drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium
Kit
Uses
Drospirenone, ethinyl estradiol and levomefolate calcium tablet and levomefolate calcium tablet is a combination of drospirenone, a progestin and ethinyl estradiol, an estrogen containing a folate, indicated for use by females of reproductive potential to: Prevent pregnancy. ( 1.1 ) Treat symptoms of premenstrual dysphoric disorder (PMDD) for females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.2 ) Treat moderate acne for females of reproductive potential at least 14 years old only if the patient desires an oral contraceptive for birth control. ( 1.3 ) Raise folate levels in females of reproductive potential who choose to use an oral contraceptive for contraception. ( 1.4 ) 1.1 Oral Contraceptive Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are indicated for use by females of reproductive potential to prevent pregnancy. 1.2 Premenstrual Dysphoric Disorder (PMDD) Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in females of reproductive potential who choose to use an oral contraceptive as their method of contraception. The effectiveness of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets for PMDD when used for more than three menstrual cycles has not been evaluated. The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school, or with usual social activities and relationships with others. Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles. In making the diagnosis, care should be taken to rule out other cyclical mood disorders. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has not been evaluated for the treatment of premenstrual syndrome (PMS). 1.3 Acne Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are indicated for the treatment of moderate acne vulgaris in females of reproductive potential at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. 1.4 Folate Supplementation Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are indicated in females of reproductive potential who choose to use an oral contraceptive as their method of contraception, to raise folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product.
Dosage and administration
Take one tablet daily by mouth at the same time every day. ( 2.1 ) Tablets must be taken in the order directed on the blister. ( 2.1 ) 2.1 How to Take Drospirenone, Ethinyl Estradiol and Levomefolate Calcium Tablets and Levomefolate Calcium Tablets Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. To achieve maximum contraceptive and PMDD effectiveness, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets must be taken as directed, in the order directed on the blister. Single missed pills should be taken as soon as remembered. 2.2 How to Start Drospirenone, Ethinyl Estradiol and Levomefolate Calcium Tablets and Levomefolate Calcium Tablets Instruct the patient to begin taking drospirenone, ethinyl estradiol and levomefolate calcium tablets either on the first day of her menstrual period (Day 1 Start) or on the first Sunday after the onset of her menstrual period (Sunday Start). Day 1 Start During the first cycle of drospirenone, ethinyl estradiol and levomefolate calcium tablets use, instruct the patient to take one pink drospirenone, ethinyl estradiol and levomefolate calcium tablet daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one pink drospirenone, ethinyl estradiol and levomefolate calcium tablet daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets can be taken without regard to meals. If drospirenone, ethinyl estradiol and levomefolate calcium tablet and levomefolate calcium tablet is first taken later than the first day of the menstrual cycle, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. Sunday Start During the first cycle of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets use, instruct the patient to take one pink drospirenone, ethinyl estradiol and levomefolate calcium tablet daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink drospirenone, ethinyl estradiol and levomefolate calcium tablet daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets can be taken without regard to meals. Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should not be considered effective as a contraceptive until after the first 7 consecutive days of product administration. Instruct the patient to use a non-hormonal contraceptive as back-up during the first 7 days. The possibility of ovulation and conception prior to initiation of medication should be considered. The patient should begin her next and all subsequent 28-day regimens of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her pink tablets on the next day after ingestion of the last light orange folate tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets is started later than the day following administration of the last light orange tablet, the patient should use another method of contraception until she has taken a pink drospirenone, ethinyl estradiol and levomefolate calcium tablet daily for seven consecutive days. When Switching from a Different Birth Control Pill When switching from another birth control pill, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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 Method Other than a Birth Control Pill When switching from a transdermal patch or vaginal ring, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be started when the next application would have been due. When switching from an injection, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last pink tablet. If spotting or breakthrough bleeding occurs while taking drospirenone, ethinyl estradiol and levomefolate calcium tablets instruct the patient to continue taking drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets by the regimen described above.
