Safyral

Name: Safyral

What should I discuss with my healthcare provider before taking this medicine?

Smoking can increase your risk of blood clots, stroke, or heart attack while taking birth control pills, especially if you are older than 35 years of age. Your risk increases the more you smoke. You should not take birth control pills if you smoke and are older than 35 years of age.

Do not use birth control pills if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you recently had a baby, wait at least 4 weeks before taking this medicine.

You should not take this medicine if you have:

  • heart disease (coronary artery disease, uncontrolled heart valve disorder, history of heart attack or stroke);

  • a history of blood clots;

  • untreated or uncontrolled high blood pressure;

  • a blood-clotting disorder or circulation problems;

  • kidney disease;

  • an adrenal gland disorder;

  • problems with your eyes, kidneys, or circulation caused by diabetes;

  • liver disease or liver cancer;

  • severe migraine headaches (with aura, numbness, weakness, or vision changes);

  • abnormal vaginal bleeding that has not been checked by a doctor; or

  • a history of hormone-related cancer such as breast or uterine cancer.

To make sure this medicine is safe for you, tell your doctor if you have:

  • high levels of potassium in your blood;

  • high cholesterol or triglycerides, or if you are overweight;

  • underactive thyroid, diabetes, gallbladder disease; or

  • a history of jaundice caused by pregnancy or birth control pills.

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medicine may also slow breast milk production. Do not use if you are breast feeding.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Safyral (ethinyl estradiol, drospirenone, and levomefolate) or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Safyral. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Warnings and Precautions

Thromboembolic Disorders and Other Vascular Problems

Stop Safyral 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 Safyral 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 1.

Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Yasmin Compared to Users of Oral Contraceptives that Contain Other Progestins
* "New users" - no use of combination hormonal contraception for at least the prior 6 months † Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate ‡ Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone § Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel

Epidemiologic Study
(Author, Year of Publication)
Population Studied

Comparator Product
(all are low-dose COCs; with ≤ 0.04 mg of EE)

Hazard Ratio (HR)
(95% CI)

i3 Ingenix
(Seeger 2007) Initiators, including new users*

All COCs available in the US
during the conduct of the study†

HR: 0.9
(0.5-1.6)

EURAS
(Dinger 2007)
Initiators, including new users*

All COCs available in Europe
during the conduct of the study‡

HR: 0.9
(0.6-1.4)

Levonorgestrel/EE

HR: 1.0
(0.6-1.8)

FDA-funded study” (2011)

New users*

Other COCs available during the course of the study§

HR: 1.8
(1.3-2.4)

Levonorgestrel/0.03 mg EE

HR: 1.6
(1.1-2.2)

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
(1.4-2.1)

Levonorgestrel/0.03 mg EE

HR: 1.5
(1.2-1.8)

In addition to these “regulatory studies,” other studies of various designs have been conducted. Overall, there are two prospective cohort studies (see Table 1): the US post-approval safety study Ingenix [Seeger 2007], the European post-approval safety study EURAS (European Active Surveillance Study) [Dinger 2007]. An extension of the EURAS study, the Long-Term Active Surveillance Study (LASS), did not enroll additional subjects, but continued to assess VTE risk. There are three retrospective cohort studies: one study in the US funded by the FDA (see Table 1), and two from Denmark [Lidegaard 2009, Lidegaard 2011]. There are two case-control studies: the Dutch MEGA study analysis [van Hylckama Vlieg 2009] and the German case-control study [Dinger 2010]. There are two nested case-control studies that evaluated the risk of non-fatal idiopathic VTE: the PharMetrics study [Jick 2011] and the GPRD study [Parkin 2011]. The results of all of these studies are presented in Figure 1.

Figure 1: VTE Risk with Yasmin Relative to LNG-Containing COCs (adjusted risk#)

Risk ratios displayed on logarithmic scale; risk ratio < 1 indicates a lower risk of VTE for DRSP, > 1 indicates an increased risk of VTE for DRSP.

