Drospirenone and ethinyl estradiol

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.

Pharmacodynamics

Drospirenone is a spironolactone analogue with anti-mineralocorticoid activity. The estrogen in Yasmin is ethinyl estradiol (EE).

No specific pharmacodynamic studies were conducted with Yasmin.

Pharmacokinetics

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 Yasmin, 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 Yasmin.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of Yasmin, steady state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24h) values of DRSP following multiple dose administration of Yasmin (see Table 2).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of Yasmin serum Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table 2).

Table 2: Mean Pharmacokinetic Parameters of Yasmin (DRSP 3 mg and EE 0.03 mg)

DRSP Mean (%CV) Values
Cycle /Day	No. of Subjects	Cmax (ng/mL)	Tmax(h)	AUC(0-24h) (ng•h/mL)	t½(h)
1/1	12	36.9 (13)	1.7 (47)	288 (25)	NA
1/21	12	87.5 (59)	1.7 (20)	827 (23)	30.9 (44)
6/21	12	84.2 (19)	1.8 (19)	930(19)	32.5 (38)
9/21	12	81.3 (19)	1.6 (38)	957 (23)	31.4 (39)
13/21	12	78.7 (18)	1.6 (26)	968 (24)	31.1 (36)
EE Mean (%CV) Values
Cycle /Day	No. of Subjects	C max (pg/mL)	Tmax(h)	AUC(0-24h) (pg•h/mL)	t½(h)
1/1	11	53.5 (43)	1.9 (45)	280 (87)	NA
1/21	11	92.1 (35)	1.5 (40)	461 (94)	NA
6/21	11	99.1 (45)	1.5 (47)	346 (74)	NA
9/21	11	87 (43)	1.5 (42)	485 (92)	NA
13/21	10	90.5 (45)	1.6 (38)	469 (83)	NA
NA – Not available

Food Effect

The rate of absorption of DRSP and EE following single administration of a formulation similar to Yasmin was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.

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: Safety and efficacy of Yasmin 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.

Geriatric Use: Yasmin has not been studied in postmenopausal women and is not indicated in this population.

Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 25-35) when 3 mg DRSP/0.02 mg EE was administered daily for 21 days. Other ethnic groups have not been specifically studied.

Renal Impairment: Yasmin is contraindicated in patients with 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 0.33 mEq/L. [See CONTRAINDICATIONSand WARNINGS AND PRECAUTIONS]

Hepatic Impairment: Yasmin is contraindicated in patients with hepatic disease.

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. Yasmin has not been studied in women with severe hepatic impairment. [See CONTRAINDICATIONS  and WARNINGS AND PRECAUTIONS]

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(0-24h) 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 Cmax 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].

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 Yasmin with other drugs that may increase serum potassium concentration [see WARNINGS AND PRECAUTIONS].

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 Cmax 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).

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.

Do not use birth control pills if you are pregnant or if you have recently had a baby.

You should not take birth control pills if you have any of the following conditions: uncontrolled high blood pressure, heart disease, a blood-clotting disorder, circulation problems, diabetic problems with your eyes or kidneys, unusual vaginal bleeding, liver disease or liver cancer, severe migraine headaches, if you smoke and are over 35, or if you have ever had breast or uterine cancer, jaundice caused by birth control pills, a heart attack, a stroke, or a blood clot.

Smoking can increase your risk of blood clots, stroke, or heart attack caused by birth control pills, especially if you are older than 35. Drospirenone may be more likely to cause blood clots than other types of birth control pills.

You may need to use back up birth control, such as condoms or a spermicide, when you first start using this medication or if you miss a dose. Follow your doctor's instructions.

Missing a pill increases your risk of becoming pregnant. Carefully follow the "missed dose" instructions if you forget to take your birth control pills.

Some drugs can make birth control pills less effective in preventing pregnancy, including antibiotics, hepatitis C medications, HIV/AIDS medications, seizure medications, or barbiturate sedatives. Tell your doctor about all other medications you use.

Follow the patient instructions provided with your medicine. Ask your doctor or pharmacist if you do not understand these instructions. Missing a pill increases your risk of becoming pregnant.

If you miss one active pill, take two pills on the day that you remember. Then take one pill per day for the rest of the pack.

If you miss two active pills in a row in Week 1 or 2, take two pills per day for two days in a row. Then take one pill per day for the rest of the pack. Use back-up birth control for at least 7 days following the missed pills.

If you miss two active pills in a row in Week 3, throw out the rest of the pack and start a new pack the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that day.

If you miss three active pills in a row in Week 1, 2, or 3, throw out the rest of the pack and start a new pack on the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new pack that day.

If you miss two or more pills, you may not have a period during the month. If you miss a period for two months in a row, call your doctor because you might be pregnant.

