drospirenone and ethinyl estradiol

RECENT MAJOR CHANGES Dosage and Administration ( 2.3 ) 5/2023 Contraindications, Pregnancy ( 4 ) Removed 5/2023 Warnings and Precautions, ( 5.11 ) Removed 5/2023

1 INDICATIONS AND USAGE 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. ( 1.1 ) • Treat symptoms of premenstrual dysphoric disorder (PMDD) for females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.2 ) • Treat moderate acne for women at least 14 years old only if the patient desires an oral contraceptive for birth control. ( 1.3 ) 1.1 Oral Contraceptive Drospirenone and ethinyl estradiol tablets are indicated for use by females of reproductive potential to prevent pregnancy. 1.2 Premenstrual Dysphoric Disorder (PMDD) Drospirenone and ethinyl estradiol tablets are also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in females of reproductive potential who choose to use an oral contraceptive as their method of contraception. The effectiveness of drospirenone and ethinyl estradiol tablets for PMDD when used for more than three menstrual cycles has not been evaluated. The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders. Drospirenone and ethinyl estradiol tablets have not been evaluated for the treatment of premenstrual syndrome (PMS). 1.3 Acne Drospirenone and ethinyl estradiol tablets are indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Drospirenone and ethinyl estradiol tablets should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.

2 DOSAGE AND ADMINISTRATION • 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 white to off-white 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 white to off-white drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one green 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 tablets use, instruct the patient to take one white to off-white drospirenone and ethinyl estradiol tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one white to off-white drospirenone and ethinyl estradiol tablet daily for 21 consecutive days, followed by one green 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 white to off-white tablets on the next day after ingestion of the last green 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 green tablet, the patient should use another method of contraception until she has taken a white to off-white 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 b …

3 DOSAGE FORMS AND STRENGTHS Drospirenone and ethinyl estradiol tablets consists of 28, biconvex tablets in the following order (3): 21 yellow film-coated tablets, each containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol (EE), 7 inert white to off-white tablets Drospirenone and ethinyl estradiol tablets, 3 mg and 0.03 mg are available in blister packs. Each blister pack contains 28, round, bi-convex tablets in the following order: 21 yellow colored, round, biconvex, film-coated tablets, debossed with 'LU' on one side and 'K32' on the other side each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol 7 inert white to off-white round, biconvex tablets, debossed with "K33" on one side and 'LU' on the other side

4 CONTRAINDICATIONS Do not prescribe drospirenone and ethinyl estradiol tablets to women who are known to have the following: • Renal impairment • Adrenal insufficiency • A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: • Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )] • Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )] • Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )] • Have coronary artery disease [see Warnings and Precautions ( 5.1 )] • 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 )] • Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )] • Have uncontrolled hypertension [see Warnings and Precautions ( 5.6 )] • Have diabetes mellitus with vascular disease [see Warnings and Precautions ( 5.8 )] • 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 )] • Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.3 )] • Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.7 )] • Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.1 1) and Use in Specific Populations ( 8.1 )] • 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 ( 5.6 ) and Drug Interactions ( 7.3 )]. • Renal impairment ( 4 ) • Adrenal insufficiency ( 4 ) • A high risk of arterial or venous thrombotic diseases ( 4 ) • Undiagnosed abnormal uterine bleeding ( 4 ) • Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 ) • Liver tumors or liver disease ( 4 ) • Pregnancy ( 4 ) • Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir ( 4 )

6 ADVERSE REACTIONS 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%) in contraception and acne clinical trials were: headache/migraine (6.7%), menstrual irregularities (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4.0%) and mood changes (2.2%). ( 6.1 ) • The most frequent adverse reactions (≥ 2%) in PMDD clinical trials were: menstrual irregularities (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). ( 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, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Contraception and Acne Clinical Trials The data provided reflect the experience with the use of drospirenone and ethinyl estradiol tablets in the adequate and well-controlled studies for contraception (N=1,056) and for moderate acne vulgaris (N=536). For contraception, a Phase 3, multicenter, multinational, open-label study was conducted to evaluate safety and efficacy up to one year in 1,027 women aged 17 to 36 who took at least one dose of drospirenone and ethinyl estradiol tablets. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of drospirenone and ethinyl estradiol tablets on carbohydrate metabolism, lipids and hemostasis in 29 women aged 18 to 35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14 to 45 with moderate acne vulgaris who took at least one dose of drospirenone and ethinyl estradiol tablets, evaluated the safety and efficacy during up to 6 cycles. The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: headache/migraine (6.7%), menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (mood swings, depression, depressed mood and affect lability) (2.2%). PMDD Clinical Trials Safety data from trials for the indication of PMDD are reported separately due to differences in study design and setting in the Contraception and Acne studies as compared to the PMDD clinical program. Two (one parallel and one crossover designed) multicenter, double-blind, randomized, placebo-controlled trials for the secondary indication of treating the symptoms of PMDD evaluated safety and efficacy of drospirenone and ethinyl estradiol tablets during up to 3 cycles among 285 women aged 18–42, diagnosed with PMDD and who took at least one dose of drospirenone and ethinyl estradiol tablets. Common adverse reactions (≥ 2% of users) were: menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). Adverse Reactions (≥1%) Leading to Study Discontinuation: Contraception Clinical Trials Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1 …

