DROSPIRENONE AND ETHINYL ESTRADIOL- drospirenone and ethinyl estradiol

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity. The estrogen in drospirenone and ethinyl estradiol tablets is ethinyl estradiol (EE). No specific pharmacodynamic studies were conducted with drospirenone and ethinyl estradiol tablets. Absorption The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of EE is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of drospirenone and ethinyl estradiol tablets, which is a combination tablet of DRSP and EE, has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1-2 hours after administration of drospirenone and ethinyl estradiol tablets. The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of drospirenone and ethinyl estradiol tablets, steady state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum C max For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol tablets serum C max Table 3: Mean Pharmacokinetic Parameters of Drospirenone and Ethinyl Estradiol Tablets (DRSP 3 mg and EE 0. 03 mg) NA en dash Not available DRSP Mean (%CV) Values Cycle / Day No. of Subjects C max T max AUC (0-24h) t 1/2 1/1 12 36. 7 (47) 288 (25) NA 1/21 12 87. 7 (20) 827 (23) 30. 9 (44) 6/21 12 84. 8 (19) 930 (19) 32. 5 (38) 9/21 12 81. 6 (38) 957 (23) 31. 4 (39) 13/21 12 78. 6 (26) 968 (24) 31. 1 (36) EE Mean (%CV) Values Cycle / Day No. of Subjects C max T max AUC (0-24h) t 1/2 1/1 11 53. 9 (45) 280 (87) NA 1/21 11 92. 5 (40) 461 (94) NA 6/21 11 99. 5 (47) 346 (74) NA 9/21 11 87 (43) 1. 5 (42) 485 (92) NA 13/21 10 90. 6 (38) 469 (83) NA Food Effect The rate of absorption of DRSP and EE following single administration of a formulation similar to drospirenone and ethinyl estradiol tablets was slower under fed (high fat meal) conditions with the serum C max Distribution DRSP and EE serum concentrations decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4-5 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98. 5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg. Metabolism The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically active. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. EE has been reported to be subject to significant gut and hepatic first-pass metabolism. Metabolism of EE and its oxidative metabolites occur primarily by conjugation with glucuronide or sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion. Excretion DRSP serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38-47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17-20% of the metabolites were excreted as glucuronides and sulfates. For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation. Use in Specific Populations Pediatric Use Geriatric Use Race: Renal Impairment The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n=28, age 30-65). All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50-79 mL/min were comparable to those in the control group with CLcr >= 80 mL/min. The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30-49 mL/min compared to those in the control group. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium concentrations increased by up to 0. [See Contraindications (4) Warnings and Precautions (5. 2) Hepatic Impairment: The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Drospirenone and ethinyl estradiol tablets have not been studied in women with severe hepatic impairment. 4) 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: Substances increasing the plasma concentrations of COCs: max [see Warnings and Precautions (5. 2) HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Antibiotics: 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 in vitro in vivo in vitro 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 [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.

Drospirenone and ethinyl estradiol tablets, 3 mg/0. 03 mg 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 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. 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). 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. 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 not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. 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 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 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 white to off-white 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 white to off-white 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 green tablets, she should still be protected against pregnancy provided she begins taking a new cycle of white to off-white 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. Table 1: Instructions for Drospirenone and Ethinyl Estradiol Tablets Missed Doses If one white to off-white 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 white to off-white 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 white to off-white active tablets in a row are missed in Week 3 or Week 4 Day 1 Start: Sunday Start: 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 three or more white to off-white active tablets in a row are missed during any week Day 1 Start: Sunday Start: 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 any of the seven green 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. In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet.

The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: [see Boxed Warning Warnings and Precautions (5. 1) [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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch 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). pivotal clinical study (N=326) was a multicenter, open-label trial in healthy women aged 18-35 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. 150 mg desogestrel/0. 03 mg EE conducted in healthy women aged 17-40 who were treated for up to 26 cycles. The most common adverse reactions (>= 2% of users) were: premenstrual syndrome (13. 2%), headache/migraine (10. 5%) abdominal pain/discomfort/tenderness (2. 3%) and mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2. 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. Serious Adverse Reactions Depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma. 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. 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. 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 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.