If you miss a reminder pill, throw it away and keep taking one reminder pill per day until the pack is empty. You do not need back-up birth control if you miss a reminder pill.

In the U.S.

• Gianvi
• Loryna
• Nikki
• Ocella
• Syeda
• Vestura
• Yasmin
• YAZ
• Yaz 28
• Zarah

Available Dosage Forms:

• Tablet

Therapeutic Class: Monophasic Contraceptive Combination

Pharmacologic Class: Progestin

To make using oral contraceptives as safe and reliable as possible, you should understand how and when to take them and what effects may be expected.

drospirenone and ethinyl estradiol comes with patient instructions. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions.

drospirenone and ethinyl estradiol is available in blister packs. Each blister pack contains 28 tablets with different colors that need to be taken in the same order as directed on the blister pack.

When you begin using drospirenone and ethinyl estradiol, your body will require at least 7 days to adjust before a pregnancy will be prevented. Use a second form of contraception, such as a condom, spermicide, or diaphragm, for the first 7 days of your first cycle of pills.

Take drospirenone and ethinyl estradiol at the same time each day, after the evening meal or at bedtime. You may take drospirenone and ethinyl estradiol with or without food.

Do not skip or delay taking your pill by more than 24 hours. If you miss a dose, you could get pregnant. Ask your doctor for ways to help you remember to take your pills or about using another method of birth control.

You may have light bleeding or spotting when you first take the pill.

You may feel sick or nauseous, especially during the first few months that you take drospirenone and ethinyl estradiol. If your nausea is continuous and does not go away, call your doctor.

If you vomit or have diarrhea within 3 to 4 hours of taking drospirenone and ethinyl estradiol, follow the instructions in the patient leaflet or call your doctor.

If you are switching from a combination hormonal method (e.g., another pill, patch, vaginal ring) to using Yasmin® or Yaz®, take drospirenone and ethinyl estradiol on the first day of your period. If you do not start your period, see your doctor for a pregnancy test. If you have used a vaginal ring or patch, take the pill on the day the ring or patch is removed. You must also use a second method of birth control (e.g., condom, diaphragm, spermicide) for the first 7 days you take drospirenone and ethinyl estradiol.

If you are switching from a progestin-only method (e.g., progestin-only pill, implant, injection, intrauterine system) to using Yasmin® or Yaz®, take the medicine on the day you would have taken your next progestin-only pill, or on the day your implant or IUD is removed, or on the day you would have your next injection. You must also use a second method of birth control (e.g., condom, diaphragm, spermicide) for the first 7 days you take drospirenone and ethinyl estradiol.

Dosing

The dose of drospirenone and ethinyl estradiol will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of drospirenone and ethinyl estradiol. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Your doctor may ask you to begin your dose on the first day of your menstrual period (called Day 1 start) or on the first Sunday after your menstrual period starts (called Sunday start). When you begin on a certain day it is important that you follow that schedule, even if you miss a dose. Do not change your schedule on your own. If the schedule that you use is not convenient, check with your doctor about changing it. For a Sunday start, you need to use another form of birth control (e.g., condom, diaphragm, spermicide) for the first 7 days.

You should begin your next and all subsequent 28-day regimens of therapy on the same day of the week as the first regimen began and follow the same schedule.

• For oral dosage form (tablets):
  • For contraception (to prevent pregnancy), PMDD, or acne:
    • Adults and teenagers—
      • Yasmin®: One yellow tablet taken at the same time each day for 21 consecutive days followed by one white (inert) tablet daily for 7 days per menstrual cycle.
      • Yaz®: One pink tablet taken at the same time each day for 24 consecutive days followed by one white (inert) tablet daily for 4 days per menstrual cycle.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

Call your doctor or pharmacist for instructions.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits to make sure drospirenone and ethinyl estradiol is working properly and does not cause unwanted effects. These visits will usually be every 6 to 12 months, but some doctors require them more often. Your doctor may also want to check your blood pressure while taking drospirenone and ethinyl estradiol.

Although you are using drospirenone and ethinyl estradiol to prevent pregnancy, you should know that using drospirenone and ethinyl estradiol while you are pregnant could harm the unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away. Make sure your doctor knows if you have had a baby within 4 weeks before you start using drospirenone and ethinyl estradiol.

Vaginal bleeding of various amounts may occur between your regular menstrual periods during the first 3 months of use. This is sometimes called spotting when slight, or breakthrough bleeding when heavier.

• If this should occur, continue with your regular dosing schedule.
• The bleeding usually stops within 1 week. Check with your doctor if the bleeding continues for more than 1 week.
• If the bleeding continues after you have been taking hormonal contraceptives on schedule and for more than 3 months, check with your doctor.