Dosage forms and strengths
Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are available in blister containing 28 tablets packed in a pouch. Such three pouches are packaged in a carton. Each blister contains 28 film-coated, round, biconvex tablets in the following order: 24 pink tablets each containing 3 mg drospirenone (DRSP), 0.02 mg ethinyl estradiol (EE) and 0.451 mg levomefolate calcium 4 light orange tablets each containing 0.451 mg levomefolate calcium Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets consist of 28 film-coated, biconvex tablets in the following order ( 3 ): 24 pink tablets, each containing 3 mg drospirenone (DRSP), 0.02 mg ethinyl estradiol (EE) and 0.451 mg levomefolate calcium 4 light orange tablets, each containing 0.451 mg levomefolate calcium
Contraindications
Drospirenone, ethinyl estradiol and levomefolate calcium tablet and levomefolate calcium tablet is contraindicated in females who are known to have or develop the following conditions: Renal impairment Adrenal insufficiency A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 [see Boxed Warning and Warnings And Precautions ( 5.1 )] Have deep vein thrombosis or pulmonary embolism, now or in the past [see Warnings And Precautions ( 5.1 )] Have cerebrovascular disease [see Warnings And Precautions ( 5.1 )] Have coronary artery disease [see Warnings And Precautions ( 5.1 )] Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see Warnings And Precautions ( 5.1 )] Have inherited or acquired hypercoagulopathies [see Warnings And Precautions ( 5.1 )] Have uncontrolled hypertension [see Warnings And Precautions ( 5.6 )] Have diabetes mellitus with vascular disease [see Warnings And Precautions ( 5.8 )] Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see Warnings And Precautions ( 5.9 )] Undiagnosed abnormal uterine bleeding [see Warnings And Precautions ( 5.10 )] Current diagnosis of, or history of, breast cancer, which may be hormone-sensitive [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 )] Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations [see Warnings And Precautions ( 5.5 ) and Drug Interactions ( 7.3 )]. Renal impairment ( 4 ) Adrenal insufficiency ( 4 ) A high risk of arterial or venous thrombotic diseases ( 4 ) Undiagnosed abnormal uterine bleeding ( 4 ) Breast cancer ( 4 ) Liver tumors or liver disease ( 4 ) Co-administration with Hepatitis C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir ( 4 )
Warnings and precautions
Vascular risks : Stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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. ( 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if jaundice occurs. ( 5.4 ) High blood pressure : Do not prescribe drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets. Consider an alternate contraceptive method for women with uncontrolled dyslipidemia. ( 5.8 ) Headache : Evaluate significant change in headaches and discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if indicated. ( 5.9 ) Uterine bleeding : Evaluate irregular bleeding or amenorrhea. ( 5.10 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, Yasmin ® ), 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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 Yasmin ® (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 2 Table 2: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Yasmin ® 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 "New users" - no use of combination hormonal contraception for at least the prior 6 months All COCs available in the US during the conduct of the study Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate 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 Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone Levonorgestrel/EE HR: 0.9 (0.6 to 1.4) HR: 1.0 (0.6 to 1.8) "FDA-funded study" (2011) New users Other COCs available during the course of the study Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel 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 2): 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 2), 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.
