Syeda: Package Insert and Label Information

SYEDA- drospirenone and ethinyl estradiol
Xiromed, LLC.

syedasyeda-carton

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)].

1 INDICATIONS AND USAGE

SyedaTM (drospirenone and ethinyl estradiol tablets) are indicated for use by women to prevent pregnancy.

2 DOSAGE AND ADMINISTRATION

2.1 How to Take SyedaTM

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, SyedaTM 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 SyedaTM

Instruct the patient to begin taking SyedaTM 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 SyedaTM use, instruct the patient to take one yellow SyedaTM daily, beginning on Day 1 of her menstrual cycle. (The first day of menstruation is Day 1.) She should take one yellow SyedaTM daily for 21 consecutive days, followed by one white tablet daily on Days 22 through 28. SyedaTM 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. SyedaTM can be taken without regard to meals. If SyedaTM is first taken later than the first day of the menstrual cycle, SyedaTM 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 SyedaTM use, instruct the patient to take one yellow SyedaTM daily, beginning on the first Sunday after the onset of her menstrual period. She should take one yellow SyedaTM daily for 21 consecutive days, followed by one white tablet daily on Days 22 through 28. SyedaTM 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. SyedaTM can be taken without regard to meals. SyedaTM 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 SyedaTM on the same day of the week that she began her first regimen, following the same schedule. She should begin taking her yellow tablets on the next day after ingestion of the last white tablet, regardless of whether or not a menstrual period has occurred or is still in progress. Anytime a subsequent cycle of SyedaTM is started later than the day following administration of the last white tablet, the patient should use another method of contraception until she has taken a yellow SyedaTM daily for seven consecutive days.

When switching from a different birth control pill

When switching from another birth control pill, SyedaTM 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, SyedaTM should be started when the next application would have been due. When switching from an injection, SyedaTM should be started when the next dose would have been due. When switching from an intrauterine contraceptive or an implant, SyedaTM should be started on the day of removal.

Withdrawal bleeding usually occurs within 3 days following the last yellow tablet. If spotting or breakthrough bleeding occurs while taking SyedaTM , instruct the patient to continue taking SyedaTM 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 SyedaTM 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 SyedaTM if pregnancy is confirmed.

The risk of pregnancy increases with each active yellow 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 white tablets, she should still be protected against pregnancy provided she begins taking a new cycle of yellow tablets on the proper day.

For postpartum women who do not breastfeed or after a second trimester abortion, start SyedaTM no earlier than 4 weeks postpartum due to the increased risk of thromboembolism. If the patient starts SyedaTM 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 SyedaTM 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 to 4 hours after tablet-taking, this can be regarded as a missed tablet.

3 DOSAGE FORMS AND STRENGTHS

SyedaTM (drospirenone and ethinyl estradiol tablets, USP) are available in blister packs.

Each blister pack contains 28 tablets in the following order:

21 active tablets are yellow colored, round , film-coated tablets, “SZ” and “U3” are debossed on opposite sides of the tablet and containing 3 mg drospirenone (DRSP) and 0.03 mg ethinyl estradiol (EE)
7 inert white tablets are white film-coated, round, ‘SZ” and J1 are debossed on opposite sides of the tablet

4 CONTRAINDICATIONS

Do not prescribe SyedaTM 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 thorombosis 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 fibrilation) [see WARNINGS AND PRECAUTIONS (5.1)]
    • Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1)]
    • Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.5)]
    • Have diabetes mellitus with vascular disease [see WARNINGS AND PRECAUTIONS (5.7)]
    • Have headaches with focal neurological symptoms or have migrane headaches with or without aura if over age 35 [see WARNINGS AND PRECAUTIONS (5.8)]
  • Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS (5.9)]
  • 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 (5.10) and USE IN SPECIFIC POPULATIONS (8)]
  • Use of Hepatits C drug combinations containing ombitasvir, paritaprevir/ritonavir, with or without dasabuvir due to the potential for ALT elevations [see WARNINGS AND PRECUTIONS (5.5) and DRUG INTERACTIONS (7.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Problems

Stop drospirenone and ethinyl estradiol if an arterial or venous thrombotic (VTE) event occurs.

Based on presently available information on drospirenone and ethinyl estradiol, DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of drospirenone and ethinyl estradiol in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see CONTRAINDICATIONS (4)].

A number of studies have compared the risk of VTE for users of drospirenone and ethinyl estradiol to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 1.

Table 1: Estimates (Hazard Ratios) of Venous Thromboembolism Risk in Current Users of Drospirenone and Ethinyl Estradiol Compared to Users of Oral Contraceptives that Contain Other Progestins

Epidemiologic Study (Author, Year of Publication) Population Studied

Comparator Product

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

Hazard Ratio (HR)

(95% CI)

i3 Ingenix

(Seeger 2007)

Initiators, including new users*

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

HR: 0.9

(0.5-1.6)

EURAS

(Dinger 2007)

Initiators, including new users*

All COC’s available in Europe during the conduct of the study

Levonorgestrel/EE

HR: 0.9

(0.6 -1.4)

HR: 1

(0.6-1.8)

“FDA-funded study” (2011)

New users*

All users

(i.e., initiation and continuing use of study combination hormonal contraception)

Other COCs available during the course of the study§

Levonorgestrel/0.03 mg EE

Other COCs available during the course of the study§

Levonorgestrel/0.03 mg EE

HR: 1.8

(1.3-2.4)

HR: 1.6

(1.1-2.2)

HR: (1.7)

(1.4-2.1)

HR: 1.5

(1.2-1.8)

* “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

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
(click image for full-size original)

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

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

LASS is an extension of the EURAS study

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

(References: Ingenix [Seeger 2007]1 , EURAS (European Active Surveillance Study) [Dinger 2007]2 , LASS (Long-Term Active Surveillance Study) [Dinger, unpublished document on file], FDA-funded study [Sidney 2011]3 , Danish [Lidegaard 2009]4 , Danish re-analysis [ Lidegaard 2011]5 , MEGA study [van Hylckama Vlieg 2009]6 , German Case-Control study [Dinger 2010]7 , PharMetrics [Jick 2011]8 , GPRD study [Parkin 2011]9)

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

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

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

Figure 2
(click image for full-size original)

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

Start drospirenone and ethinyl estradiol 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 drospirenone and ethinyl estradiol if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [see ADVERSE REACTIONS (6)]

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