Check with your doctor right away if you miss a menstrual period. Missed periods may occur if you skip one or more tablets and have not taken your pills exactly as directed. If you miss two periods in a row, talk to your doctor. You might need a pregnancy test.

If you suspect that you may be pregnant, stop taking drospirenone and ethinyl estradiol immediately and check with your doctor.

Do not use drospirenone and ethinyl estradiol if you smoke cigarettes or if you are over 35 years of age. If you smoke while using birth control pills containing drospirenone, you increase your risk of having a blood clot, heart attack, or stroke. Your risk is even higher if you are over age 35, if you have diabetes, high blood pressure, high cholesterol, or if you are overweight. Talk with your doctor about ways to stop smoking. Keep your diabetes under control. Ask your doctor about diet and exercise to control your weight and blood cholesterol level.

Using drospirenone and ethinyl estradiol may increase your risk of having blood clotting problems, especially in the first 6 months of use. This risk may be higher if you are using a birth control pill containing drospirenone and ethinyl estradiol. Stop using drospirenone and ethinyl estradiol and check with your doctor right away if you have pain in the chest, groin, or legs, especially the calves, difficulty with breathing, a sudden, severe headache, slurred speech, a sudden, unexplained shortness of breath, a sudden loss of coordination, or vision changes while using drospirenone and ethinyl estradiol.

Check with your doctor immediately if you wear contact lenses or if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want an eye doctor to check your eyes.

Stop using drospirenone and ethinyl estradiol and check with your doctor right away if you have pain or tenderness in the upper stomach, dark urine or pale stools, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Check with your doctor before refilling an old prescription, especially after a pregnancy. You will need another physical examination and your doctor may change your prescription.

Make sure any doctor or dentist who treats you knows that you are using drospirenone and ethinyl estradiol. The results of some medical tests may be affected by drospirenone and ethinyl estradiol. You may also need to stop using drospirenone and ethinyl estradiol at least 4 weeks before and 2 weeks after having major surgery.

drospirenone and ethinyl estradiol may cause skin discoloration. Use a sunscreen when you are outdoors. Avoid sunlamps and tanning beds.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's wort) or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Breast pain or tenderness
• headache, severe and throbbing
• heavy non-menstrual vaginal bleeding
• irregular menstrual periods
• nausea
• normal menstrual bleeding occurring earlier, possibly lasting longer than expected

Less common

• Longer or heavier menstrual periods
• unusual tiredness or weakness
• vomiting

Incidence not known

• Abdominal or stomach pain
• chills
• clay-colored stools
• dark urine
• difficulty with breathing
• dizziness
• fever
• headache
• itching
• loss of appetite
• pain in the chest, groin, or legs, especially the calves
• rash
• slurred speech
• sudden loss of coordination
• sudden, severe weakness or numbness in the arm or leg
• sudden, unexplained shortness of breath
• unpleasant breath odor
• unusual tiredness or weakness
• vision changes
• vomiting of blood
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Crying
• decreased interest in sexual intercourse
• delusions of persecution, mistrust, suspiciousness, and/or combativeness
• false or unusual sense of well-being
• inability to have or keep an erection
• irritability
• loss in sexual ability, desire, drive, or performance
• mental depression
• quick to react or overreact emotionally
• rapidly changing moods
• weight gain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early 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 low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than four weeks postpartum.

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 tablets, 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.

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.

Geriatric Use

Drospirenone and Ethinyl Estradiol tablets have not been studied in postmenopausal women and are not indicated in this population.

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 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)].

Patients with Hepatic Impairment

Drospirenone and Ethinyl Estradiol tablets are contraindicated in patients with hepatic disease [see Contraindications (4) and Warnings and Precautions (5.4)]. 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.

Race

No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see Clinical Pharmacology (12.3)].

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.

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.

Pharmacodynamics

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.

Pharmacokinetics

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 to 2 hours after administration of Drospirenone and Ethinyl Estradiol tablets.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 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 Cmax and AUC (0-24h) values of DRSP following multiple dose administration of Drospirenone and Ethinyl Estradiol tablets (see Table 2).

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 Cmax and AUC (0-24h) values of EE accumulate by a factor of about 1.5 to 2 (see Table 2).