Side effects
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings And Precautions ( 5.1 )] Vascular events [see Warnings And Precautions ( 5.1 )] Liver disease [see Warnings And Precautions ( 5.4 )] The most frequent adverse reactions (≥2%) in contraception, acne and folate clinical trials are headache/migraine (5.9%), menstrual irregularities (4.1%), nausea/vomiting (3.5%) and breast pain/tenderness (3.2%). ( 6.1 ) The most frequent adverse reactions (≥2%) in PMDD clinical trials are menstrual irregularities (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Contraception, Acne and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of YAZ ® (3 mg DRSP/0.02 mg EE), in the adequate and well-controlled studies for contraception (N=1,056), for moderate acne vulgaris (N=536) and folate supplementation (N=379). 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 YAZ ® . A second Phase 3 study was a single center, open-label, active-controlled study to evaluate the effect of 7 28-day cycles of YAZ ® 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 YAZ ® , evaluated the safety and efficacy during up to 6 cycles. For folate supplementation, the primary efficacy study using drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18 to 40 who were treated with drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets or YAZ ® for up to 24 weeks. The adverse reactions seen across the 3 indications overlapped, and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥2% of users) were: headache/migraine (5.9%), menstrual irregularities (including vaginal hemorrhage [primarily spotting], metrorrhagia and menorrhagia) (4.1%), nausea/vomiting (3.5%), and breast pain/tenderness (3.2%). PMDD Clinical Trials Safety data from trials for the indication of PMDD are reported separately due to differences in study design and setting in the OC, Acne and Folate Supplementation studies as compared to the PMDD clinical program. Two (one parallel and one crossover designed) multicenter, double-blind, randomized, placebo-controlled trials for the secondary indication of treating the symptoms of PMDD evaluated safety and efficacy of YAZ ® during up to 3 cycles among 285 women aged 18 to 42, diagnosed with PMDD and who took at least one dose of YAZ ® . Common adverse reactions (≥2% of users) were: menstrual irregularities (including vaginal hemorrhage [primarily spotting] and metrorrhagia) (24.9%), nausea (15.8%), headache (13.0%), breast tenderness (10.5%), fatigue (4.2%), irritability (2.8%), decreased libido (2.8%), increased weight (2.5%), and affect lability (2.1%). Adverse Reactions (≥1%) Leading to Study Discontinuation Contraception Clinical Trials: Of 1,056 women, 6.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were headache/migraine (1.6%) and nausea/vomiting (1.0%). 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%). Folate Clinical Trial: Of 285 women, 4.6% who used drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets or YAZ ® discontinued from the clinical trials due to an adverse reaction; no reaction leading to discontinuation occurred in ≥ 1% of women. PMDD Clinical Trials: Of 285 women, 11.6% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reactions leading to discontinuation were: nausea/vomiting (4.6%), menstrual irregularity (including vaginal hemorrhage, menorrhagia, menstrual disorder, menstruation irregular and metrorrhagia) (4.2%), fatigue (1.8%), breast tenderness (1.4%), depression (1.4%), headache (1.1%), and irritability (1.1%). Serious Adverse Reactions Contraception Clinical Trials: Migraine and cervical dysplasia Acne Clinical Trials: None reported in the clinical trials Folate Supplementation Clinical Trial: Cervix carcinoma stage 0 PMDD Clinical Trials: Cervical dysplasia 6.2 Postmarketing Experience Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 3). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use.
Drug interactions
Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Diminishing the Efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John's wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing the Plasma Concentrations of COCs Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see Warnings And Precautions ( 5.2 ) And Clinical Pharmacology ( 12.3 )]. Human Immunodeficiency Virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. COCs Increasing the Plasma Concentrations of CYP450 Enzymes In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Clinical studies did not indicate an inhibitory potential of DRSP towards human CYP enzymes at clinically relevant concentrations [see And 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets with other drugs that may increase serum potassium concentration [see Warnings And Precautions ( 5.2 ) and And Clinical Pharmacology ( 12.3 )]. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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 )]. 7.4 Effects of Folates on Other Drugs Folates may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs, e.g., antiepileptics (such as phenytoin), methotrexate or pyrimethamine, and may result in a decreased pharmacological effect of the antifolate drug. 7.5 Effects of Other Drugs on Folates Several drugs have been reported to reduce folate concentrations by inhibition of the dihydrofolate reductase enzyme (e.g., methotrexate and sulfasalazine) or by reducing folate absorption (e.g., cholestyramine), or via unknown mechanisms (e.g., antiepileptics such as carbamazepine, phenytoin, phenobarbital, primidone and valproic acid). 7.6 Interference 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.