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning Women over 35 years old who smoke should not use drospirenone and ethinyl estradiol tablets. ( 4 Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. ( 4 Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications (4).
CONTRAINDICATIONS
Drosperinone and ethinyl estradiol tablets are contraindicated in females who are known to have or develop the following conditions: o [see Boxed Warning Warnings and Precautions (5. 1 o [see Warnings and Precautions (5. 1) o [see Warnings and Precautions (5. 6) o [see Warnings and Precautions (5. 8) o [see Warnings and Precautions (5. 9) [see Warnings and Precautions (5. 10) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) Use in Specific Populations (8. 7) [see Warnings and Precautions (5. 5) Drug Interactions (7. 2) 4 4 4 4 4 4 4.

Lactation: Can reduce milk production in breast-feeding females ( 8. 2 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. 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. 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. 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. 0 ng/mL, with a mean +/- standard deviation value of 3. 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 breastnot-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 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. 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 postnot-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. The DRSP concentration in breast milk over the 24-hour period following dosing ranged from 1. 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. Safety and efficacy of drospirenone and ethinyl estradiol tablets have 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. Drospirenone and ethinyl estradiol tablets have not been studied in postmenopausal women and are not indicated in this population. Drospirenone and ethinyl estradiol tablets are contraindicated in patients with renal impairment [see Contraindications (4) Warnings and Precautions (5. 2) In subjects with creatinine clearance (CLcr) of 50-79 mL/min, serum DRSP concentrations were comparable to those in a control group with CLcr >= 80 mL/min. In subjects with CLcr of 30-49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs [see Clinical Pharmacology (12. 3) Drospirenone and ethinyl estradiol tablets are contraindicated in patients with hepatic disease [see Contraindications (4) Warnings and Precautions (5. 4) No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see Clinical Pharmacology (12.

RECENT MAJOR CHANGES
Dosage and Administration ( 2.3 Contraindications, Pregnancy ( 4 Warnings and Precautions, ( 5.11
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. 1 Substances diminishing the efficacy of COCs: Substances increasing the plasma concentrations of COCs: Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e. , ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e. , 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) Clinical Pharmacology (12. 3) Human immunodeficiency virus (HIV)/Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Antibiotics: 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: 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: [see Warnings and Precautions (5. 3) 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) 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) Drug Interactions (7.

