Drospirenone and ethinyl estradiol tablets are an estrogen/progestin COC, indicated for use by women to:
Prevent pregnancy. ( 1.1 )
Treat moderate acne for women at least 14 years old only if the patient desires an oral contraceptive for birth control. ( 1.3 )
1.1Oral Contraceptive Drospirenone
and ethinyl estradiol tablets are indicated for use by women to prevent pregnancy.
1.3Acne Drospirenone
and ethinyl estradiol tablets are indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Drospirenone and ethinyl estradiol tablets should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.
Contraindications
Do not prescribe drospirenone and ethinyl estradiol tablets to women who are known to have the following:
Renal impairment
Adrenal insufficiency
A high risk of arterial or venous thrombotic diseases. Examples include women who are known to:
Smoke, if over age 35 [see Boxed Warning and Warnings and Precautions ( 5.1 )]
Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings and Precautions ( 5.1 )]
Have cerebrovascular disease [see Warnings and Precautions ( 5.1 )]
Have coronary artery disease [see Warnings and Precautions ( 5.1 )]
Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings and Precautions ( 5.1 )]
Have inherited or acquired hypercoagulopathies [see Warnings and Precautions ( 5.1 )]
Have uncontrolled hypertension [see Warnings and Precautions ( 5.6 )]
Two medicines in one question?
Name two or more medicines and Osler runs an interaction check. A severe interaction is stated at the very top of the answer.
Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions ( 5.3 )]
Liver tumors, benign or malignant, or liver disease [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.7 )]
Pregnancy, because there is no reason to use COCs during pregnancy [see Warnings and Precautions ( 5.1 1) and Use in Specific Populations ( 8.1 )]
Use of Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations [see Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7.3 )].
Renal impairment ( 4 )
Adrenal insufficiency ( 4 )
A high risk of arterial or venous thrombotic diseases ( 4 )
Undiagnosed abnormal uterine bleeding ( 4 )
Breast cancer or other estrogen- or progestin-sensitive cancer ( 4 )
Liver tumors or liver disease ( 4 )
Pregnancy ( 4 )
Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir ( 4 )
Warnings and precautions
Vascular risks : Stop drospirenone and ethinyl estradiol tablets if a thrombotic event occurs. Stop at least 4 weeks before and through 2 weeks after major surgery. Start no earlier than 4 weeks after delivery, in women who are not breastfeeding. ( 5.1 ) COCs containing DRSP may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing levonorgestrel or some other progestins. Before initiating drospirenone and ethinyl estradiol tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP-containing COC in light of her risk of a VTE. ( 5.1 )
Hyperkalemia : DRSP has anti-mineralocorticoid activity. Do not use in patients predisposed to hyperkalemia. Check serum potassium concentration during the first treatment cycle in women on long-term treatment with medications that may increase serum potassium concentration. ( 5.2 , 7.1 , 7.2 )
Liver disease : Discontinue drospirenone and ethinyl estradiol tablets if jaundice occurs. ( 5.4 )
High blood pressure : Do not prescribe drospirenone and ethinyl estradiol tablets for women with uncontrolled hypertension or hypertension with vascular disease. ( 5. 6)
Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking drospirenone and ethinyl estradiol tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5. 8)
Headache : Evaluate significant change in headaches and discontinue drospirenone and ethinyl estradiol tablets if indicated. ( 5. 9)
5.1Thromboembolic Disorders and Other Vascular Problems
Stop drospirenone and ethinyl estradiol tablets if an arterial or venous thrombotic (VTE) event occurs. Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, drospirenone and ethinyl estradiol tablets), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins.
Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of drospirenone and ethinyl estradiol tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications ( 4 )] .
A number of studies have compared the risk of VTE for users of drospirenone and ethinyl estradiol tablets (which contains 0.03 mg of EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 1. Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Drospirenone and Ethinyl Estradiol Tablets Compared to Users of Oral Contraceptives that Contain Other Progestins Epidemiologic Study (Author, Year of Publication) Population Studied Comparator Product (all are low-dose COCs; with ≤ 0.04 mg of EE) Hazard Ratio (HR) (95% CI) i3 Ingenix (Seeger 2007) Initiators, including new users All COCs available in the US during the conduct of the study HR: 0.9 (0.5 to 1.6) EURAS (Dinger 2007) Initiators, including new users All COCs available in Europe during the conduct of the study HR: 0.9 (0.6 to 1.4) Levonorgestrel/EE HR: 1.0 (0.6 to 1.8) “FDA-funded study” (2011) New users a Other COCs available during the course of the study HR: 1.8 (1.3 to 2.4) Levonorgestrel/0.03 mg EE HR: 1.6 (1.1 to 2.2) All users (i.e., initiation and continuing use of study combination hormonal contraception) Other COCs available during the course of the study HR: 1.7 (1.4 to 2.1) Levonorgestrel/0.03 mg EE HR: 1.5 (1.2 to 1.8) In addition to these “regulatory studies,” other studies of various designs have been conducted.
Overall, there are two prospective cohort studies (see Table 1): the US post-approval safety study Ingenix [Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study) [Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 1), and two from Denmark [Lidegaard 2009, Lidegaard 2011].