*Comparator “Other COCs”, including LNG- containing COCs

† LASS is an extension of the EURAS study

#Some adjustment factors are indicated by superscript letters: a) Current heavy smoking, b) hypertension, c) obesity, d) family history, e) age, f) BMI, g) duration of use, h) VTE history, i) period of inclusion, j) calendar year, k) education, l) length of use, m) parity, n) chronic disease, o) concomitant medication, p) smoking, q) duration of exposure, r) site

(References: Ingenix [Seeger 2007]2, EURAS (European Active Surveillance Study) [Dinger 2007]3, LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011]4, Danish [Lidegaard 2009]5, Danish re-analysis [ Lidegaard 2011]6, MEGA study [van Hylckama Vlieg 2009]7, German Case-Control study [Dinger 2010]8, PharMetrics [Jick 2011]9, GPRD study [Parkin 2011]10)

Although the absolute VTE rates are increased for users of hormonal contraceptives compared to non-users, the rates during pregnancy are even greater, especially during the post-partum period (see Figure 2). The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.

The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

Figure 2 shows the risk of developing a VTE for women who are not pregnant and do not use oral contraceptives, for women who use oral contraceptives, for pregnant women, and for women in the postpartum period. To put the risk of developing a VTE into perspective: If 10,000 women who are not pregnant and do not use oral contraceptives are followed for one year, between 1 and 5 of these women will develop a VTE.

Figure 2: Likelihood of Developing a VTE

If feasible, stop Safyral at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Safyral no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop Safyral if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [See Adverse Reactions (6).]

Hyperkalemia

Safyral contains 3 mg of the progestin DRSP, which has anti-mineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Safyral is contraindicated in patients with conditions that predispose to hyperkalemia (that is, renal impairment, hepatic impairment, and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium concentration should have their serum potassium concentration checked during the first treatment cycle. Medications that may increase serum potassium concentration include ACE inhibitors, angiotensin–II receptor antagonists, potassium-sparing diuretics, potassium supplementation, heparin, aldosterone antagonists, and NSAIDs. Consider monitoring serum potassium concentration in high-risk patients who take a strong CYP3A4 inhibitor long-term and concomitantly. Strong CYP3A4 inhibitors include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole), HIV/HCV protease inhibitors (e.g., indinavir, boceprevir), and clarithromycin [see Clinical Pharmacology (12.3)].

Carcinoma of the Breasts and Reproductive Organs

Women who currently have or have had breast cancer should not use Safyral because breast cancer is a hormonally-sensitive tumor.

There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings.

Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

Liver Disease

Discontinue Safyral if jaundice develops. Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis. Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

High Blood Pressure

For women with well-controlled hypertension, monitor blood pressure and stop Safyral if blood pressure rises significantly. Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin.

Gallbladder Disease

Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

Carbohydrate and Lipid Metabolic Effects

Carefully monitor prediabetic and diabetic women who are taking Safyral. COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia. A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Headache

If a woman taking Safyral develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Safyral if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

Bleeding Irregularities

Unscheduled (breakthrough or intracyclic) bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use. If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Data from ten Yasmin contraceptive efficacy clinical trials (N=2,467) show that the percent of women who took Yasmin and experienced unscheduled bleeding decreased over time from 12% at cycle 2 to 6% (cycle 13). A total of 25 subjects out of 3,009 in the Yasmin and Safyral trials (<1%) discontinued due to bleeding complaints. These are described as metrorrhagia, vaginal hemorrhage, menorrhagia, abnormal withdrawal bleeding, and menometrorrhagia.

The average duration of scheduled bleeding episodes in the majority of subjects (86%–88%) was 4–7 days. Women who use Safyral may experience absence of withdrawal bleeding, even if they are not pregnant. Based on subject diaries from Yasmin contraceptive efficacy trials, during cycles 2–13, 1–11% of women per cycle experienced no withdrawal bleeding. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.

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.

COC Use Before or During Early Pregnancy

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect when COCs are taken inadvertently during early pregnancy, particularly in so far as cardiac anomalies and limb-reduction defects are concerned. Discontinue Safyral if pregnancy is confirmed and initiate a prenatal vitamin containing folate supplementation.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations (8.1)].

Depression

Women with a history of depression should be carefully observed and Safyral discontinued if depression recurs to a serious degree.

Interference with Laboratory Tests

The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Drug Interactions (7.2)].

DRSP causes an increase in plasma renin activity and plasma aldosterone induced by its mild anti-mineralocorticoid activity.

Folates may mask vitamin B12 deficiency.

Monitoring

A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

Other Conditions

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

Use in specific populations

Pregnancy

There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

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

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

Nursing Mothers

When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. Estrogen-containing COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

After oral administration of 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.

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.

Geriatric Use

Safyral has not been studied in postmenopausal women and is not indicated in this population.

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)].

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.

Race

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

Safyral - Clinical Pharmacology

Mechanism of Action

COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

Pharmacodynamics

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

Contraception

No specific pharmacodynamic studies were conducted with Safyral.

