Data from FDA - Curated by Toby Galbraith - Last updated 10 October 2017

Indication(s)

1 INDICATIONS AND USAGE Safyral is an estrogen/progestin COC containing a folate, indicated for use by women to: •Prevent pregnancy. (1.1) •Raise folate levels in women who choose to use an oral contraceptive for contraception. (1.2) 1.1 Oral Contraceptive Safyral is indicated for use by women to prevent pregnancy. 1.2 Folate Supplementation Safyral is indicated in women 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS Do not prescribe Safyral 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 )] •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 )] •Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see Warnings and Precautions (5.3)] •Liver tumor (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 ( 5.11 ) 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 (5.5) 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 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)
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)] Adverse reactions commonly reported by COC users are: •Irregular uterine bleeding •Nausea •Breast tenderness •Headache •The most frequent adverse reactions (≥ 2%) in contraception and folate clinical trials are premenstrual syndrome (12.4%), headache /migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (2.3%) and abdominal pain/tenderness/discomfort (2.2%). (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 and Folate Supplementation Clinical Trials The data provided reflect the experience with the use of Yasmin (3 mg DRSP/0.03 mg EE) in the adequate and well-controlled studies for contraception (N=2,837) and folate supplementation (N=172). For contraception, the US pivotal clinical study (N=326) for the oral contraception indication for Yasmin was a multicenter, open-label trial in healthy women aged 18–35 who were treated with Yasmin for up to 13 cycles. The second contraceptive pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of Yasmin vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17–40 who were treated for up to 26 cycles. The primary efficacy study using Safyral for folate supplementation was a randomized, single-center European trial in 172 healthy, female subjects aged 18–40 years comparing the pharmacodynamic effects of Yasmin + 0.451 mg levomefolate calcium to Yasmin co-administered with folic acid during 24 weeks of treatment followed by 20 weeks of open-label Yasmin. 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: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%), and abdominal pain/discomfort/tenderness (2.2%). Adverse Reactions (≥1%) Leading to Study Discontinuation Contraception Clinical Trials Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%). Folate Clinical Trial There were no subjects who discontinued due to an adverse reaction. Serious Adverse Reactions: Contraception Clinical Trials: depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma. Folate Supplementation Clinical Trial: none reported in the clinical trial 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Yasmin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions, including fatalities, are grouped into System Organ Classes and ordered by frequency. Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension Hepatobiliary disorders: Gallbladder disease Immune system disorders: Hypersensitivity Metabolism and nutrition disorders: Hyperkalemia Skin and subcutaneous tissue disorders: Chloasma

Usage information

Dosing 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 Safyral Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly. To achieve maximum contraceptive effectiveness, Safyral 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 Safyral Instruct the patient to begin taking Safyral 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 Safyral use, instruct the patient to take one orange Safyral daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one orange Safyral daily for 21 consecutive days, followed by one light orange tablet, containing levomefolate alone, daily on Days 22 through 28. Safyral 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. Safyral can be taken without regard to meals. If Safyral is first taken later than the first day of the menstrual cycle, Safyral 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 Safyral use, instruct the patient to take one orange Safyral daily, beginning on the first Sunday after the onset of her menstrual period. She should take one orange Safyral daily for 21 consecutive days, followed by one light orange tablet, containing levomefolate alone, daily on Days 22 through 28. Safyral 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. Safyral can be taken without regard to meals. Safyral 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 Safyral on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her orange 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 Safyral 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 an orange Safyral daily for seven consecutive days. When switching from a different birth control pill When switching from another birth control pill, Safyral 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, Safyral should be started when the next application would have been due. When switching from an injection, Safyral should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, Safyral should be started on the day of removal. Withdrawal bleeding usually occurs within 3 days following the last orange tablet. If spotting or breakthrough bleeding occurs while taking Safyral, instruct the patient to continue taking Safyral by the regimen described above. Counsel her that this type of bleeding is usually transient and without significance; however, advise her that if the bleeding is persistent or prolonged, she should consult her healthcare provider. Although the occurrence of pregnancy is low if Safyral is taken according to directions, if withdrawal bleeding does not occur, consider the possibility of pregnancy. If the patient has not adhered to the prescribed dosing schedule (missed one or more active tablets or started taking them on a day later than she should have), consider the possibility of pregnancy at the time of the first missed period and take appropriate diagnostic measures. If the patient has adhered to the prescribed regimen and misses two consecutive periods, rule out pregnancy. Discontinue Safyral if pregnancy is confirmed. The risk of pregnancy increases with each active orange tablet missed. For additional patient instructions regarding missed pills, see the “WHAT TO DO IF YOU MISS PILLS” section in the FDA-Approved Patient Labeling. If breakthrough bleeding occurs following missed tablets, it will usually be transient and of no consequence. If the patient misses one or more light orange tablets, she should still be protected against pregnancy provided she begins taking a new cycle of orange tablets on the proper day. For postpartum women who do not breastfeed or after a second trimester abortion, start Safyral no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts Safyral postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Safyral for 7 consecutive days. 2.3 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, this can be regarded as a missed tablet. 2.4 Folate Supplementation The U.S. Preventive Services Task Force recommends that women of childbearing age consume supplemental folic acid in a dose of at least 0.4 mg (400 mcg) daily.1 Consider other folate supplementation that a woman may be taking before prescribing Safyral. Ensure that folate supplementation is maintained if a woman discontinues Safyral due to pregnancy.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Nursing mothers: Not recommended; can decrease milk production. (8.3) 8.1 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. 8.3 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 3 mg DRSP/0.03 mg EE tablets (Yasmin), 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. Studies to date indicate there is no adverse effect of folate on nursing infants. 8.4 Pediatric Use Safety and efficacy of Safyral 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 Safyral has not been studied in postmenopausal women and is not indicated in this population. 8.6 Patients with Renal Impairment Safyral is contraindicated in patients with renal impairment [see Contraindications (4) and Warnings and Precautions (5.2)]. In subjects with creatinine clearance (CLcr) of 50–79 mL/min, serum DRSP concentrations were comparable to those in a control group with CLcr ≥ 80 mL/min. In subjects with CLcr of 30–49 mL/min, serum DRSP concentrations were on average 37% higher than those in the control group. In addition, there is a potential to develop hyperkalemia in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium-sparing drugs [see Clinical Pharmacology (12.3)]. 8.7 Patients with Hepatic Impairment Safyral is 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. Safyral 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 and lactation
8.3 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 3 mg DRSP/0.03 mg EE tablets (Yasmin), 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. Studies to date indicate there is no adverse effect of folate on nursing infants.

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 with 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 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 Safyral with other drugs that may increase serum potassium concentration [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. 7.3 Concomitant Use with HCV Combination Therapy – Liver Enzyme Elevation Do not co-administer Safyral 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. Folates may mask vitamin B12 deficiency. [See Warnings and Precautions ( 5.13 ) and Drug Interactions (7.2).]

More information

Category Value
Authorisation number NDA022574
Orphan designation No
Product NDC 50419-403
Date Last Revised 08-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1050494
Marketing authorisation holder Bayer HealthCare Pharmaceuticals Inc.
Warnings 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 Safyral. (4) • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. (4)