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Drospirenone/Ethinyl Estradiol/Levomefolate Calcium And Levomefolate Calcium
FDA Drug Information • Also known as: Beyaz, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium And Levomefolate Calcium, Safyral
- Brand Names
- Beyaz, Drospirenone/Ethinyl Estradiol/Levomefolate Calcium And Levomefolate Calcium, Safyral
- Dosage Form
- KIT
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke [see Contraindications ( 4 )] . WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning.
Women over 35 years old who smoke should not use Beyaz. ( 4 ) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. ( 4 ) WARNING TO WOMEN WHO SMOKE Do not use Beyaz if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects (heart and blood vessel problems) from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke.Description
11 DESCRIPTION Beyaz (drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets) provides 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 as betadex clathrate, 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 lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose NF, magnesium stearate NF, hypromellose USP, titanium dioxide USP, talc USP, polyethylene glycol NF, ferric oxide pigment, red NF. The light orange film-coated tablets contain 0.451 mg of levomefolate calcium. The inactive ingredients in the light orange tablets are lactose monohydrate NF, microcrystalline cellulose NF, croscarmellose sodium NF, hydroxypropyl cellulose NF, magnesium stearate NF, hypromellose USP, titanium dioxide USP talc USP, polyethylene glycol NF, ferric oxide pigment, red NF, ferric oxide pigment, yellow NF. Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3',4',6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa- [6,7:15,16] cyclopenta[a]phenanthrene-17,2'(5H)-furan]-3,5'(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C 24 H 30 O 3 . Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C 20 H 24 O 2 . Levomefolate calcium (N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-(6S)-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....What Is Drospirenone/Ethinyl Estradiol/Levomefolate Calcium And Levomefolate Calcium Used For?
1 INDICATIONS AND USAGE Beyaz 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 Beyaz ® is indicated for use by females of reproductive potential to prevent pregnancy. 1.2 Premenstrual Dysphoric Disorder (PMDD) Beyaz is 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 Beyaz 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. Beyaz has not been evaluated for the treatment of premenstrual syndrome (PMS). 1.3 Acne Beyaz is 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. Beyaz should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control. 1.4 Folate Supplementation Beyaz is 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
2 DOSAGE AND ADMINISTRATION
Take one tablet daily by mouth at the same time every day. ( 2.1 ) Tablets must be taken in the order directed on the blister pack. ( 2.1 ) 2.1 How to Take Beyaz 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, Beyaz must be taken as directed, in the order directed on the blister pack. Single missed pills should be taken as soon as remembered. 2.2 How to Start Beyaz Instruct the patient to begin taking Beyaz 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 Beyaz use, instruct the patient to take one pink Beyaz daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one pink Beyaz daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Beyaz 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. Beyaz can be taken without regard to meals. If Beyaz is first taken later than the first day of the menstrual cycle, Beyaz 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 Beyaz use, instruct the patient to take one pink Beyaz daily, beginning on the first Sunday after the onset of her menstrual period. She should take one pink Beyaz daily for 24 consecutive days, followed by one light orange tablet daily on Days 25 through 28. Beyaz 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. Beyaz can be taken without regard to meals. Beyaz 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 Beyaz 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 Beyaz is started later than the day following administration of the last light orange tablet, the patient should use another method of...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vascular events [see Warnings and Precautions ( 5.1 )] Liver disease [see Warnings and Precautions ( 5.4 )] 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 Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 17–36 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 18–35. For acne, two multicenter, double-blind, randomized, placebo-controlled studies, in 536 women aged 14–45 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 Beyaz was a multicenter, double-blind, randomized, active-controlled US trial in 379 healthy women aged 18–40 who were treated with Beyaz 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 18–42, 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%...Drug Interactions
7 DRUG INTERACTIONS Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations .
Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. ( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St. John’s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. The exposure of EE was increased mildly [see 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...Contraindications
4 CONTRAINDICATIONS Beyaz 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...Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There is no use for contraception in pregnancy; therefore, Beyaz 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 Beyaz in pregnant women suggest that frequencies of miscarriage and congenital anomalies were not higher than the estimated background risk in the general population.
Overdosage
10 OVERDOSAGE There have been no reports of serious ill effects from overdose, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. DRSP is a spironolactone analogue which has anti-mineralocorticoid properties. Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose. Levomefolate calcium doses of 17 mg/day (37-fold higher than the levomefolate calcium dose of Beyaz) were well tolerated after long-term treatment up to 12 weeks.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Beyaz (drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets) are available in packages of three blister packs (NDC 50419-407-03). The film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with Z+ or M+. Each blister pack (28 film-coated tablets) contains in the following order:
24 round, biconvex, pink, film-coated tablets with embossed “Z+” in a regular hexagon on one side each containing 3 mg drospirenone, 0.02 mg ethinyl estradiol, and 0.451 mg levomefolate calcium 4 round, biconvex, light orange, film-coated tablets with embossed “M+” in a regular hexagon on one side each containing 0.451 mg levomefolate calcium 16.2 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.