Syeda

RECENT MAJOR CHANGES Warnings and Precautions (5.3) 4/2022

1 INDICATIONS AND USAGE Syeda ® (drospirenone and ethinyl estradiol tablets) is indicated for use by women to prevent pregnancy. Syeda ® (drospirenone and ethinyl estradiol tablets) is an estrogen/progestin COC indicated for use by women to prevent pregnancy. ( 1 )

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 Syeda 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, Syeda 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 Syeda Instruct the patient to begin taking Syeda 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 Syeda use, instruct the patient to take one yellow Syeda daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one yellow Syeda daily for 21 consecutive days, followed by one white tablet daily on Days 22 through 28. Syeda 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. Syeda can be taken without regard to meals. If Syeda is first taken later than the first day of the menstrual cycle, Syeda 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 Syeda use, instruct the patient to take one yellow Syeda daily, beginning on the first Sunday after the onset of her menstrual period. She should take one yellow Syedadaily for 21 consecutive days, followed by one white tablet daily on Days 22 through 28. Syeda 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. Syeda can be taken without regard to meals. Syeda 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 Syeda on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her yellow tablets on the next day after ingestion of the last white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of Syeda is started later than the day following administration of the last white tablet, the patient should use another method of contraception until she has taken a yellow Syeda daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, Syeda 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, Syeda should be started when the next application would have been due. When switching from an injection, Syeda should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Syedashould be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last yellow tablet. If spotting or breakthrough bleeding occurs while taking Syeda, instruct the patient to continue taking Syeda by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleedin …

3 DOSAGE FORMS AND STRENGTHS Syeda (drospirenone and ethinyl estradiol tablets, USP) are available in blister packs. Each blister pack contains 28 tablets in the following order: • 21 active tablets are yellow colored, round, film-coated tablets, “SZ” and “U3” are debossed on opposite sides of the tablet and containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol (EE) • 7 inert white tablets are white film-coated, round, ‘SZ” and J1 are debossed on opposite sides of the tablet Syeda consists of 28 film-coated, tablets in the following order ( 3 ): • 21 yellow tablets, each containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol (EE), • 7 inert white tablets

4 CONTRAINDICATIONS Syeda is 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: 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 fibrilation) [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 migrane 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 )] Pregnancy, because there is no reason to use COCs during pregnancy [see WARNINGS AND PRECAUTIONS ( 5.11 ) 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 ( 5.5 ) 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 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 ) ] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 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 Xiromed, LLC. at 1-844-XIROMED (1-844-947-6633) 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(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 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 - 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 - 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 8-10 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. 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 …

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 WARINGS 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-use 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 hum …

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended; can decrease milk production. ( 8.3 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Syeda 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 DRSP/EE 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 Syeda 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 Syeda 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 breast-feeding [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 Syeda and any potential adverse effects on the breast-fed child from Syeda 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 post- partum. 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. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-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. After oral administration of drospirenone and ethinyl estradiol, about 0.02% of the DRSP dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 0.003 mg DRSP in an infant. 8.4 Pediatric Use Safety and efficacy of drospirenone and ethinyl estradiol 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 has not been studied in postmenopausal women and is not indicated in this population. 8.6 Pati …

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 endometrial changes that reduce the likelihood of implantation.

11 DESCRIPTION Syeda (drospirenone/ethinyl estradiol) tablets provide an oral contraceptive regimen consisting of 28 film-coated tablets that contain the ingredients specified for each tablet below: • 21 yellow tablets each containing 3 mg drospirenone and 0.03 mg ethinyl estradiol • 7 inert white tablets The inactive ingredients are corn starch, crospovidone (Polyplasdone XL), crospovidone (Polyplasdone XL-10), lactose fast flo, macrogol/PEG 3350, magnesium stearate vegetable (kemilub em-f-v), polysorbate 80 (tween 80), polyvinyl alcohol-part. hydrolyzed, povidone k-30 (kollidon K-30), pregelatinized starch (sepistab ST200), talc and titanium dioxide. In addition, each active tablet contains yellow iron oxide. Drospirenone(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-hexadecahydro-10,13-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 366.5 and a molecular formula of C 24 H 30 O 3 . Ethinyl estradiol (19-nor-17 -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: Structure

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 Syeda (drospirenone and ethinyl estradiol tablets, USP) are (active tablets), round, yellow colored, film coated tablets, SZ and U3 are debossed on opposite sides of the tablet. Inert/Placebo, are round, white film coated tablets, SZ and J1 are debossed on opposite sides of the tablet. NDC 70700-115-85, Carton containing three blister cards. 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].