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.
NONCLINICAL TOXICOLOGY
In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of DRSP and EE, 0.1 to 2 times the exposure (AUC of DRSP) of women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of DRSP alone. In a similar study in rats given 10 mg/kg/day DRSP alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day DRSP and EE, 0.8 to 10 times the exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of DRSP. Mutagenesis studies for DRSP were conducted in vivo in vitro [See Warnings and Precautions (5.3 5.4)
CLINICAL STUDIES
In the clinical efficacy studies of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 +/- 4.7 years. The age range was 16 to 37 years. The racial demographic was: 83% Caucasian, 1% Hispanic, 1% Black, ˂ 1% Asian, ˂ 1% other, ˂ 1% missing data, 14% not inquired and ˂ 1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.
REFERENCES
1. 110 2. 75 3. 4. 339 5. 343 6. 339 7. 36 8. 342 9. 342
FDA Approved Patient Labeling
Guide for Using Drospirenone and Ethinyl Estradiol Tablets WARNING TO WOMEN WHO SMOKE Do not use drospirenone and ethinyl estradiol tablets if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. Birth control pills help to lower the chances of becoming pregnant when taken as directed. They do not protect against HIV infection (AIDS) and other sexually transmitted diseases. What Are Drospirenone and Ethinyl Estradiol Tablets? Drospirenone and ethinyl estradiol tablets are a birth control pill. It contains two female hormones, a synthetic estrogen called ethinyl estradiol and a progestin called drospirenone. The progestin drospirenone may increase potassium. Therefore, you should not take drospirenone and ethinyl estradiol tablets if you have kidney, liver or adrenal disease because this could cause serious heart and health problems. Other drugs may also increase potassium. If you are currently on daily, long-term treatment for a chronic condition with any of the medications below, you should consult your healthcare provider about whether drospirenone and ethinyl estradiol tablets are right for you, and during the first month that you take drospirenone and ethinyl estradiol tablets, you should have a blood test to check your potassium level. How Well Do Drospirenone and Ethinyl Estradiol Tablets Work? Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The better you follow the directions, the less chance you have of getting pregnant. Based on the results of two clinical studies, about 1 woman out of 100 women may get pregnant during the first year they use drospirenone and ethinyl estradiol tablets. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. How Do I Take Drospirenone and Ethinyl Estradiol Tablets? 1. Be sure to read these directions 2. If you have any questions or are unsure about the information in this leaflet, call your healthcare provider. Before You Start Taking Your Pills 1. 21 white to off-white pills 7 green pills 3. When To Start the First Pack of Pills You have a choice for which day to start taking your first pack of pills. Decide with your healthcare provider which is the best day for you. Pick a time of day which will be easy to remember. Day 1 Start: Take the first white to off-white pill of the pack during the first 24 hours of your period. Sunday Start: 1. When You Switch 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 birth control pill would have been started. When You Switch From Another Type of Birth Control Method 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. What to Do During the Month 1. What to Do if You Miss Pills If you miss 1 white to off-white pill of your pack: 1. If you miss 2 white to off-white pills in a row in Week 1 or Week 2 of your pack: 1. If you miss 2 white to off-white pills in a row in Week 3 or Week 4 of your pack: 1. If you miss 3 or more white to off-white pills in a row during any week: 1. If you miss any of the 7 green pills in Week 4: Finally, if you are still not sure what to do about the pills you have missed: WHO SHOULD NOT TAKE DROSPIRENONE AND ETHINYL ESTRADIOL TABLETS? Your healthcare provider will not give you drospirenone and ethinyl estradiol tablets if you: Also, do not take birth control pills if you: Birth control pills may not be a good choice for you if you have ever had jaundice (yellowing of the skin or eyes) caused by pregnancy (also called cholestasis of pregnancy). Tell your healthcare provider if you have ever had any of the above conditions (your healthcare provider can recommend another method of birth control). What Else Should I Know about Taking Drospirenone and Ethinyl Estradiol Tablets? Birth control pills do not protect you against any sexually transmitted disease, including HIV, the virus that causes AIDS. Do not skip any pills, even if you do not have sex often. If you miss a period, you could be pregnant. However, some women miss periods or have light periods on birth control pills, even when they are not pregnant. Contact your healthcare provider for advice if you: Birth control pills should not be taken during pregnancy. However, birth control pills taken by accident during pregnancy are not known to cause birth defects. Due to an increased risk of blood clots, you should stop drospirenone and ethinyl estradiol tablets at least four weeks before you have major surgery and not restart it until at least two weeks after the surgery. If you are breastfeeding, consider another birth control method until you are ready to stop breastfeeding. Birth control pills that contain estrogen, like drospirenone and ethinyl estradiol tablets, may decrease the amount of milk you make. A small amount of the pill''s hormones pass into breast milk. If you have vomiting or diarrhea, your birth control pills may not work as well. Take another pill if you vomit