown no consistent effect of antibiotics on plasma concentrations of anabolic steroids. [See [Drug Interactions]]
Effect of compounded oral contraceptives on other drugs
COCs containing ethinylestradiol can inhibit the metabolism of other compounds. COCs have been found to significantly reduce plasma concentrations of lamotrigine, possibly due to the induction of glucuronide binding of lamotrigine. This can reduce the seizure control effect of lamotrigine; therefore, it may be necessary to adjust the dose of lamotrigine. For additional information on interactions with COCs or potential enzyme changes, refer to the instructions for the currently used drug [see [Drug Interactions]]
The metabolism of drospirenone and the potential effects of drospirenone on hepatic cytochrome P450 (CYP) enzymes have been studied in in vitro and in vivo trials. In in vitro assays, drospirenone did not affect the conversion rate of CYP1A2 and CYP2D6 model substrates and inhibited the conversion rate of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4, with CYP2C19 being the most sensitive enzyme. In a clinical pharmacokinetic trial, the potential effect of drospirenone on CYP2C19 activity was investigated using omeprazole as a marker substrate. In 24 postmenopausal women in this trial [including 12 women with the pure (wild-type) CYP2C19 genotype and 12 with the heterozygous CYP2C19 genotype], 14 days of once-daily oral administration of 3 mg drospirenone did not affect the oral clearance of omeprazole (40 mg drospirenone sub-oral administration) or the CYP2C19 product 5-hydroxylation of omeprazole. In addition, drospirenone had no significant effect on the systemic clearance of the CYP3A product omeprazole sulfate. These results suggest that drospirenone does not inhibit CYP2C19 and CYP3A4 in vivo. 2 additional clinical drug-drug interaction trials were conducted in 24 postmenopausal women using simvastatin and midazolam as marker substrates for CYP3A4. The results of these trials demonstrated that the steady-state drospirenone concentrations achieved after 3 mg drospirenone/day administration did not affect the pharmacokinetics of CYP3A4 substrates. [See [Drug Interactions]]
Interactions with drugs that may elevate blood potassium concentrations
Potassium may be elevated in women receiving this product in combination with potassium-elevating drugs [see [Precautions]].
A drug-drug interaction trial with drospirenone 3 mg/estradiol (E2) 1 mg was conducted in 24 women with mild postmenopausal hypertension who were taking enalapril maleate and was compared with placebo in the trial. In all subjects, blood potassium concentrations were measured every other day for a total of 2 weeks. In the drospirenone/estradiol group, mean blood potassium concentrations were 0.22 mEq/L higher relative to change from baseline than in the placebo group. blood potassium concentrations were also measured at baseline and at multiple time points over 24 hours on day 14. At day 14, the ratio of Cmax and AUC of potassium in the drospirenone/estradiol group to the placebo group was 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentration >5.5 mEq/L).
[Storage].
Store below 30°C.
Package】
Packaging material: blister eye package consisting of aluminum foil and polyvinyl chloride transparent film (heat sealed at the edge).
Package specification: 28 tablets/plate/box
【Expiration date】
60 months
【Execution standard
Imported drug registration standard: JX20130288
Approval number
Imported drug registration certificate No. XXXX
【Manufacturer】
Production plant
Company name: Bayer Weimar GmbH und Co. KG
Production Address: Döbereinerstrabe 20, 99427 Weimar, Thuringia, Germany
Tel: 0049 3643 4331354
Fax: 0049 3643 4332611354
Foreign packaging plant: Bayer Pharma AG
Address: Mullerstrabe 178 13353 Berlin, Germany
Tel: 0049 30 4681 4875
Fax: 0049 30 4681 1570
Domestic Contact
Bayer Pharma HealthCare Co.
No. 7 Rongjing East Street, Beijing Economic and Technological Development Zone
Postal Code: 100176
Telephone number: 010 59218282
Fax Number: 010 59218181
Hotline
400 810 0360
If you have any questions, you can contact with the manufacturer.