DROSPIRENONE AND ETHINYL ESTRADIOL

Drospirenone and Ethinyl Estradiol Tablets, USP 3 mg/ 0.03 mg provide an oral contraceptive regimen consisting of 28 film-coated tablets that contain the ingredients specified for each tablet below: • 21 light yellow to yellow tablets each containing 3 mg DRSP and 0.03 mg EE • 7 inert white to off-white tablets The inactive ingredients in the light yellow to yellow tablets are corn starch, crospovidone, hypromellose, iron oxide yellow, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, talc, titanium dioxide. The white to off-white inert film-coated tablets contain anhydrous lactose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polacrilin potassium, polyethylene glycol, polysorbate 80 and titanium dioxide. Drospirenone, USP (6R, 7R, 8R, 9S, 10R, 13S, 14S, 15S, 16S, 17S)-1,3’,4’,6, 6a, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15a, 16-hexadecahydro10, 13-dimethylspiro-[17H-dicyclopropa-[6 ,7:15, 16] cyclopenta[a]phenanthrene-17, 2’(5H)-furan]-3, 5’(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.49 and a molecular formula of C 24 H 30 O 3 . Ethinyl estradiol, USP (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C 20 H 24 O 2 . The structural formulas are as follows: Drospirenone, USP Ethinyl Estradiol, USP USP Dissolution Test pending. drospirenone structure ethinylestradiolstructure

Drospirenone and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy. Drospirenone and ethinyl estradiol tablets are a combination of drospirenone, a progestin, and ethinyl estradiol, an estrogen, indicated for use by females of reproductive potential to prevent pregnancy. ( 1 )

• Take one tablet daily by mouth at the same time every day. ( 2.1 ) • Tablets must be taken in the order directed on the blister pack. ( 2.1 ) 2.1 How to Take Drospirenone and Ethinyl Estradiol Tablets Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. To achieve maximum contraceptive effectiveness, drospirenone and ethinyl estradiol tablets must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered. 2.2 How to Start Drospirenone and Ethinyl Estradiol Tablets Instruct the patient to begin taking drospirenone and ethinyl estradiol tablets either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start). Day 1 Start During the first cycle of drospirenone and ethinyl estradiol tablets use, instruct the patient to take one light yellow to yellow drospirenone and ethinyl estradiol tablet daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one light yellow to yellow drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one white to off-white tablet daily on Days 22 through 28. Drospirenone and ethinyl estradiol tablets should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone and ethinyl estradiol tablets can be taken without regard to meals. If drospirenone and ethinyl estradiol tablets are first taken later than the first day of the menstrual cycle, drospirenone and ethinyl estradiol tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. Sunday Start During the first cycle of drospirenone and ethinyl estradiol tablet use, instruct the patient to take one light yellow to yellow drospirenone and ethinyl estradiol tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one light yellow to yellow drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one white to off-white tablet daily on Days 22 through 28. Drospirenone and ethinyl estradiol tablets should be taken in the order directed on the package at the same time each day, preferably after the evening meal or at bedtime with some liquid, as needed. Drospirenone and ethinyl estradiol tablets can be taken without regard to meals. Drospirenone and ethinyl estradiol tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should begin her next and all subsequent 28-day regimens of drospirenone and ethinyl estradiol tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her light yellow to yellow tablets on the next day after ingestion of the last white to off-white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of drospirenone and ethinyl estradiol tablets is started later than the day following administration of the last white to off-white tablet, the patient should use another method of contraception until she has taken a light yellow to yellow drospirenone and ethinyl estradiol tablet daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, drospirenone and ethinyl estradiol tablets should be started on the same day that a new pack of the previous oral contraceptive would have been started. When switching from a method other than a birth control pill When switching from a transdermal patch or vaginal ring, drospirenone and ethinyl estradiol tablets should be started when the next application would have been due. When switching from an injection, drospirenone and ethinyl estradiol tablets should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, drospirenone and ethinyl estradiol tablets should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last light yellow to yellow tablet. If spotting or breakthrough bleeding occurs while taking drospirenone and ethinyl estradiol tablets, instruct the patient to continue taking drospirenone and ethinyl estradiol tablets by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider. Although the occurrence of pregnancy is low if drospirenone and ethinyl estradiol tablets are taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue drospirenone and ethinyl estradiol tablets if pregnancy is confirmed. The risk of pregnancy increases with each active light yellow to yellow tablet missed. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more white to off-white tablets, she should still be protected against pregnancy provided she begins taking a new cycle of light yellow to yellow tablets on the proper day. For postpartum women who do not breastfeed or after a second trimester abortion, start drospirenone and ethinyl estradiol tablets no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts drospirenone and ethinyl estradiol tablets postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken drospirenone and ethinyl estradiol tablets for 7 consecutive days. 2.3 Missed Doses Table 1: Instructions for Drospirenone and Ethinyl Estradiol Tablets Missed Doses If one light yellow to yellow active tablet is missed Take it as soon as possible. Take the next tablet at the regular time. This means two tablets may be taken in one day. A back-up birth control method is not required if the patient has sex. If two light yellow to yellow active tablets in a row are missed in Week 1 or Week 2 Take two tablets as soon as possible and two tablets the next day. Then take one tablet a day until the pack is finished. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. If two light yellow to yellow active tablets in a row are missed in Week 3 or Week 4 Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. The patient may not have their period this month but this is expected. However, if they miss their period two months in a row, they should call their healthcare provider because they might be pregnant. If three or more light yellow to yellow active tablets in a row are missed during any week Day 1 Start: Throw out the rest of the pack and start a new pack that same day. Sunday Start: Keep taking one tablet every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that same day. Additional nonhormonal contraception (such as condoms and spermicide) should be used as back-up if the patient has sex within 7 days after missing tablets. The patient may not have their period this month but this is expected. However, if they miss their period two months in a row, they should call their healthcare provider because they might be pregnant. If any of the seven white to off-white inactive tablets are missed in Week 4 Throw away the tablets that were missed. Keep taking one tablet each day until the pack is empty. They do not need a back-up method. Finally, if they are still not sure what to do about the tablets they have missed Use nonhormonal contraception (such as condoms and spermicides) anytime they have sex. Contact their healthcare provider and continue taking one active yellow tablet each day until otherwise directed. 2.4 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3 to 4 hours after tablet-taking, this can be regarded as a missed tablet.