Table 2: Mean Pharmacokinetic Parameters of Drospirenone and Ethinyl Estradiol Tablets (DRSP 3 mg and EE 0.03 mg )

DRSP Mean (%CV) Values
Cycle / Day	No. of Subjects	Cmax (ng/mL)	Tmax (h)	AUC(0–24h) (ng•h/mL)	t1/2 (h)
1/1	12	36.9 (13)	1.7 (47)	288 (25)	NA
1/21	12	87.5 (59)	1.7 (20)	827 (23)	30.9 (44)
6/21	12	84.2 (19)	1.8 (19)	930 (19)	32.5 (38)
9/21	12	81.3 (19)	1.6 (38)	957 (23)	31.4 (39)
13/21	12	78.7 (18)	1.6 (26)	968 (24)	31.1 (36)
EE Mean (%CV) Values
Cycle / Day	No. of Subjects	Cmax (pg/mL)	Tmax (h)	AUC(0–24h) (pg•h/mL)	t1/2 (h)
1/1	11	53.5 (43)	1.9 (45)	280 (87)	NA
1/21	11	92.1 (35)	1.5 (40)	461 (94)	NA
6/21	11	99.1 (45)	1.5 (47)	346 (74)	NA
9/21	11	87 (43)	1.5 (42)	485 (92)	NA
13/21	10	90.5 (45)	1.6 (38)	469 (83)	NA

NA - Not available

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 Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about 20% under fed conditions.

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 to 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 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 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: 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.

Geriatric Use: Drospirenone and Ethinyl Estradiol tablets have not been studied in postmenopausal women and are not indicated in this population.

Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 25 to 35) when 3 mg DRSP/0.02 mg EE was administered daily for 21 days. Other ethnic groups have not been specifically studied.

Renal Impairment: Drospirenone and Ethinyl Estradiol tablets are contraindicated in patients with 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 to 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 to 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 to 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 0.33 mEq/L. [See Contraindications (4) and Warnings and Precautions (5.2).]

Hepatic Impairment: Drospirenone and Ethinyl Estradiol tablets are contraindicated in patients with hepatic disease.

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. [See Contraindications (4) and Warnings and Precautions (5.4).]

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: 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 inhibitors 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 Cmax 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 Cmax 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).

1. Seeger, J.D., Loughlin, J., Eng, P.M., Clifford, C.R., Cutone, J., and Walker, A.M. (2007). Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 110, 587-593. 2. Dinger, J.C., Heinemann, L.A., and Kuhl-Habich, D. (2007). The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 75, 344-354. 3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011. 4. Lidegaard, O., Lokkegaard, E., Svendsen, A.L., and Agger, C. (2009). Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 339, b2890. 5. Lidegaard, O., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E., and Lokkegaard, E. (2011). Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423. 6. van Hylckama Vlieg, A., Helmerhorst, F.M., Vandenbroucke, J.P., Doggen, C.J., and Rosendaal, F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339, b2921. 7. Dinger, J., Assmann, A., Mohner, S., and Minh, T.D. (2010). Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care 36, 123-129. 8. Jick, S.S., and Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 342, d2151. 9. Parkin, L., Sharples, K., Hernandez, R.K., and Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 342, d2139.

How Supplied

Drospirenone and Ethinyl Estradiol Tablets USP, 3 mg/ 0.03 mg are available in packages of three blister packs (NDC 68462-733-29).

The film-coated tablets are round and biconvex, one side is debossed with E5 or E6.

Each blister pack contains 28 film-coated tablets in the following order:

• 21 round, biconvex, light yellow to yellow, film-coated tablets debossed with “E5” on one side, each containing 3 mg drospirenone, USP and 0.03 mg ethinyl estradiol, USP • 7 round, biconvex, white to off-white, film-coated tablets debossed with “E6” on one side.

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs. • Counsel patients that the increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. • Counsel patients about the information regarding the risk of VTE with DRSP-containing COCs compared to COCs that contain levonorgestrel or some other progestins. • Counsel patients that Drospirenone and Ethinyl Estradiol tablets do not protect against HIV infection (AIDS) and other sexually transmitted diseases. • Counsel patients on Warnings and Precautions associated with COCs. • Counsel patients that Drospirenone and Ethinyl Estradiol tablets contain DRSP. Drospirenone may increase potassium. Patients should be advised to inform their healthcare provider if they have kidney, liver or adrenal disease because the use of Drospirenone and Ethinyl Estradiol tablets in the presence of these conditions could cause serious heart and health problems. They should also inform their healthcare provider if they are currently on daily, long-term treatment (NSAIDs, potassium-sparing diuretics, potassium supplementation, ACE inhibitors, angiotensin-II receptor antagonists, heparin or aldosterone antagonists) for a chronic condition or taking strong CYP3A4 inhibitors. • Inform patients that Drospirenone and Ethinyl Estradiol tablets are not indicated during pregnancy. If pregnancy occurs during treatment with Drospirenone and Ethinyl Estradiol tablets, instruct the patient to stop further intake. • Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. See “What to Do if You Miss Pills” section in FDA-Approved Patient Labeling. • Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. • Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. • Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a light yellow to yellow tablet for 7 consecutive days. • Counsel patients that amenorrhea may occur. Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.

Manufactured by:

Glenmark Pharmaceuticals Ltd.

Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888)721-7115

www.glenmarkpharma.com/usa

September 2017