Drospiren-Eth estra 3-0.02 MG (24) Oral Tablet / Inert 1 MG (4) Oral Tablet 28 Day Pack

Generic Name: DROSPIRENONE AND ETHINYL ESTRADIOL
Brand Name: Yaz

DRUG INTERACTIONS

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

Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding.

Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.

(7.1) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding.

Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St.

John’s wort.

Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure.

Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%.

Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation.

Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.

In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure.

The exposure of EE was increased mildly [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

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

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

7.2 Effects of Combined 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 Yaz 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 Yaz 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 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.

[See Warnings and Precautions ( 5.13 ) and Drug Interactions (7.2).]

OVERDOSAGE

10 There have been no reports of serious ill effects from overdose, including ingestion by children.

Overdosage may cause withdrawal bleeding in females and nausea.

DRSP is a spironolactone analogue which has anti-mineralocorticoid properties.

Serum concentration of potassium and sodium, and evidence of metabolic acidosis, should be monitored in cases of overdose.

DESCRIPTION

11 Yaz (drospirenone/ethinyl estradiol tablets) provides an oral contraceptive regimen consisting of 24 light pink active film-coated tablets each containing 3 mg of drospirenone and 0.02 mg of ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex) and 4 white inert film coated tablets.

The inactive ingredients in the light pink tablets are lactose monohydrate NF, corn starch NF, magnesium stearate NF, hypromellose USP, talc USP, titanium dioxide USP, ferric oxide pigment, red NF.

The white inert film-coated tablets contain lactose monohydrate NF, microcrystalline cellulose NF, magnesium stearate NF, hypromellose USP, talc USP, titanium dioxide USP.

Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11, 12,13,14,15,15a,16-hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa- [6,7:15,16]cyclopenta[a]phenanthrene-17,2’(5H)-furan]-3,5’(2H)-dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24H30O3.

Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3, 17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C20H24O2.

The structural formulas are as follows: Structural formulas

CLINICAL STUDIES

14 14.1 Oral Contraceptive Clinical Trial In the primary contraceptive efficacy study of Yaz (3 mg DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 28-day cycles of use.

The age range was 17 to 36 years.

The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other.

Women with a BMI greater than 35 were excluded from the trial.

The pregnancy rate (Pearl Index) was 1.41 (95% CI [0.73, 2.47]) per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment and within 14 days after the last dose of Yaz in women 35 years of age or younger during cycles in which no other form of contraception was used.

14.2 Premenstrual Dysphoric Disorder Clinical Trials Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate the effectiveness of Yaz in treating the symptoms of PMDD.

Women aged 18–42 who met DSM-IV criteria for PMDD, confirmed by prospective daily ratings of their symptoms, were enrolled.

Both studies measured the treatment effect of Yaz using the Daily Record of Severity of Problems scale, a patient-rated instrument that assesses the symptoms that constitute the DSM-IV diagnostic criteria.

The primary study was a parallel group design that included 384 evaluable reproductive-aged women with PMDD who were randomly assigned to receive Yaz or placebo treatment for 3 menstrual cycles.

The supportive study, a crossover design, was terminated prematurely prior to achieving recruitment goals due to enrollment difficulties.

A total of 64 women of reproductive age with PMDD were treated initially with Yaz or placebo for up to 3 cycles followed by a washout cycle and then crossed over to the alternate medication for 3 cycles.

Efficacy was assessed in both studies by the change from baseline during treatment using a scoring system based on the first 21 items of the Daily Record of Severity of Problems.

Each of the 21 items was rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum score of 126 was possible.

In both trials, women who received Yaz had statistically significantly greater improvement in their Daily Record of Severity of Problems scores.

In the primary study, the average decrease (improvement) from baseline was 37.5 points in women taking Yaz, compared to 30.0 points in women taking placebo.

14.3 Acne Clinical Trials In two multicenter, double-blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to 45 years, with moderate acne received Yaz or placebo for six 28-day cycles.

The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a “clear” or “almost clear” rating on the Investigator’s Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented in Table 3: Table 3: Efficacy Results for Acne Trials* Study 1 Study 2 YAZ Placebo YAZ Placebo N=228 N=230 N=218 N=213 ISGA Success Rate 35 (15%) 10 (4%) 46 (21%) 19 (9%) Inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction 33 15 (48%) 33 11 (32%) 32 16 (51%) 32 11 (34%) Non-inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction 47 18 (39%) 47 10 (18%) 44 17 (42%) 44 11 (26%) Total Lesions Mean Baseline Count Mean Absolute (%) Reduction 80 33 (42%) 80 21 (25%) 76 33 (46%) 76 22 (31%) * Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Yaz (drospirenone/ethinyl estradiol tablets) are available in packages of three blister packs (NDC 50419-405-03).

The film-coated tablets are rounded with biconvex faces, one side is embossed with DS or DP in a regular hexagon.