Use in specific populations
Lactation: Can reduce milk production in breast-feeding females. ( 8.2 ) 8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. Data Human Data A retrospective database study of women in Norway, that included 44,734 pregnancies of which 368 were women who inadvertently took drospirenone/ethinyl estradiol during the first trimester of a pregnancy, found there were no adverse effects on pre-term birth, small for gestational age, or birth weight Z-scores. Post-marketing adverse event data on the use of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population. 8.2 Lactation Risk Summary DRSP is present in human milk. After a single oral administration of 3 mg DRSP/0.03 mg EE tablets, DRSP concentration in breast milk over the 24-h period ranged from 1.4 to 7.0 ng/mL, with a mean ± standard deviation value of 3.7 ± 1.9 ng/mL. The estimated mean infant dose was 0.003 mg/day, which is about 0.1% of maternal dose (see Data). There is limited information on the effects of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets on the breast-fed infant. CHCs can reduce milk production in breast- feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established. When possible, advise the nursing female to use other methods of contraception until she discontinues breast-feeding. [See also Dosage and Administration (2.2)]. Increase in folate concentration in milk is not expected (see Data). The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets and any potential adverse effects on the breast-fed child from drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets or from the underlying maternal condition. Data Human Data An open-label study evaluated the degree of DRSP transfer into milk within 72 hours following a single oral administration of 3 mg DRSP/0.03 mg EE tablets to 6 healthy lactating women who were 1 week to 3 months post-partum. DRSP was present in breast milk with a mean Cmax of 13.5 ng/mL, while the mean Cmax in serum of lactating women was 30.8 ng/mL. The DRSP concentration in breast milk over the 24-hour period following dosing ranged from 1.4 to 7.0 ng/mL, with a mean ± standard deviation value of 3.7 ± 1.9 ng/mL. Based on single dose data, the maximal daily infant dose of DRSP was calculated to be 0.003 mg/day, which represented a mean of 0.1% of the maternal dose. A study in approximately 60 lactating women demonstrated no significant differences in folate concentrations in milk between women who received 416mcg/day [6S]-5-methyltetrahydrofolate or 400 mcg/day folic acid and women who received placebo over a 16 week period. Studies to date indicate there is no adverse effect of folate on nursing infants. 8.4 Pediatric Use Safety and efficacy of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not indicated. 8.5 Geriatric Use Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has not been studied in postmenopausal women and is not indicated in this population. 8.6 Patients with Renal Impairment Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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 )]. 8.7 Patients with Hepatic Impairment Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has not been studied in women with severe hepatic impairment. 8.8 Race No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women [see Clinical Pharmacology ( 12.3 )].
Pregnancy
8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets should be discontinued during pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 percent and 15 to 20 percent, respectively. Data Human Data A retrospective database study of women in Norway, that included 44,734 pregnancies of which 368 were women who inadvertently took drospirenone/ethinyl estradiol during the first trimester of a pregnancy, found there were no adverse effects on pre-term birth, small for gestational age, or birth weight Z-scores. Post-marketing adverse event data on the use of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population.
Pediatric use
8.4 Pediatric Use Safety and efficacy of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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
8.5 Geriatric Use Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets has not been studied in postmenopausal women and is not indicated in this population.
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. Levomefolate calcium doses of 17 mg/day (37-fold higher than the levomefolate calcium dose of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets) were well tolerated after long-term treatment up to 12 weeks.
Description
Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets provide an oral contraceptive regimen consisting of 28 film-coated tablets that contain the active ingredients specified for each tablet below: 24 pink tablets each containing 3 mg DRSP, 0.02 mg EE, and 0.451 mg levomefolate calcium 4 light orange tablets each containing 0.451 mg levomefolate calcium The inactive ingredients in the pink tablets are ascorbic acid, corn starch, croscarmellose sodium, ferric oxide red, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide. The light orange film-coated tablets contain 0.451 mg of levomefolate calcium. The inactive ingredients in the light orange tablets are ascorbic acid, corn starch, croscarmellose sodium, ferric oxide yellow, ferric oxide red, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, pregelatinized starch, talc and titanium dioxide. Drospirenone ((2', S ,6 R ,7 R ,8 R ,9 S ,10 R ,13 S ,14 S ,15 S ,16 S )-1,3',4',6,7,8,9,10,11,12,13,14,15, 16,20,21-Hexadecadydro-10,13-dimethylspirol[17 H -dicyclopropa [6,7:15,16] cyclopenta [a] phenanthrene-17, 2', (5' H )-furan] -3, 5' (2 H ) dione is a synthetic progestational compound and has a molecular weight of 366.49 and a molecular formula of C 24 H 30 O 3 . Ethinyl estradiol 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol is a synthetic estrogenic compound and has a molecular weight of 296.40 and a molecular formula of C 20 H 24 O 2 . Levomefolate calcium N-{4-[[((6S)-2-amino-3,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl) methyl] amino] benzoyl}-L-glutamic acid, calcium salt is a synthetic calcium salt of L-5-methyltetrahydrofolate (L-5-methyl-THF), which is a metabolite of vitamin B 9 and has a molecular weight of 497.5 and a molecular formula of C 20 H 23 CaN 7 O 6 . The structural formulas are as follows: Drospirenone Ethinyl Estradiol Levomefolate Calcium Image Image Image