Drospirenone and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions: • Renal impairment • Adrenal insufficiency • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: o Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] o Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] o Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] o Have coronary artery disease [see Warnings and Precautions ( 5.1 )] o Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )] o Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] o Have uncontrolled hypertension [see Warnings and Precautions ( 5.6 )] o Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.8 )] o Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings and Precautions ( 5.9 )] • Undiagnosed abnormal uterine bleeding [see Warnings and Precautions ( 5.10 )] • Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [see Warnings and Precautions ( 5.3 )] • Liver tumor (benign or malignant) or liver disease [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.7 )] • Use of Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations [see Warnings and Precautions ( 5.5 ) and Drug Interactions ( 7.2 )]. • Renal impairment ( 4 ) • Adrenal insufficiency ( 4 ) • A high risk of arterial or venous thrombotic diseases ( 4 ) • Undiagnosed abnormal uterine bleeding ( 4 ) • Breast cancer ( 4 ) • Liver tumors or liver disease ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir ( 4 )

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: • Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Vascular events [see Warnings and Precautions ( 5.1 )] • Liver disease [see Warnings and Precautions ( 5.4 )] The most frequent adverse reactions (≥ 2%) are premenstrual syndrome (13.2%), headache /migraine (10.7%), breast pain/tenderness/discomfort (8.3%), nausea/vomiting (4.5%), abdominal pain/tenderness/discomfort (2.3%), mood changes (2.3%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The data provided reflect the experience with the use of drospirenone and ethinyl estradiol tablets (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837). The US pivotal clinical study (N=326) was a multicenter, open-label trial in healthy women aged 18 to 35 who were treated for up to 13 cycles. The second pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of drospirenone and ethinyl estradiol tablets vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17 to 40 who were treated for up to 26 cycles. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (13.2%), headache/migraine (10.7%), breast pain/tenderness/discomfort (8.3%), nausea/vomiting (4.5%) abdominal pain/discomfort/tenderness (2.3%) and mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%). Adverse Reactions (≥ 1%) Leading to Study Discontinuation : Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%). Serious Adverse Reactions : Depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma. 6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 to 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 to 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8 to 10 years of COC use. Figure 3: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs. The following adverse reactions have been identified during post-approval use of drospirenone and ethinyl estradiol tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions, including fatalities, are grouped into System Organ Classes and ordered by frequency. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Hyperkalemia Skin and subcutaneous tissue disorders: Chloasma figure-3

Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations . Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]. Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. COCs Increasing the Plasma Concentrations of CYP450 Enzymes: In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations [see Clinical Pharmacology ( 12.3 )]. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Potential to Increase Serum Potassium Concentration: There is a potential for an increase in serum potassium concentration in women taking drospirenone and ethinyl estradiol tablets with other drugs that may increase serum potassium concentration [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer drospirenone and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions ( 5.5 )] . 7.4 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity [see Warnings and Precautions ( 5.12 ) and Drug Interactions ( 7.2 )] . Drug Interactions Consult the labeling of all concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations. Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. In a clinical drug-drug interaction study conducted in 20 premenopausal women, co-administration of a DRSP (3 mg)/EE (0.02 mg) COC with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily) for 10 days increased the AUC (0 to 24h) of DRSP and EE by 2.68-fold (90% CI: 2.44, 2.95) and 1.40-fold (90% CI: 1.31, 1.49), respectively. The increases in C max were 1.97-fold (90% CI: 1.79, 2.17) and 1.39-fold (90% CI: 1.28, 1.52) for DRSP and EE, respectively. Although no clinically relevant effects on safety or laboratory parameters including serum potassium were observed, this study only assessed subjects for 10 days. The clinical impact for a patient taking a DRSP-containing COC concomitantly with chronic use of a CYP3A4/5 inhibitor is unknown [see Warnings and Precautions ( 5.2 )]. HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. In vitro, EE is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19, and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo . Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Interactions With Drugs That Have the Potential to Increase Serum Potassium Concentration: There is a potential for an increase in serum potassium concentration in women taking drospirenone and ethinyl estradiol tablets with other drugs that may increase serum potassium concentration [see Warnings and Precautions ( 5.2 )] . A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium C max and AUC in the DRSP/E2 group to those in the placebo group were 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 concentrations > 5.5 mEq/L).