Each blister pack (28 film-coated tablets) contains in the following order: •24 active light pink round, unscored, film-coated tablets debossed with a “DS” in a regular hexagon on one side, each containing 3 mg drospirenone and 0.02 mg ethinyl estradiol •4 inert white round, unscored, film-coated tablets debossed with a “DP” in a regular hexagon on one side.

16.2 Storage Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Contraindications (4) 8/2017 Warnings and Precautions (5.5) 8/2017

GERIATRIC USE

8.5 Geriatric Use Yaz has not been studied in postmenopausal women and is not indicated in this population.

DOSAGE FORMS AND STRENGTHS

3 Yaz (drospirenone/ethinyl estradiol tablets) is available in blister packs.

Each blister pack (28 film-coated tablets) contains in the following order: •24 light pink tablets each containing 3 mg drospirenone (DRSP) and 0.02 mg ethinyl estradiol (EE) as betadex clathrate •4 white inert tablets •Yaz consists of 28 film-coated, biconvex tablets in the following order (3): •24 light pink tablets, each containing 3 mg drospirenone (DRSP) and 0.02 mg ethinyl estradiol (EE) as betadex clathrate •4 white inert tablets

MECHANISM OF ACTION

12.1 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 the endometrial changes that reduce the likelihood of implantation.

INDICATIONS AND USAGE

1 Yaz is an estrogen/progestin COC, indicated for use by women to: •Prevent pregnancy.

(1.1) •Treat symptoms of premenstrual dysphoric disorder (PMDD) for women who choose to use an oral contraceptive for contraception.

(1.2) •Treat moderate acne for women at least 14 years old only if the patient desires an oral contraceptive for birth control.

(1.3) 1.1 Oral Contraceptive Yaz® is indicated for use by women to prevent pregnancy.

1.2 Premenstrual Dysphoric Disorder (PMDD) Yaz is also indicated for the treatment of symptoms of premenstrual dysphoric disorder (PMDD) in women who choose to use an oral contraceptive as their method of contraception.

The effectiveness of Yaz for PMDD when used for more than three menstrual cycles has not been evaluated.

The essential features of PMDD according to the Diagnostic and Statistical Manual-4th edition (DSM-IV) include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability.

Other features include decreased interest in usual activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.

Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain.

In this disorder, these symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school, or with usual social activities and relationships with others.

Diagnosis is made by healthcare providers according to DSM-IV criteria, with symptomatology assessed prospectively over at least two menstrual cycles.

In making the diagnosis, care should be taken to rule out other cyclical mood disorders.

Yaz has not been evaluated for the treatment of premenstrual syndrome (PMS).

1.3 Acne Yaz is indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche.

Yaz should be used for the treatment of acne only if the patient desires an oral contraceptive for birth control.

PEDIATRIC USE

8.4 Pediatric Use Safety and efficacy of Yaz 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.

PREGNANCY

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.

NUSRING MOTHERS

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 (Yasmin) tablets, 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.

BOXED WARNING

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 Yaz (4).

•Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

(4)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Vascular risks: Stop Yaz if a thrombotic event occurs.

Stop at least 4 weeks before and through 2 weeks after major surgery.

Start no earlier than 4 weeks after delivery, in women who are not breastfeeding.

(5.1) COCs containing DRSP may be associated with a higher risk of venous thromboembolism (VTE) than COCs containing levonorgestrel or some other progestins.

Before initiating Yaz 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.

(5.1) • Hyperkalemia: DRSP has anti-mineralocorticoid activity.

Do not use in patients predisposed to hyperkalemia.

Check serum potassium concentration during the first treatment cycle in women on long-term treatment with medications that may increase serum potassium concentration.

(5.2, 7.1, 7.2) • Liver disease: Discontinue Yaz if jaundice occurs.

(5.4) • High blood pressure: Do not prescribe Yaz for women with uncontrolled hypertension or hypertension with vascular disease.

(5.6) • Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Yaz.

Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.

(5.8) • Headache: Evaluate significant change in headaches and discontinue Yaz if indicated.

(5.9) • Uterine bleeding: Evaluate irregular bleeding or amenorrhea.

(5.10) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Yaz 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 Yaz 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 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“New users” – no use of combination hormonal contraception for at least the prior 6 months All COCs available in the US during the conduct of the studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, levonorgestrel, desogestrel, norgestrel, medroxyprogesterone, or ethynodiol diacetate HR: 0.9 (0.5-1.6) EURAS (Dinger 2007) Initiators, including new users All COCs available in Europe during the conduct of the studyIncludes low-dose COCs containing the following progestins: levonorgestrel, desogestrel, dienogest, chlormadinone acetate, gestodene, cyproterone acetate, norgestimate, or norethindrone 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 studyIncludes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel 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 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: Likelihood of Developing a VTE If feasible, stop Yaz at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Yaz 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 Yaz if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Evaluate for retinal vein thrombosis immediately.

[See Adverse Reactions (6).] fig 1 Figure 2 Likelihood of Developing a VTE 5.2 Hyperkalemia Yaz 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.

Yaz 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 )] .