Folate Supplementation

Two studies evaluated the impact of Safyral on plasma folate and red blood cell (RBC) folate levels. A randomized, double-blind, active-controlled, parallel group study compared plasma folate and RBC folate levels during a 24-week treatment with 3 mg DRSP/0.02 mg EE (YAZ)+0.451 mg levomefolate calcium as compared to YAZ alone in a U.S. population. The pharmacodynamic effect on plasma folate, RBC folate, and the profile of circulating folate metabolites was assessed during 24 weeks of treatment with 0.451 mg levomefolate calcium or with 0.4 mg folic acid (equimolar dose to 0.451 mg levomefolate calcium), both in combination with 3 mg DRSP/0.03 mg EE (Yasmin) followed by 20 weeks of open-label treatment with Yasmin only (elimination phase). [See Clinical Studies, (14.2).]

Pharmacokinetics

Absorption

Safyral and Yasmin are bioequivalent with respect to DRSP and EE.

The absolute bioavailability of DRSP from a single entity tablet is about 76%. The absolute bioavailability of EE is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of Safyral, which is a combination tablet of DRSP and EE stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within 1–2 hours after administration of Safyral.

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

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

Levomefolate calcium is structurally identical to L-5-methyltetrahydrofolate (L-5-methyl-THF), a metabolite of vitamin B9. Mean baseline concentrations of about 15 nmol/L are reached in populations without folate food fortification under normal nutritional conditions. Orally administered levomefolate calcium is absorbed and is incorporated into the body folate pool. Peak plasma concentrations of about 50 nmol/L above baseline are reached within 0.5–1.5 hours after single oral administration of 0.451 mg levomefolate calcium.

Steady state conditions for total folate in plasma after intake of 0.451 mg levomefolate calcium are reached after about 8–16 weeks depending on the baseline levels. In red blood cells achievement of steady state is delayed due to the long life-span of red blood cells of about 120 days.

Table 2: Mean Pharmacokinetic Parameters of Yasmin (DRSP 3 mg and EE 0.03 mg)
* NA - Not available

DRSP
Mean (%CV) Values

Cycle / Day

No. of Subjects

Cmax
(ng/mL)

Tmax
(h)

AUC(0-24h) (ng•h/mL)

t1/2 (h)

1/1

12

36.9 (13)

1.7 (47)

288 (25)

NA*

1/21

12

87.5 (59)

1.7 (20)

827 (23)

30.9 (44)

6/21

12

84.2 (19)

1.8 (19)

930 (19)

32.5 (38)

9/21

12

81.3 (19)

1.6 (38)

957 (23)

31.4 (39)

13/21

12

78.7 (18)

1.6 (26)

968 (24)

31.1 (36)

EE
Mean (%CV) Values

Cycle/Day

No. of Subjects

Cmax
(pg/mL)

Tmax
(h)

AUC(0-24h) (pg•h/mL)

t1/2
(h)

1/1

11

53.5 (43)

1.9 (45)

280 (87)

NA*

1/21

11

92.1 (35)

1.5 (40)

461 (94)

NA*

6/21

11

99.1 (45)

1.5 (47)

346 (74)

NA*

9/21

11

87 (43)

1.5 (42)

485 (92)

NA*

13/21

10

90.5 (45)

1.6 (38)

469 (83)

NA*

Food Effect

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

The effect of food on absorption of levomefolate calcium following administration of Safyral has not been evaluated.

Distribution

DRSP and EE serum concentrations decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4–5 L/kg.

DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough concentrations). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.

Biphasic kinetics is reported for folates with a fast- and a slow-turnover pool. The fast-turnover pool, probably reflecting newly absorbed folate, is consistent with the terminal half-life of approximately 4–5 hours after single oral administration of 0.451 mg levomefolate calcium. The slow-turnover pool reflecting turnover of folate polyglutamate has a mean residence time of greater than or equal to 100 days.

Metabolism

The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfatation. These metabolites were shown not to be pharmacologically active. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.

EE has been reported to be subject to significant gut and hepatic first-pass metabolism. Metabolism of EE and its oxidative metabolites occur primarily by conjugation with glucuronide or sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.

L-5-methyl-THF is the predominant folate transport form in blood under physiological conditions and during folic acid and levomefolate calcium administration.

Excretion

DRSP serum concentrations are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38–47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17–20% of the metabolites were excreted as glucuronides and sulfates.