There are two case-control studies: the Dutch MEGA study analysis [van Hylckama Vlieg 2009] and the German case-control study [Dinger 2010]. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011] and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1. Figure 1: VTE Risk with Drospirenone and Ethinyl Estradiol Tablets 3 mg/0.03 mg Relative to LNG-Containing COCs (adjusted risk # ) Risk ratios displayed on logarithmic scale; risk ratio < 1 indicates a lower risk of VTE for DRSP, > 1 indicates an increased risk of VTE for DRSP. *Comparator “Other COCs”, including LNG- containing COCs † LASS is an extension of the EURAS study #Some adjustment factors are indicated by superscript letters: a) Current heavy smoking, b) hypertension, c) obesity, d) family history, e) age, f) BMI, g) duration of use, h) VTE history, i) period of inclusion, j) calendar year, k) education, l) length of use, m) parity, n) chronic disease, o) concomitant medication, p) smoking, q) duration of exposure, r) site (References: Ingenix [Seeger 2007] 1 , EURAS (European Active Surveillance Study) [Dinger 2007] 2 , LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011] 3 , Danish [Lidegaard 2009] 4 , Danish re-analysis [ Lidegaard 2011] 5 , MEGA study [van Hylckama Vlieg 2009] 6 , German Case-Control study [Dinger 2010] 7 , PharMetrics [Jick 2011] 8 , GPRD study [Parkin 2011] 9 ) Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period (see Figure 2).The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years.
The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.
The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued. Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE.
Figure 2: Likelihood of Developing a VTE If feasible, stop drospirenone and ethinyl estradiol tablets at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism. Start drospirenone and ethinyl estradiol tablets no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.
Use
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.
( 7.1 )
7.1Effects of Other Drugs on Combined Oral Contraceptives
Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St.
John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%.
Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.
In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] . Human immunodeficiency virus (HIV)/ Hepatitis C virus (HCV) protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.
Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.
7.2Effects of Combined Oral Contraceptives on Other Drugs
COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.
COCs Increasing the Plasma Concentrations of CYP450 Enzymes : In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.
Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations [see Clinical Pharmacology ( 12.3 ) ]. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Potential to Increase Serum Potassium Concentration : There is a potential for an increase in serum potassium concentration in women taking drospirenone and ethinyl estradiol tablets with other drugs that may increase serum potassium concentration [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] .
7.3Concomitant Use of HCV Combination
Therapy – Liver Enzyme Elevation Do not co-administer drospirenone and ethinyl estradiol tablets with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see Warnings and Precautions (5.5) ] .
7.4Interference with Laboratory Tests
The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity. [See Warnings and Precautions ( 5.1 3) and Drug Interactions ( 7.2 ).]
Pregnancy and breastfeeding
8.1Pregnancy
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.
Adverse reactions
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )]
Vascular events [see Warnings and Precautions ( 5.1 )]
Liver disease [see Warnings and Precautions ( 5.4 )] Adverse reactions commonly reported by COC users are:
Irregular uterine bleeding
Nausea
Breast tenderness
Headache
The most frequent adverse reactions (≥ 2%) in contraception and acne clinical trials were: headache/migraine (6.7%), menstrual irregularities (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4.0%) and mood changes (2.2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888)721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Contraception and Acne Clinical Trials: The data provided reflect the experience with the use of drospirenone and ethinyl estradiol tablets in the adequate and well-controlled studies for contraception (N=1,056) and for moderate acne vulgaris (N=536).
For contraception, a Phase 3, multicenter, multinational, open-label study was conducted to evaluate safety and efficacy up to one year in 1,027 women aged 17 to 36 who took at least one dose of drospirenone and ethinyl estradiol tablets. A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of drospirenone and ethinyl estradiol tablets on carbohydrate metabolism, lipids and hemostasis in 29 women aged 18 to 35.
For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14 to 45 with moderate acne vulgaris who took at least one dose of drospirenone and ethinyl estradiol tablets, evaluated the safety and efficacy during up to 6 cycles. The adverse reactions seen across the 2 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: headache/migraine (6.7%), menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia (4.7%), nausea/vomiting (4.2%), breast pain/tenderness (4%) and mood changes (mood swings, depression, depressed mood and affect lability) (2.2%).
Adverse Reactions (≥1%) Leading to Study Discontinuation: Contraception Clinical Trials Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1%). Acne Clinical Trials Of 536 women, 5.4% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was menstrual irregularities (including menometrorrhagia, menorrhagia, metrorrhagia and vaginal hemorrhage) (2.2%).
Serious Adverse Reactions Contraception Clinical Trials : migraine and cervical dysplasia Acne Clinical Trials: none reported in the clinical trials
6.2Postmarketing Experience
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 are grouped into System Organ Classes, and ordered by frequency. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, cerebral thrombosis, retinal thrombosis, myocardial infarction and stroke), hypertension (including hypertensive crisis) Hepatobiliary disorders: Gallbladder disease, liver function disturbances, liver tumors Immune system disorders: Hypersensitivity (including anaphylactic reaction) Metabolism and nutrition disorders: Hyperkalemia, hypertriglyceridemia, changes in glucose tolerance or effect on peripheral insulin resistance (including diabetes mellitus) Skin and subcutaneous tissue disorders: Chloasma, angioedema, erythema nodosum, erythema multiforme Gastrointestinal disorders: Inflammatory bowel disease Musculoskeletal and connective tissue disorders: Systemic lupus erythematosus
Composition
Active ingredients
DROSPIRENONE 3MG; ETHINYL ESTRADIOL 0.02MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