Mechanism of action
12.1 MECHANISM OF ACTION COCs lower the risk of becoming pregnant primarily by suppressing ovulation.
How supplied
16.1 How Supplied Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are available in 28 tablets blister containing 28 tablets packed in a pouch (NDC 68180-894-71). Such three pouches are packaged in a carton (NDC 68180-894-73). Each blister contains 28 film-coated tablets in the following order: 24 pink, round shaped, biconvex film-coated tablets debossed with "LU" on one side and "J61" on other side each containing 3 mg drospirenone, 0.02 mg ethinyl estradiol and 0.451 mg levomefolate calcium. 4 light orange, round shaped, biconvex film-coated tablets debossed with "LU" on one side and "J62" on other side each containing 0.451 mg levomefolate calcium. 16.2 Storage Store at 25 ° C (77 ° F); excursions permitted to 15 ° to 30 ° C (59 ° to 86 ° F) [See USP Controlled Room Temperature]. 16.1 How Supplied Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are available in 28 tablets blister containing 28 tablets packed in a pouch (NDC 68180-894-71). Such three pouches are packaged in a carton (NDC 68180-894-73). Each blister contains 28 film-coated tablets in the following order: 24 pink, round shaped, biconvex film-coated tablets debossed with "LU" on one side and "J61" on other side each containing 3 mg drospirenone, 0.02 mg ethinyl estradiol and 0.451 mg levomefolate calcium. 4 light orange, round shaped, biconvex film-coated tablets debossed with "LU" on one side and "J62" on other side each containing 0.451 mg levomefolate calcium.
Patient information
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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets does not protect against HIV-infection (AIDS) and other sexually transmitted diseases. Counsel patients on Warnings and Precautions associated with COCs. Counsel patients that drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets contains 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are not indicated during pregnancy. If pregnancy occurs during treatment with drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets, instruct the patient to stop further intake. However, women should be advised on the continued need of sufficient folate 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. 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 pink 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. Counsel patients to report whether they are taking folate supplements. drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets contains the equivalent of 0.4mg (400 mcg) of folic acid. Counsel patients to maintain folate supplementation if they discontinue drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets due to pregnancy. ®The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Distributed by: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited Pithampur (M.P.) - 454 775 India Revised: December 2024 IMAGE trade mark
Label text from the FDA structured product label by Lupin Pharmaceuticals, Inc. (revised Dec 8, 2025). Long sections are shortened; the complete label is on DailyMed.
drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 68180-894 | Kit | Lupin Pharmaceuticals, Inc. | ANDA |
Frequently asked questions
What is drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium used for?
Drospirenone, ethinyl estradiol and levomefolate calcium tablet and levomefolate calcium tablet is a combination of drospirenone, a progestin and ethinyl estradiol, an estrogen containing a folate, indicated for use by females of reproductive potential to: Prevent pregnancy. ( 1.1 ) Treat symptoms of premenstrual dysphoric disorder (PMDD) for females of reproductive potential who choose to use an…
What are the side effects of drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium?
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see Boxed Warning and Warnings And Precautions ( 5.1 )] Vascular events [see Warnings And Precautions ( 5.1 )] Liver disease [see Warnings And Precautions ( 5.4 )] The most frequent adverse reactions (≥2%) in contraception, acne and folate clinical trials… See the full label for the complete list.
Who makes drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium?
drospirenone, ethinyl estradiol and levomefolate calcium and levomefolate calcium is listed by 1 labeler in the FDA NDC directory, including Lupin Pharmaceuticals, Inc..