7 DRUG INTERACTIONS 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 h …

8 USE IN SPECIFIC POPULATIONS Lactation: Can reduce milk production in breast-feeding females. ( 8.2 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, drospirenone and ethinyl estradiol tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. Data Human Data A retrospective database study of women in Norway, that included 44,734 pregnancies of which 368 were women who inadvertently took drospirenone/ethinyl estradiol during the first trimester of a pregnancy, found there were no adverse effects on pre-term birth, small for gestational age, or birth weight Z-scores. Post-marketing adverse event data on the use of drospirenone and ethinyl estradiol tablets in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population. 8.2 Lactation Risk Summary DRSP is present in human milk. After a single oral administration of 3 mg DRSP/0.03 mg EE tablets, DRSP concentration in breast milk over the 24-h period ranged from 1.4 to 7.0 ng/mL, with a mean ± standard deviation value of 3.7 ± 1.9 ng/mL. The estimated mean infant dose was 0.003 mg/day, which is about 0.1% of maternal dose (see Data). There is limited information on the effects of drospirenone and ethinyl estradiol tablets on the breast-fed infant. CHCs can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breastfeeding. [See also Dosage and Administration ( 2.2 )]. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for drospirenone and ethinyl estradiol tablets and any potential adverse effects on the breast-fed child from drospirenone and ethinyl estradiol tablets or from the underlying maternal condition. Data Human Data An open-label study evaluated the degree of DRSP transfer into milk within 72 hours following a single oral administration of 3 mg DRSP/0.03 mg EE tablets to 6 healthy lactating women who were 1 week to 3 months postpartum. DRSP was present in breast milk with a mean Cmax of 13.5 ng/mL, while the mean Cmax in serum of lactating women was 30.8 ng/mL. The DRSP concentration in breast milk over the 24-hour period following dosing ranged from 1.4 to 7.0 ng/mL, with a mean ± standard deviation value of 3.7 ± 1.9 ng/mL. Based on single dose data, the maximal daily infant dose of DRSP was calculated to be 0.003 mg/day, which represented a mean of 0.1% of the maternal dose. 8.4 Pediatric Use Safety and efficacy of drospirenone and ethinyl estradiol tablets has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Drospirenone and ethinyl estradiol tablets have not been studied in postmenopausal women and are not indicated in this population. 8.6 Patients with Renal Impairment Drospirenone and ethinyl estradiol tablets are contraindicated in patients with renal impairment [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )] . In subjects with creatinine clearance (CLcr) of 50 to 79 mL/min, serum DRSP concentrations were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30 to 49 mL/min, serum DRSP concentrations were on averag …

12.1 Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and the endometrial changes that reduce the likelihood of implantation.

11 DESCRIPTION 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

10 OVERDOSAGE There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. DRSP is a spironolactone analogue which has anti-mineralocorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Drospirenone and ethinyl estradiol tablets USP, 3 mg and 0.03 mg are available in a blister pack (NDC 68180-868-71) containing 28 tablets packed in a pouch (NDC 68180-868-71). Such three pouches are packaged in a carton (NDC 68180-868-73). Each blister pack contains 28 tablets in the following order: 21 active yellow colored, round, biconvex, film-coated tablets, debossed with 'LU' on one side and 'K32' on the other side each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol 7 inert white to off-white round, biconvex tablets, debossed with "K33" on one side and 'LU' on the other side. 16.2 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

16.1 How Supplied Drospirenone and ethinyl estradiol tablets USP, 3 mg and 0.03 mg are available in a blister pack (NDC 68180-868-71) containing 28 tablets packed in a pouch (NDC 68180-868-71). Such three pouches are packaged in a carton (NDC 68180-868-73). Each blister pack contains 28 tablets in the following order: 21 active yellow colored, round, biconvex, film-coated tablets, debossed with 'LU' on one side and 'K32' on the other side each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol 7 inert white to off-white round, biconvex tablets, debossed with "K33" on one side and 'LU' on the other side.