within 3-4 hours after taking your pill, or use another birth control method, like condoms and a spermicide, until you check with your healthcare provider. If you are scheduled for any laboratory tests, tell your doctor you are taking birth-control pills. Certain blood tests may be affected by birth-control pills. Tell your healthcare provider about all the medicines you take Drospirenone and ethinyl estradiol tablets may affect the way other medicines work, and other medicines may affect how well drospirenone and ethinyl estradiol tablets work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. What are the Most Serious Risks of Taking Birth Control Pills? Like pregnancy, birth control pills increase the risk of serious blood clots (see following graph), especially in women who have other risk factors, such as smoking, obesity, or age greater than 35. This increased risk is highest when you first start taking birth control pills and when you restart the same or different birth control pills after not using them for a month or more. Women who use birth control pills with drospirenone (like drospirenone and ethinyl estradiol tablets) may have a higher risk of getting a blood clot. Some studies reported that the risk of blood clots was higher for women who use birth control pills that contain drospirenone than for women who use birth control pills that do not contain drospirenone. Talk with your healthcare provider about your risk of getting a blood clot before deciding which birth control pill is right for you. It is possible to die or be permanently disabled from a problem caused by a blood clot, such as a heart attack or a stroke. Some examples of serious clots are blood clots in the: To put the risk of developing a blood clot into perspective: If 10,000 women who are not pregnant and do not use birth control pills are followed for one year, between 1 and 5 of these women will develop a blood clot. The figure below shows the likelihood of developing a serious blood clot for women who are not pregnant and do not use birth control pills, for women who use birth control pills, for pregnant women, and for women in the first 12 weeks after delivering a baby. Likelihood of Developing a Serious Blood Clot A few women who take birth control pills may get: All of these events are uncommon in healthy women. Call your healthcare provider right away if you have: What are the Common Side Effects of Birth Control Pills? The most common side effects of birth control pills are: These side effects are usually mild and usually disappear with time. Less common side effects are: This is not a complete list of possible side effects. Talk to your healthcare provider if you develop any side effects that concern you. You may report side effects to the FDA at 1-800-FDA-1088. No serious problems have been reported from a birth control pill overdose, even when accidentally taken by children. Do Birth Control Pills Cause Cancer? Birth control pills do not seem to cause breast cancer. However, if you have breast cancer now, or have had it in the past, do not use birth control pills because some breast cancers are sensitive to hormones. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. However, this may be due to other reasons such as having more sexual partners. What Should I Know about My Period when Taking Drospirenone and Ethinyl Estradiol Tablets? Irregular vaginal bleeding or spotting may occur while you are taking drospirenone and ethinyl estradiol tablets. Irregular bleeding may vary from slight staining between menstrual periods to breakthrough bleeding, which is a flow much like a regular period. Irregular bleeding occurs most often during the first few months of oral contraceptive use, but may also occur after you have been taking the pill for some time. Such bleeding may be temporary and usually does not indicate any serious problems. It is important to continue taking your pills on schedule. If the bleeding occurs in more than one cycle, is unusually heavy, or lasts for more than a few days, call your healthcare provider. Some women may not have a menstrual period but this should not be cause for alarm as long has you have taken the pills regularly on time. What if I Miss My Scheduled Period when Taking Drospirenone and Ethinyl Estradiol Tablets? It is not uncommon to miss your period. However, if you miss two periods in a row or miss one period when you have not taken your birth control pills regularly on time, call your healthcare provider. Also notify your healthcare provider if you have symptoms of pregnancy such as morning sickness or unusual breast tenderness. It is important that your healthcare provider checks you to find out if you are pregnant. Stop taking drospirenone and ethinyl estradiol tablets if you are pregnant. What if I Want to Become Pregnant? You may stop taking the pill whenever you wish. Consider a visit with your healthcare provider for a pre-pregnancy checkup before you stop taking the pill. General Advice about Drospirenone and Ethinyl Estradiol Tablets Your healthcare provider prescribed drospirenone and ethinyl estradiol tablets for you. Please do not share drospirenone and ethinyl estradiol tablets with anyone else. Keep drospirenone and ethinyl estradiol tablets out of the reach of children. If you have concerns or questions, ask your healthcare provider. You may also ask your healthcare provider for a more detailed label written for medical professionals. Manufactured for: Mylan Pharmaceuticals Inc. Manufactured by: Mylan Laboratories Limited Code No. : GUJ-DRUGS/G/28/1297 75099301 Revised: 9/2023 FC:OT:7300:R9 Figure 4 Figure 5 Blister Figure 6 Likelihood of Developing a Serious Blood Clot.

Mylan Pharmaceuticals Inc.

DROSPIRENONE AND ETHINYL ESTRADIOL- drospirenone and ethinyl estradiol Product manual source documgent