DROSPIRENONE, ETHINYL ESTRADIOL AND LEVOMEFOLATE CALCIUM AND LEVOMEFOLATE CALCIUM (Page 2 of 9)

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.

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 drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets. Ensure that folate supplementation is maintained if a woman discontinues drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets due to pregnancy.

3 DOSAGE FORMS AND STRENGTHS

Drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets are available in blister containing 28 tablets packed in a pouch. Such three pouches are packaged in a carton.

Each blister contains 28 film-coated, round, biconvex tablets in the following order:

  • 24 pink tablets each containing 3 mg drospirenone (DRSP), 0.02 mg ethinyl estradiol (EE) and 0.451 mg levomefolate calcium
  • 4 light orange tablets each containing 0.451 mg levomefolate calcium

4 CONTRAINDICATIONS

Do not prescribe drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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 andWarnings 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 (5.5)]
    • Have diabetes mellitus with vascular disease [see Warnings And Precautions (5.7)]
    • Have headaches with focal neurological symptoms or have migraine 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 tumors, 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 (8.1)]
  • 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)]. (

5 WARNINGS AND PRECAUTIONS

5.1 Thromboembolic Disorders and Other Vascular Problems

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

Based on presently available information on DRSP-containing COCs with 0.03 mg ethinyl estradiol (that is, Yasmin®), DRSP-containing COCs may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing the progestin levonorgestrel or some other progestins. Epidemiologic studies that compared the risk of VTE reported that the risk ranged from no increase to a three-fold increase. Before initiating use of drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets in a new COC user or a woman who is switching from a contraceptive that does not contain DRSP, consider the risks and benefits of a DRSP-containing COC in light of her risk of a VTE. Known risk factors for VTE include smoking, obesity, and family history of VTE, in addition to other factors that contraindicate use of COCs [see Contraindications (4)].

A number of studies have compared the risk of VTE for users of Yasmin® (which contains 0.03 mg of EE and 3 mg of DRSP) to the risk for users of other COCs, including COCs containing levonorgestrel. Those that were required or sponsored by regulatory agencies are summarized in Table 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

a) “New users” — no use of combination hormonal contraception for at least the prior 6 months

b) Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate

c) Includes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone

d) 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 usersa All COCs available in the US during the conduct of the study b HR: 0.9 (0.5-1.6)
EURAS (Dinger 2007) Initiators, including new usersa All COCs available in Europe during the conduct of the studyc HR: 0.9 (0.6-1.4)
Levonorgestrel/EEHR: 1.0 (0.6-1.8)
“FDA-funded study” (2011) New usersa Other COCs available during the course of the studyd 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 studyd HR: 1.7 (1.4-2.1)
Levonorgestrel/0.03 mg EEHR: 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#)

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.

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

2 LASS is an extension of the EURAS study

3 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

Figure 2
(click image for full-size original)

If feasible, stop drospirenone, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets 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, ethinyl estradiol and levomefolate calcium tablets and levomefolate calcium tablets if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. [see Adverse Reaction (6).]

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