For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

L-5-methyl-THF is eliminated from the body by urinary excretion of intact folates and catabolic products as well as fecal excretion through a biphasic kinetics process.

Use in Specific Populations

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.

Geriatric Use: Safyral has not been studied in postmenopausal women and is not indicated in this population. Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or EE in Japanese versus Caucasian women (age 25–35) when 3 mg DRSP/0.02 mg EE was administered daily for 21 days. Other ethnic groups have not been specifically studied.

Renal Impairment: Safyral is contraindicated in patients with renal impairment.

The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n=28, age 30-65). All subjects were on a low potassium diet. During the study, 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50–79 mL/min were comparable to those in the control group with CLcr ≥ 80 mL/min. The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30–49 mL/min compared to those in the control group. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium-sparing drugs during the study, mean serum potassium concentrations increased by up to 0.33 mEq/L. [See Contraindications (4) and Warnings and Precautions (5.2).]

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

The mean exposure to DRSP in women with moderate liver impairment is approximately three times higher than the exposure in women with normal liver function. Safyral has not been studied in women with severe hepatic impairment. [See Contraindications (4) and Warnings and Precautions (5.4).]

Drug Interactions

Consult the labeling of all concurrently used drugs to obtain further information about interactions with oral contraceptives or the potential for enzyme alterations.

Effects of Other Drugs on Combined Oral Contraceptives

Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding.

Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin 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. In a clinical drug-drug interaction study conducted in 20 premenopausal women, co-administration of a DRSP (3 mg)/EE (0.02 mg) COC with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily) for 10 days increased the AUC(0-24h) of DRSP and EE by 2.68-fold (90% CI: 2.44, 2.95) and 1.40-fold (90% CI: 1.31, 1.49), respectively. The increases in Cmax were 1.97-fold (90% CI: 1.79, 2.17) and 1.39-fold (90% CI: 1.28, 1.52) for DRSP and EE, respectively. Although no clinically relevant effects on safety or laboratory parameters including serum potassium were observed, this study only assessed subjects for 10 days. The clinical impact for a patient taking a DRSP-containing COC concomitantly with chronic use of a CYP3A4/5 inhibitor is unknown [see Warnings and Precautions (5.2)].

HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

Effects of Combined Oral Contraceptives on Other Drugs:

COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

In vitro, EE is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19, and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day. 

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs.

Interactions With Drugs That Have the Potential to Increase Serum Potassium

Concentration: There is a potential for an increase in serum potassium concentration in women taking Safyral with other drugs that may increase serum potassium concentration [see Warnings and Precautions (5.2)].

A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations >5.5 mEq/L).

Effects of Folates on Other Drugs

There is a potential that folates such as folic acid and levomefolate calcium may modify the pharmacokinetics or pharmacodynamics of certain antifolate drugs (e.g., antiepileptics, methotrexate).

Effects of other Drugs on Folate

Several drugs (e.g., methotrexate, sulfasalazine, cholestyramine, antiepileptics) have been reported to reduce folate concentrations.

References

1. US Preventive Services Task Force. Folic Acid for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009;150:626-631. 2. Seeger, J.D., Loughlin, J., Eng, P.M., Clifford, C.R., Cutone, J., and Walker, A.M. (2007). Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 110, 587-593. 3. Dinger, J.C., Heinemann, L.A., and Kuhl-Habich, D. (2007). The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 75, 344-354. 4. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed Oct 27, 2011. 5. Lidegaard, O., Lokkegaard, E., Svendsen, A.L., and Agger, C. (2009). Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 339, b2890. 6. Lidegaard, O., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E., and Lokkegaard, E. (2011). Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423. 7. van Hylckama Vlieg, A., Helmerhorst, F.M., Vandenbroucke, J.P., Doggen, C.J., and Rosendaal, F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 339, b2921. 8. Dinger, J., Assmann, A., Mohner, S., and Minh, T.D. (2010). Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care 36, 123-129. 9. Jick, S.S., and Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 342, d2151. 10. Parkin, L., Sharples, K., Hernandez, R.K., and Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 342, d2139. 11. Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR 1992;41(No. RR-14).