5.3 Carcinoma of the Breasts and Reproductive Organs Women who currently have or have had breast cancer should not use Yaz 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.

5.4 Liver Disease Discontinue Yaz 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.

5.5 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs.

Discontinue Yaz prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see Contraindications (4)].

Yaz can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen.

5.6 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Yaz 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.

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

5.8 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Yaz.

COCs may decrease glucose intolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemias.

A small proportion of women will have adverse lipid changes while on COC’s.

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

5.9 Headache If a woman taking Yaz develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Yaz 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.

5.10 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.

Based on patient diaries from two contraceptive clinical trials of Yaz, 8 to 25% of women experienced unscheduled bleeding per 28-day cycle.

A total of 12 subjects out of 1,056 (1.1%) discontinued due to menstrual disorders including intermenstrual bleeding, menorrhagia, and metrorrhagia.

Women who use Yaz may experience absence of withdrawal bleeding, even if they are not pregnant.

Based on subject diaries from contraception trials for up to 13 cycles, 6 to 10% of women experienced cycles with 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.

5.11 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, particularly in so far as cardiac anomalies and limb‑reduction defects are concerned, when taken inadvertently during early pregnancy.

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)].

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

5.13 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.

5.14 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.

5.15 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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

•Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.

•Counsel patients that the increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC.

•Counsel patients about the information regarding the risk of VTE with DRSP-containing COCs compared to COCs that contain levonorgestrel or some other progestins.

•Counsel patients that Yaz does not protect against HIV-infection (AIDS) and other sexually transmitted diseases.

•Counsel patients on Warnings and Precautions associated with COCs.

•Counsel patients that Yaz contains DRSP.

Drospirenone may increase potassium.

Patients should be advised to inform their healthcare provider if they have kidney, liver or adrenal disease because the use of Yaz in the presence of these conditions could cause serious heart and health problems.

They should also inform their healthcare provider if they are currently on daily, long-term treatment (NSAIDs, potassium-sparing diuretics, potassium supplementation, ACE inhibitors, angiotensin-II receptor antagonists, heparin or aldosterone antagonists) for a chronic condition or taking strong CYP3A4 inhibitors.

•Inform patients that Yaz is not indicated during pregnancy.

If pregnancy occurs during treatment with Yaz, instruct the patient to stop further intake.

•Counsel patients to take one tablet daily by mouth at the same time every day.

Instruct patients what to do in the event pills are missed.

See “What to Do if You Miss Pills” section in FDA-Approved Patient Labeling.

•Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.

•Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production.

This is less likely to occur if breastfeeding is well established.

•Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken a light pink tablet for 7 consecutive days.

•Counsel patients that amenorrhea may occur.

Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.

Manufactured for Bayer HealthCare Pharmaceuticals Inc.

Whippany, NJ 07981 Manufactured in Germany © 2001 Bayer HealthCare Pharmaceuticals Inc.

All Rights Reserved.

Bayer HealthCare Pharmaceuticals Inc.

DOSAGE AND ADMINISTRATION

2 •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 Yaz Take one tablet by mouth at the same time every day.

The failure rate may increase when pills are missed or taken incorrectly.

To achieve maximum contraceptive and PMDD effectiveness, Yaz must be taken exactly 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 Yaz Instruct the patient to begin taking Yaz 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 Yaz use, instruct the patient to take one light pink Yaz daily, beginning on Day 1 of her menstrual cycle.

(The first day of menstruation is Day 1.) She should take one light pink Yaz daily for 24 consecutive days, followed by one white inert tablet daily on Days 25 through 28.

Yaz 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.

Yaz can be taken without regard to meals.

If Yaz is first taken later than the first day of the menstrual cycle, Yaz 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 Yaz use, instruct the patient to take one light pink Yaz daily, beginning on the first Sunday after the onset of her menstrual period.

She should take one light pink Yaz daily for 24 consecutive days, followed by one white inert tablet daily on Days 25 through 28.

Yaz 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.

Yaz can be taken without regard to meals.

Yaz 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 Yaz on the same day of the week that she began her first regimen, following the same schedule.

She should begin taking her light pink 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 Yaz 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 light pink Yaz daily for seven consecutive days.

When switching from a different birth control pill When switching from another birth control pill, Yaz 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, Yaz should be started when the next application would have been due.

When switching from an injection, Yaz should be started when the next dose would have been due.

When switching from an intrauterine contraceptive or an implant, Yaz should be started on the day of removal.

Withdrawal bleeding usually occurs within 3 days following the last light pink tablet.

If spotting or breakthrough bleeding occurs while taking Yaz, instruct the patient to continue taking Yaz 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 Yaz 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 Yaz if pregnancy is confirmed.

The risk of pregnancy increases with each active light pink 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 light pink tablets on the proper day.

For postpartum women who do not breastfeed or after a second trimester abortion, start Yaz no earlier than 4 weeks postpartum due to the increased risk of thromboembolism.

If the patient starts on Yaz 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 Yaz 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.