Package/label principal display panel

Safyral Trade Carton

NDA 50419-403-01

1 Unit

Rx only

This product (like all oral contraceptives) in intended to prevent pregnancy. It does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Safyral™

(drospirenone/ethinyl estradiol/levomefolate calcium tablets and levomefolate calcium tablets)

3mg/0.03 mg/0.451 mg and 0.451 mg

28 tablets

Oral

Safyral 
drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium kit
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50419-403
Packaging
# Item Code Package Description
1 NDC:50419-403-00 90 BLISTER PACK in 1 PACKAGE
1 1 KIT in 1 BLISTER PACK
2 NDC:50419-403-03 3 BLISTER PACK in 1 PACKAGE
2 NDC:50419-403-01 1 KIT in 1 BLISTER PACK
3 NDC:50419-403-75 12 PACKAGE in 1 CARTON
3 5 BLISTER PACK in 1 PACKAGE
3 NDC:50419-403-71 1 KIT in 1 BLISTER PACK
4 NDC:50419-403-70 90 BLISTER PACK in 1 PACKAGE
4 1 KIT in 1 BLISTER PACK
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 21 
Part 2
Part 1 of 2
Safyral 
drospirenone/ ethinyl estradiol/ levomefolate calcium tablet, film coated
Product Information
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DROSPIRENONE (DROSPIRENONE) DROSPIRENONE 3 mg
ETHINYL ESTRADIOL (ETHINYL ESTRADIOL) ETHINYL ESTRADIOL 0.03 mg
LEVOMEFOLATE CALCIUM (LEVOMEFOLIC ACID) LEVOMEFOLIC ACID 0.451 mg
Inactive Ingredients
Ingredient Name Strength
FERRIC OXIDE YELLOW  
HYPROMELLOSES  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
TITANIUM DIOXIDE  
BETADEX  
CELLULOSE, MICROCRYSTALLINE  
CROSCARMELLOSE SODIUM  
POLYETHYLENE GLYCOLS  
TALC  
FERRIC OXIDE RED  
Product Characteristics
Color ORANGE Score no score
Shape ROUND Size 6mm
Flavor Imprint Code Y
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA022574 02/13/2012
Part 2 of 2
Safyral 
levomefolate calcium tablet, film coated
Product Information
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LEVOMEFOLATE CALCIUM (LEVOMEFOLIC ACID) LEVOMEFOLIC ACID 0.451 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSES  
LACTOSE MONOHYDRATE  
MAGNESIUM STEARATE  
TALC  
TITANIUM DIOXIDE  
CELLULOSE, MICROCRYSTALLINE  
CROSCARMELLOSE SODIUM  
HYDROXYPROPYL CELLULOSE (TYPE H)  
POLYETHYLENE GLYCOLS  
FERRIC OXIDE RED  
FERRIC OXIDE YELLOW  
Product Characteristics
Color ORANGE (Light) Score no score
Shape ROUND Size 6mm
Flavor Imprint Code M
Contains     
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA022574 02/13/2012
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA022574 02/13/2012
Labeler - Bayer HealthCare Pharmaceuticals Inc. (005436809)
Establishment
Name Address ID/FEI Operations
Bayer Weimar GmbH und Co. KG 331485631 MANUFACTURE(50419-403)
Establishment
Name Address ID/FEI Operations
Bayer Pharma AG 315015982 PACK(50419-403)
Revised: 06/2015   Bayer HealthCare Pharmaceuticals Inc.

What is Safyral?

Safyral contains a combination of drospirenone, ethinyl estradiol, and levomefolate. Drospirenone and ethinyl estradiol prevent ovulation (the release of an egg from an ovary) and also cause changes in your cervical and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus. Levomefolate is a type of B vitamin that helps prevent a rare birth defect that could occur in a baby if pregnancy occurs while taking birth control pills or shortly after stopping them.

Safyral is a birth control pill and is used as contraception to prevent pregnancy.

Safyral is also used to raise folate levels in women who choose to use a birth control pill for contraception.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include nausea, vomiting, and vaginal bleeding.

Safyral side effects

Get emergency medical help if you have signs of an allergic reaction to Safyral: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Safyral and call your doctor at once if you have:

  • a change in the pattern or severity of migraine headaches;

  • swelling in your hands, ankles, or feet;

  • symptoms of depression - sleep problems, weakness, tired feeling, mood changes;

  • signs of a stroke - sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;

  • signs of a blood clot in the lung - chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

  • signs of a blood clot in your leg - pain, swelling, warmth, or redness in one or both legs;

  • heart attack symptoms - chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating; or

  • liver problems - nausea, upper stomach pain, itching, tiredness, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common Safyral side effects may include:

  • light vaginal bleeding or spotting;

  • breast pain or tenderness;

  • nausea; or

  • headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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